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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5265_Библиотеки_им_академика_М_И_Перельмана.pdf
Analgesic and Anti-inflammatory Agents 257
Storage Conditions: Morphine sulphate injection should be protected from light and stored at
15°C to 30°C. Morphine sulphate extended-release liposomal injection should be stored under
refrigeration at 2°C to 8°C. Morphine sulphate soluble tablets, extended-release capsules and
tablets and oral solution should be stored in tight, light-resistant containers at 15°C to 30°C.
Freezing of the oral solution should be avoided.
Officials:
➢ Morphine sulphate, I.P.
➢ Morphine sulphate Injection, I.P.
➢ Morphine sulphate and Atropine Sulphate Injection, I.P.
10.1.2 Codeine
Brand Names: Ascomp, Cheratussin, Cheratussin Dac, Covan, Dimetapp,
Codeine is one of the natural plant alkaloids found in extracts of opium. It is an opioid
analgesic and commonly used to treat mild-to-moderate pain and cough when the use of an opioid
is indicated.
Chemistry: Chemically, codeine is Morphinan-6-ol,7,8-didehydro-4,5-epoxy-3-methoxy-17-
methyl-(5α,6α)-, sulfate (2:1) (salt) and trihydrate. Its empirical formula is C
18
H
21
NO
3
and its
molecular weight is 299.36. Its structure is as follows:
IUPAC Name: (4R,4aR,7S,7aR,12bS)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1H-4,12-
methanobenzofuro [3,2-e]isoquinolin-7-ol.
Properties: Codeine appears as colorless, odorless, and has bitter taste, white crystalline or white
powder. It is slightly soluble in water; soluble in ethyl ether, benzene, chloroform, and toluene;
very soluble in ethanol; and insoluble in petroleum ether. Codeine phosphate appears as colorless
small crystals or white powder.
Uses:
➢ Codeine is an opioid analgesic related to morphine but with less potent analgesic
properties and mild sedative effects. It also acts centrally to suppress cough.
➢ It is used to treat mild to moderate pain. It is commonly used to treat post-surgical dental
pain.
258 Text Book of Pharmaceutical Chemistry
➢ It is useful in cancer pain.
➢ It is used to relieve coughing.
➢ It is used to treat diarrhoea and diarrhoea-predominant irritable bowel syndrome. This
medicine acts on the central nervous system (CNS) to relieve pain.
Dosage Forms and Strengths:
➢ Tablet – 15 mg and 30 mg
➢ Codeine Phosphate Tablets BP – 30 mg
➢ Codeine Sulphate Tablets – 15 mg, 30 mg and 60 mg
Stability and Storage: It should be store at controlled room temperature 15-30°C. Protect from
moisture and light. Codeine is stable under recommended storage conditions. It effloresces slowly
in dry air, affected by light. Store codeine phosphate injection between 15-30°C and protected
from light. Freezing should be avoided. Do not use the injection if it is discolored or contains a
precipitate.
10.1.3 Pethidine
Brand Name: Demerol
Synonym: Meperidine
Pethidine is a piperidine carboxylate ester that is piperidine which is substituted by a methyl
group at position 1 and by phenyl and ethoxy carbonyl groups at position 4. It is also known as
Meperidine which is used for the treatment of moderate to severe pain, including postoperative
pain and labor pain. The structure of pethidine is given below:
IUPAC Name: Ethyl 1-methyl-4-phenylpiperidine-4-carboxylate
Properties: It occurs as fine, white, crystalline powder and odorless. Melting point is 186-189°C.
It has a slightly bitter taste. It is very soluble in water; soluble in alcohol, acetone, and ethyl
acetate; sparingly soluble in ether; slightly soluble in isopropanol; and insoluble in benzene.
Uses: Meperidine is used for the treatment of moderate to severe pain. It can be given as a tablet,
liquid or injection, usually several times. It is most widely used opioid in labour and delivery.
