Medicinal Chemistry 1 Unit-5

Drugs Acting on Central Nervous System

General Anaesthetics

General anaesthetics are CNS depressants which induce reversible loss of all sensation & loss of awareness of pain.

The term anaesthetic is of Greek origin & means without perception or insensibility. They cause non-selective & reversible CNS depression.

There are 4 stages of anaesthetics

1. Stage 1 (Analgesia) - This stage begins with the inhalation of anaesthetic gas & ends with the loss of consciousness.
2. Stage 2 (Delusion or Excitement) - This stage starts with the loss of consciousness.
3. Stage 3 (Surgical Anaesthetics) - This stage involves loss of consciousness & reflexes.
4. Stage 4 (Medullary Paralysis) - This stage should be avoided. It starts with respiratory failure & ends with cardiac failure & death.

Inhalation Anaesthetics

They are gases or volatile liquids which are mixed with oxygen & administered through inhalation. They cause CNS depression & anaesthesia by rapidly reaching the blood & brain in sufficient conc.

There is the Minimum Alveolar concentration (MAC) for anaesthesia, which is inversely proportional to potency.

Halothane - It is a non flammable, halogenated, hydrocarbon anaesthetic which causes rapid induction with little or no excitement.

Synthesis - $CF_{3}-CH_{2}-Cl + Br_{2} \xrightarrow{450^\circ C} CF_{3}-CHBrCl + HBr$

Mechanism of Action - It causes general anaesthesia by acting on multiple ion channels & depressing nerve conduction, breathing & cardiac contractility.

Uses - It is used for inducing & maintaining general anaesthesia.

Methoxyflurane - It is an inhalation anaesthetic that is used for inducing & maintaining general anaesthesia.

[Image description: Chemical structure of Methoxyflurane: $H_{3}C-O-CF_{2}-CHCl_{2}$]

Mechanism of Action - It reduces functional conductance by decreasing the opening times & increasing the closing times of gap junction. It also binds to the D-subunit of ATP synthase & NADH dehydrogenase.

Uses - It alters tissue excitability to induce muscle relaxation & reduce pain sensitivity. Presently, it is rarely used in dental, surgical, & obstetric procedures.

Enflurane - It is an extremely stable inhalation anaesthetic in which rapid adjustment of anaesthesia depth can be done by little alterations in pulse or respiratory rate.

[Image description: Chemical structure of Enflurane: $CHF_{2}-O-CF_{2}-CHFCl$]

Mechanism of Action - Same as Methoxyflurane.

Uses - It is used for inducing & maintaining general anaesthesia during surgery & caesarean section. It is also used for analgesia during vaginal delivery.

Sevoflurane - It is a sweet-smelling, non-flammable, highly fluorinated methyl isopropyl ether that is used for inducing & maintaining general anaesthesia.

[Image description: Chemical structure of Sevoflurane: $CH_{2}F-O-CH(CF_{3})_{2}$]

Mechanism of Action - Same as methoxyflurane.

Uses - It is used for inducing & maintaining general anaesthesia in adults & paediatrics for inpatient & outpatient surgery.

Isoflurane - It is a stable, non-explosive inhalation anaesthetic, which is free from significant side effects.

[Image description: Chemical structure of Isoflurane: $CF_{3}-CHCl-O-CHF_{2}$]

Mechanism of Action - Same as methoxyflurane.

Uses - It is used for inducing & maintaining general anaesthesia. It alters tissue excitability for inducing muscle relaxation & reducing pain sensitivity.

Desflurane - It is a highly fluorinated methyl ethyl ether used for maintaining general anaesthesia. It is a volatile agent which hyperpolarizes the cell membrane.

[Image description: Chemical structure of Desflurane: $CF_{3}-CHF-O-CHF_{2}$]

Mechanism of Action - Same as methoxyflurane.

Uses - It is used as an inhalation agent for inducing & maintaining anaesthesia in adults for inpatient & outpatient surgeries.

Ultra Short Acting Barbiturates

They are intravenously administered for producing rapid unconsciousness in surgical & general anaesthesia.

Methohexital Sodium - It is a short-acting intravenous anaesthetic which is used for inducing anaesthesia.

