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Home , Ethoheptazine

agents, Antipyretic agents, Anti-inflammatory Agents ______

Pain (algesia) can be defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage. Pain can be classified as acute or chronic. Acute pain is usually of short duration and the cause often identifiable (disease, trauma). Chronic pain persists after healing is expected to be complete, or is caused by a chronic disease. Pain may be modified by psychological factors and attention to these is essential in pain management. Drug treatment aims to modify the peripheral and central mechanisms involved in the development of pain.

Analgesics: A drug that selectively relieves pain by acting in CNS or on peripheral pain mechanism, without significantly altering consciousness.

Anesthesia: Anesthesia means loss of sensation. Anesthetic agent is one which bring about loss of all modalities of sensation, particularly pain, along with a reversible loss of consciousness.

Analgesics can be divided into two groups: - 1. Non- Analgesics -NSAIDs/Non-narcotic/ like analgesics 2. Opioid Analgesics -Narcotics/ like analgesics

Non-opioid analgesics are particularly suitable for pain in musculoskeletal conditions whereas the opioid analgesics are more suitable for moderate to severe visceral pain. Those non-opioid analgesics which also have anti-inflammatory actions include salicylates and NSAIDs (Non-Steroidal Anti-Inflammatory Drugs); they can reduce both pain and inflammation of chronic inflammatory disorders such as rheumatoid arthritis, but they do not alter or modify the disease process itself. For the management of rheumatoid arthritis DMARDs (disease-modifying antirheumatic drugs) may favorably influence the outcome of the disease. The pain and inflammation of an acute attack of gout is treated with a NSAID or colchicine; a xanthine-oxidase inhibitor is used for long-term control of gout.

HG@SNC Functions of NSAIDs

Analgesia– PGs induce hyperalgesia by affecting the transducing property of free nerve endings – stimuli that normally do not elicit pain are able to do so. NSAIDs do not affect the tenderness induces by direct application of PGs but block the pain sensitization mechanism induced by bradykinin. Antipyresis– NSAIDs reduce body temperature in fever, but do not cause hypothermia in normothermic individuals. NSAIDs block the action of pyrogens but not that of PGE2 injected into the hypothalamus. Anti - inflammatory – Due to inhibition of PG synthesis at the site of injury. Inflammatory cells express integrins and selectins and NSAIDs act by inhibiting some of these molecules. Growth factor like GM-CSF, IL-6, lymphocyte transformation factor may also be affected. Stabilization of leukocyte lysosomal membrane and antagonism of certain actions of kinin may be contributing to NSAIDs action. Antiplatelet aggregatory – NSAIDs inhibit synthesis of both proaggregatory{TXA2} and antiaggregatory {PGI2} prostanoids, but effect on platelet aggregation TXA2 predominated producing therapeutic doses of most NSAIDs inhibit platelet aggregation: bleeding time is prolonged.

Non-opioid analgesics with anti-inflammatory activity include salicylates such as acetylsalicylic acid (Aspirin) and other nonsteroidal anti-inflammatory drugs such as . Non-opioid analgesics with little or no anti-inflammatory activity include . ……………………………………………………………………………………………………

ASPIRIN COOH OAc

Acetylsalicyclic Acid (Aspirin) The principal effects of acetylsalicylic acid are anti-inflammatory, , antipyretic and antiplatelet. Oral doses are absorbed rapidly from the gastrointestinal tract; rectal absorption is less reliable but suppositories are useful in patients unable to take oral dosage forms. Acetylsalicylic acid is used for the management of mild to moderate pain such as headache, acute migraine attacks, transient musculoskeletal pain and dysmenorrhoea, and for reducing fever. Although it may be used in higher doses in the management of pain and inflammation of rheumatoid arthritis, other NSAIDs are preferred because they are likely to be better tolerated. Acetylsalicylic acid is also used for its antiplatelet properties.

HG@SNC Adverse effects with analgesic doses are generally mild but include a high incidence of gastrointestinal irritation with slight blood loss, bronchospasm and skin reactions in hypersensitive patients, and increased bleeding time. Anti-inflammatory doses are associated with a much higher incidence of adverse reactions, and they also cause mild chronic salicylism which is characterized by tinnitus and deafness. Acetylsalicylic acid should be avoided in children under 16 years, unless specifically indicated (for example juvenile arthritis), because of an association with Reye syndrome (encephalopathy and liver damage); it should particularly be avoided during fever or viral infection in children and adolescents.