Dosage Forms and Strengths:
➢ Syrup: 50 mg/5 mL
➢ Tablet: 50 mg, 100 mg
➢ Injectable solution: 25 mg/mL, 50 mg/mL, 75 mg/mL, 100 mg/mL
Analgesic and Anti-inflammatory Agents 259
Storage and Stability: Meperidine is stored in a tightly sealed container, stable at room
temperature. Avoid freezing the injectable solution and protect from light during storage. It is
stable in syrup formation. Protect it from freezing. When heated to decomposition, it emits toxic
fumes of nitrogen oxides.
Officials:
➢ Pethidine Hydrochloride, I.P.
➢ Pethidine Hydrochloride Injection, I.P.
➢ Pethidine Hydrochloride Tablet, I.P.
10.1.4 Methadone
Brand Names: Dolophine, Methadose, Methadose Sugar-free, Diskets
Methadone is a medication used to treat opioid use disorder (OUD). It is indicated for
management of severe pain that is not responsive to alternative treatments. Actions of methadone
are similar to those of morphine and morphine-like agents like effects include analgesia, euphoria,
sedation, respiratory depression, miosis, bradycardia and physical dependence. Methadone is a
racemic mixture of two enantiomers: (S)-methadone and (R)-methadone. Its structure is as
follows:
IUPAC Name: 6-(dimethylamino)-4,4-diphenylheptan-3-one
Properties: It is a crystalline substance with a bitter taste and odorless. Its melting point is 232°C
to 235°C. It is soluble in water, alcohol and chloroform; and practically insoluble in ether
and glycerol.
Uses:
➢ Methadone is used in the detoxification and maintenance of patients who are dependent
on opiates particularly heroin – and the treatment of patients with chronic, severe pain.
➢ It is also used for end of life care and severe pain. This is usually prescribed by a pain
specialist and comes as tablets or injections.
➢ Methadone oral tablet is used to treat pain. It is also used for detoxification or
maintenance treatment of an opioid drug addiction.
Dosage Forms: Methadone comes in the form of a tablet, dispersible tablet (tablet that can be
dissolved in liquid), concentrate solution, and solution.
260 Text Book of Pharmaceutical Chemistry
➢ Injectable solution: 10 mg/mL
➢ Oral concentrate: 10 mg/mL
➢ Oral solution: 5 mg/5 mL, 10 mg/5 mL
➢ Oral tablet: 5 mg, 10 mg
➢ Dispersible tablet: 40 mg
Storage: Oral methadone and injection should be stored at room temperature between 15°C to
30°C.
Officials:
➢ Methadone Hydrochloride, I.P.
➢ Methadone Hydrochloride Tablet, I.P.
➢ Methadone Hydrochloride Injection, I.P.
Dextropropoxyphene
Brand Names: Darvocet-N, Darvon
Dextropropoxyphene
is an analgesic in the opioid category (pain reliever). It is an optical
isomer of (1S, 2R)-(+)-diastereoisomer of propoxyphene. It works by blocking transmission of
pain signals to the brain to lower pain perception.
Chemically, it is (2S, 3R)-(+)-4-(Dimethylamino)-3-methyl-1,2-diphenyl-2-butanol propionate
(ester) hydrochloride. Its molecular weight is 375.94. Structural formula of Dextropropoxyphene
is represented as follows:
IUPAC Name: [(2S, 3S)-4-(dimethylamino)-3-methyl-1,2-diphenylbutan-2-yl] propanoate
Properties: It occurs as a white crystalline powder, odorless and has bitter taste with crystals
from methanol plus ethyl acetate. It is soluble in water, alcohol, acetone and chloroform; and
practically insoluble in benzene and ether. Its melting point is 163°C to 168.5°C.
Uses:
➢ Dextropropoxyphene is used to treat mild pain and also has anti-tussive (cough
suppressant) and local anaesthetic effects.
Analgesic and Anti-inflammatory Agents 261
➢ It is ineffective for some individuals with the “poor metabolizer” genotype of the liver
cytochrome P450 enzyme CYP2D6.
➢ It is used with digestive complaints, as it is less liable to worsen their symptoms.
➢ It is used to relieve mild to moderately severe pain associated with cancer.
➢ It may also be used in a combination with other medicines such as Paracetamol and
Ibuprofen for treating pain.
Storage: Dextropropoxyphene should be stored in tight container as defined in the USP-NF. This
material should be handled and stored as per the label instructions to ensure product integrity.
Store at 15°C to 30°C.
10.1.5 Pentazocin
Brand Names: Talwin, Talwin Lactate
Pentazocin is a synthetic opioid available only in tablet form in combination with either
acetaminophen or naloxone. Pentazocine is commercially available as the hydrochloride salt and
as the lactate salt.
IUPAC Name: (1R, 9R, 13R)-1, 13-dimethyl-10-(3-methylbut-2-enyl)-10-azatricyclo[7.3.1.0
2,7
]
trideca-2(7),3,5-trien-4-ol; hydrochloride.
Properties: White to pale cream colored, odorless, slightly bitter taste crystalline powder with
melting point 146.3°C. There are two forms melting at about 218 deg & 254°C. It is soluble in
water, alcohol and chloroform; very slightly soluble in acetone; practically insoluble in ether;
soluble in acetone; and sparingly soluble in ethyl acetate.
Uses:
➢ Pentazocin is used to supplement general, regional, or local anaesthesia.
➢ Pentazocin is used as an analgesic, often in individuals who have chronic severe pain or
in those who have drug abuse problems.
➢ It is also used as part of anaesthesia for surgery.
Storage: Pentazocin and naloxone hydrochloride tablets should be stored in tight, light-resistant
containers at temperatures less than 40°C, preferably between 15°C to 30°C. Pentazocine lactate
injection should be stored at temperatures less than 40°C, preferably between 15‒30°C.
262 Text Book of Pharmaceutical Chemistry
Stability: Stable in light, heat (ambient room temp) and air. When heated to decomposition, it
emits toxic fumes of nitroxides.
Officials:
➢ Pentazocin, I.P.
➢ Pentazocin Hydrochloide, I.P.
➢ Pentazocin Hydrochloide Tablet, I.P.
➢ Pentazocin Lactate, I.P.
➢ Pentazocin Lactate Injection, I.P.
10.2 NON-STEROIDAL ANTI-INFLAMMATORY AGENTS (NSAIDS)
NSAIDs are a class of medications used to reduce pain, reduce inflammation and bring down
a high temperature. These drugs used to relieve symptoms of headaches, painful periods, sprains
and strains, colds and flu, arthritis and other causes of long-term pain. Some analgesics can be
bought over the counter, others require a prescription.
Over-the-counter (OTC) NSAIDs include: Ibuprofen, Aspirin, and Naproxen sodium.
Prescription NSAIDs include: Oxaprozin (Daypro), Etodolac (Lodine), Indomethacin
(Indocin), Naproxen (Naprosyn), Nabumetone (Relafen), Diclofenac (Cataflam) and,
Aproxen/Esomeprazole (Vimovo).
NSAIDs drugs act by inhibiting the activity of cyclooxygenase enzymes (COX-1 or COX-2).
In cells, these enzymes are involved in the synthesis of key biological mediators, namely
prostaglandins, which are involved in inflammation, and thromboxanes, which are involved in
blood clotting.
Classification of NSAIDs
NSAIDs can be classified based on their chemical structure or mechanism of action:
1. Salicylates: Aspirin, Sodium salicylate and Diflunisal.
2. Propionic acid derivatives: Ibuprofen, Ketoprofen and Naproxen.
3. Aryl acetic acid derivatives: Diclofenac and Ketorolac.
4. Indole derivatives: Indomethacin and Sulindac.
5. Alkanones: Nabumetone.
6. Oxicams: Piroxicam and Tenoxicam.
7. Anthranilic acid derivatives (fenamates): Mefenamic acid and flufenamic acid.
8. Pyrazolone derivatives: Phenylbutazone, Oxyphenbutazone, Azapropazone (apazone)
and Dipyrone (novalgine).