Synthesis of Aspirin:- (I) Synthesis from Salicyclic Acid-

(II) Synthesis from Benzene-

………………………………………………………………………………………………… PARACETAMOL OH

NHAc N-acetyl-para-aminophenol Paracetamol is similar in analgesic and antipyretic efficacy to acetylsalicylic acid. It is used for mild to moderate pain including headache and acute migraine attacks and for reducing fever, including post-immunization pyrexia. Paracetamol is particularly useful in patients in whom salicylates or other NSAIDs are contraindicated, such as asthmatics and those with a history of peptic ulcer, or for children under the age of 16 years in whom salicylates should be avoided because of the risk of Reye syndrome. It is generally preferred to acetylsalicylic acid(aspirin), particularly in the elderly, because it is less irritant to the stomach. Unlike acetylsalicylic acid and other NSAIDs, paracetamol has little anti-inflammatory activity which limits its usefulness for long-term treatment of pain associated with inflammation; however, it is useful in the management of osteoarthritis, a condition with only a small inflammatory component. In normal doses adverse effects are rare, but over-dosage with a single dose of 10–15 g is particularly dangerous because it may cause hepatocellular necrosis and, less frequently, renal tubular necrosis.

HG@SNC Synthesis of Paracetamol:-

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NSAIDs, including ibuprofen, have analgesic, anti-inflammatory and antipyretic properties. In single doses NSAIDs have analgesic activity comparable to that of paracetamol. In regular full dosage, they have a lasting analgesic and anti- inflammatory effect, which makes them useful for continuous or regular pain due to inflammation. Differences in anti-inflammatory activity between different NSAIDs are small but there is considerable variation in individual patient response and in the incidence and type of adverse effects. Ibuprofen has fewer adverse effects than other NSAIDs but its anti-inflammatory properties are weaker. and (neither of which is included on the WHO Model List) combine moderately potent anti-inflammatory activity with a relatively low incidence of adverse effects (but incidence is higher than that for ibuprofen).

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Me IBUPROFEN OH O 2-(4-isobutylphenyl)propanoic acid Ibuprofen

Ibuprofen is used in the treatment of mild to moderate pain and in the management of pain and inflammation in rheumatoid arthritis and juvenile arthritis. It may also be of value in the less well-defined conditions of back pain and soft-tissue disorders. Ibuprofen is also used to reduce pain in children. With all NSAIDs caution should be exercised in the treatment of the elderly, in allergic disorders, during pregnancy and breastfeeding. In patients with renal, cardiac or hepatic impairment, the dose should be kept as low as possible and renal function should be monitored. NSAIDs should not be given to patients with active peptic ulceration and should preferably not be used in those with a history of the disease. The commonest adverse effects are generally gastrointestinal including nausea, vomiting, diarrhoea, and dyspepsia; hypersensitivity reactions including anaphylaxis, bronchospasm, and rash have been reported, as has fluid retention. Uses: pain and inflammation in rheumatic disease and other musculoskeletal disorders including juvenile arthritis; mild to moderate pain including dysmenorrhoea, headache; pain in children; acute migraine attack.

Retrosynthetic analysis of Ibuprofen

Synthesis of Ibuprofen: Boots process:

(1) Synthesis of Isobutylbenzene:-

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Mechanism: Friedel crafts Acylation:

Clemmensen Reduction:

Alternatively Friedel crafts Alkylation:

Mechanism of Friedel Craft Alkylation:

HG@SNC Synthesis of Ibuprofen from Isobutylbenzene:-

Darzens reaction:

Mechanism of Darzens reaction:

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Mechanism of oxime formation from aldehyde:

Mechanism of nitrile formation from oxime:

Hydrolysis of nitrile to carboxylic acid:

HG@SNC The Boots-Hoechst-Celanese ibuprofen synthesis

The Hoechst process for ibuprofen synthesis, developed by the Boots-Hoechst-Celanese company, was a significant improvement over the original Boots process. A synthetic scheme for this route follows. Though different reaction conditions are used, it begins like the Boots process with a Friedel-Crafts acylation of isobutylbenzene to make 4’-isobutylacetophenone (4). This route differs dramatically in how this intermediate is transformed to ibuprofen, however. First, the aromatic ketone of (4) is reduced to an (9) via catalytic hydrogenation. Ibuprofen is produced directly from (9) through carbonylation with carbon monoxide in the presence of a palladium catalyst.

______OPIOD ANALGESICS:- Natural alkaloids: Morphine & .

Morphine is effective in relieving moderate to severe pain, particularly of visceral origin; there is a large variation in patient response. Weaker such as codeine are suitable for mild to moderate pain. Morphine remains the most valuable analgesic for severe pain. In addition to pain relief it confers a state of euphoria and mental detachment; repeated administration may cause dependence and tolerance, but this should not be a deterrent in the control of pain in terminal illness. Regular use may also be appropriate for certain cases of non-malignant pain, but specialist

HG@SNC supervision is required. In normal doses common adverse effects include nausea, vomiting, constipation and drowsiness; larger doses produce respiratory depression and hypotension. Codeine is an opioid analgesic much less potent than morphine and much less liable, in normal doses, to produce adverse effects including dependency. It is effective for mild to moderate pain but is too constipating for long-term use. Codeine phosphate

Semi synthetic : Diacetylmorphine, , Pholcodeine

Synthetic opioids: , , , , Ethoheptazine,

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