9. Aniline derivatives (analgesic only): Paracetamol.
Analgesic and Anti-inflammatory Agents 263
10.2.1 Aspirin
Brand Names: Arthritis Pain, Aspi-Cor, Aspir 81, Aspir-Low, Bayer Plus, Bufferin, Durlaza,
Ecotrin, Ecpirin, Miniprin, Vazalore.
IUPAC Name: 2-acetyloxybenzoic acid
Asprin or Acetylsalicylic Acid (ASA) is a commonly used drug for the treatment of pain and
fever due to various causes. Acetylsalicylic acid has both anti-inflammatory and antipyretic
effects. This drug also inhibits platelet aggregation and is used in the prevention of blood clots
stroke and myocardial infarction (MI).
Properties:
➢ Physical Properties: Acetylsalicylic Acid appears as colorless to white crystalline solid.
It has a smell similar to that of vinegar. The taste of Aspirin is bitter. Its melting point is
135ºC. Thus, if kept in higher temperatures, it will decompose. It is soluble in water,
ethyl ether, ethanol, and chloroform.
Uses of Aspirin:
➢ Aspirin is used in the treatment of a number of conditions including fever, mild to
moderate pain, from conditions such as muscle aches, toothaches, common cold, and
headaches.
➢ It is used in the treatment of rheumatic fever and inflammatory conditions, such as
rheumatoid arthritis, pericarditis and Kawasaki disease.
➢ It is used as an anti-inflammatory agent for long-term as well as acute inflammation.
➢ It is used to prevent venous and arterial thrombosis.
➢ It is used in systemic lupus erythematosus.
➢ It is used in ankylosing spondylitis.
➢ It is used in osteoarthritis.
Dosage:
➢ Usual doses for mild to moderate pain are 350 or 650 mg every 4 hours or 500 mg every
6 hours.
➢ Rheumatoid arthritis include 500 mg every 4-6 hours, 650 mg every 4 hours, 1000 mg
every 4-6 hours, and 1950 mg twice daily.
➢ Heart attacks are prevented with 75, 81, 162 or 325 mg.
264 Text Book of Pharmaceutical Chemistry
Storage: Aspirin should be stored at room temperature, 20°C to 25°C, in a sealed container,
avoiding moisture.
Officials:
➢ Aspirin I.P.
➢ Aspirin Tablet, I.P.
➢ Soluble Aspirin Tablet, I.P.
➢ Aspirin and Caffeine Tablet, I.P.
10.2.2 Diclofenac
Brand Name: Cambia, Zipsor, Zorvolex, Cataflam, Voltaren, Voltaren-XR, Dyloject.
Diclofenac (NSAID) is a medicine which works by reducing substances in the body that
cause pain and inflammation. It is a monocarboxylic acid consisting of phenylacetic acid having a
(2, 6-dichlorophenyl) amino group at the 2-position.
Diclofenac is a non-selective reversible and competitive inhibitor of cyclooxygenase (COX)
which subsequently blocks the conversion of arachidonic acid into prostaglandin precursors, and
causes an inhibition of the formation of prostaglandins that are involved in pain, inflammation
and fever.
IUPAC Name: 2-[2-(2, 6-dichloroanilino) phenyl] acetic acid
Properties: It occurs as white to slightly yellowish, odorless crystalline powder. It is slightly
hygroscopic. It is sparingly soluble in water.
Uses: Diclofenac is used to relieve pain, as well as problems with joints, muscles and bones.
These include:
➢ Uses for the relief of mild to moderate pain, swelling (inflammation).
➢ Uses for the relief of the signs and symptoms of rheumatoid arthritis and osteoarthritis.
➢ It has analgesic, anti-inflammatory and antipyretic properties.
➢ Used in sprains and strains in muscles and ligaments.
➢ It is used in back pain and toothache.
➢ It is indicated for use in the treatment of migraine and gout.
Analgesic and Anti-inflammatory Agents 265
➢ It is indicated for use in the treatment of ankylosing spondylitis and for relief of acute
migraine symptoms.
➢ It is used in combination with misoprostol as a gastro-protective agent in patients with
high risk of developing NSAID-induced ulcers.
➢ Diclofenac sodium is used topically as an ophthalmic solution for the treatment of
postoperative ocular inflammation in patients undergoing cataract extraction.
Storage: Diclofenac sodium 1% gel and diclofenac epolamine transdermal system should be
stored at 25°C; diclofenac gel should not be frozen. Diclofenac sodium enteric-coated tablets and
extended-release tablets should be protected from moisture and stored in tight containers at a
temperature not exceeding 30°C.
Dosages of Diclofenac:
➢ Tablet as potassium: 50 mg
➢ Tablet delayed-release as sodium: 25 mg, 50 mg and 75 mg
➢ Tablet, extended-release: 100 mg
➢ Capsule: 18 mg, 25 mg and 35 mg
➢ Powder packet for oral solution: 50 mg
➢ Solution for IV injection: 37.5mg/mL (Dyloject)
Officials:
➢ Diclofenac Sodium, I.P.
➢ Diclofenac Sodium Injection, I.P.
➢ Diclofenac Sodium Tablet, I.P.
10.2.3 Ibuprofen
Brand Names: Advil, Genpril, IBU, Midol IB, Motrin IB, Proprinal, Smart Sense Children’s
Ibuprofen.
Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID). It is a monocarboxylic acid,
i.e., propionic acid in which one of the hydrogens at position 2 is substituted by a 4-(2-
methylpropyl) phenyl group. It works by inhibiting the production of prostaglandins by
decreasing the activity of the enzyme cyclooxygenase (COX).
IUPAC Name: 2-[4-(2-methylpropyl)phenyl]propanoic acid
266 Text Book of Pharmaceutical Chemistry
Properties: It occurs as white or almost white powder or crystals having characteristic odor.
Ibuprofen is practically insoluble in water, but very soluble in most organic solvents like ethanol,
methanol, acetone and dichloromethane.
Uses: Ibuprofen is an NSAID, and like other drugs of its class, it possesses analgesic, antipyretic,
and anti-inflammatory properties.
➢ It is used in the treatment of pain, fever, and inflammation.
➢ It is used in painful menstrual periods.
➢ It is used in the treatment of migraines, and rheumatoid arthritis.
➢ It is used in the treatment of severe orthostatic hypotension (low blood pressure when
standing up).
Dosage Forms: Oral capsule (200 mg); oral suspension (100 mg/5 mL and 50 mg/1.25 mL); oral
tablet (100 mg; 200 mg; 400 mg; 600 mg and 800 mg); oral tablet, chewable (100 mg and 50 mg).
Storage and Stability: It should be kept in well closed container. Store undiluted ibuprofen
(5 mg/mL) in glass vials and diluted ibuprofen to 2.5 mg/mL with either NS or D5W and stored
in polypropylene syringes. It will retain more than 92% of its initial concentration with storage for
up to 14 days at 4°C.
Officials:
➢ Ibuprofen, I.P.
➢ Ibuprofen Tablet I.P.
10.2.4 Piroxicam
Brand Name: Feldene
Piroxicam is a non-steroidal anti-inflammatory drug (NSAID). It is a monocarboxylic acid
amide resulting from the formal condensation of the carboxy group of 4-hydroxy-2-methyl-2H-
1,2-benzothiazine-3-carboxylic acid 1,1-dioxide with the exocyclic nitrogen of 2-aminopyridine.
It exists as alkenol tautomer in organic solvents and as zwitterionic form in water. It has the
following chemical structure:
IUPAC Name: 4-hydroxy-2-methyl-1,1-dioxo-N-pyridin-2-yl-1λ
6
,2-benzothiazine-3-carboxamide
Properties: Piroxicam occurs as a white crystalline solid. It is sparingly soluble in water, dilute
acid and most organic solvents; and slightly soluble in alcohol and in aqueous solutions.