[Image description: Chemical structure of Methohexital Sodium showing a barbiturate ring with $N-CH_{3}$, an allyl group $CH_{2}CH=CH_{2}$, and a 1-methyl-2-pentynyl group $CH(CH_{3})C\equiv C-CH_{2}CH_{3}$ at position 5]

Synthesis -

$CH_{3}CH_{2}C\equiv C-MgBr$ (1-Butynyl magnesium bromide) + $CH_{3}CHO \xrightarrow{PCl_{3}} CH_{3}CH_{2}C\equiv C-CH(Cl)CH_{3}$ (2-Chloro-3-pentyne)

$NC-CH_{2}-COOC_{2}H_{5}$ (Cyano acetic ester) + $H_{2}C=CH-CH_{2}-Br \xrightarrow{NaOC_{2}H_{5}} NC-CH(CH_{2}CH=CH_{2})-COOC_{2}H_{5}$ (Allyl cyanoacetate)

Both intermediates condense $\rightarrow$ $NC-C(CH_{2}CH=CH_{2})(CH(CH_{3})C\equiv C-CH_{2}CH_{3})-COOC_{2}H_{5}$ (Ethyl-(1-methyl-2-pentynyl)-allyl cyanoacetate) $\xrightarrow{CH_{3}NHCONH_{2}}$ Methohexital $\xrightarrow{NaOH}$ Methohexital Sodium.

Mechanism of Action

• It increases the opening duration of $Cl^{-}$ ionophore by binding to the receptor at a distinct binding site located at the $GABA_{A}$ receptor.
• Therefore it prolongs the post synaptic inhibitory effect of GABA in the thalamus.

Uses

• It is prescribed as an intravenous anaesthetic.
• It is also commonly used for inducing deep sedation.

Thiamylal Sodium - It is an intravenously administered barbiturate. It produces complete anaesthesia of short duration or general anaesthesia or hypnotic state.

[Image description: Chemical structure of Thiamylal Sodium]

Mechanism of Action - Same as Methohexital Sodium.

Uses - It is used for producing complete anaesthesia of short duration & for inducing general anaesthesia & hypnotic state.

Thiopental Sodium - It is administered intravenously for inducing general anaesthesia or for producing complete anaesthesia of short duration.

[Image description: Chemical structure of Thiopental Sodium]

Mechanism of Action - Same as Methohexital Sodium.

Uses -

• It is used as a sole anaesthetic agent for short procedures.
• It is also used for providing hypnosis during balanced anaesthesia with other agents for analgesia & muscle relaxation.

Dissociative Anaesthetics

It gives rise to catalepsy, catatonia, analgesia & amnesia. They produce this state by affecting the communication b/w different parts of the CNS.

Ketamine Hydrochloride - It is an NMDA receptor antagonist having a potent anaesthetic effect.

Synthesis -

[Image description: Synthesis scheme starting from o-chlorobenzonitrile and bromocyclopentane reacting with strong alkali, proceeding through an epoxy compound, rearranging to an imine, and finally forming Ketamine hydrochloride]

Mechanism of Action - Unlike other anaesthetic agents, Ketamine does not interact with GABA receptors but it interacts with NMDA receptors, opioid receptors, monoaminergic receptors, muscarinic receptors & voltage sensitive $Ca^{++}$ ion channels.

Uses -

• It is used as an anaesthetic agent in various diagnostic & surgical procedures.
• It can also be used for inducing anaesthesia before using other general anaesthetic agents & as a complement for low potency agents.

Narcotic & Non-Narcotic Analgesics -

• Analgesics act on the CNS & increase the pain threshold without disturbing consciousness or altering other sensory modalities, thus they relieve pain.

Analgesics are classified as:

i) Opioid analgesic or narcotic analgesic (centrally acting).
ii) Non-Opioid analgesic (Peripherally acting).

• Opioid analgesics are naturally occuring, semisynthetic & synthetic drugs having morphine-like action i.e. they provide relief from pain & cause CNS depression related to drug dependence.

• Narcotic analgesics comprise of opiates (natural alkaloids) & its derivatives & opioids (synthetic compounds with different chemical structure).

• Morphine -It is an example of both type of narcotic analgesics.
  Narcotic analgesics are either agonist or agonist-antagonist.

• Agonist - (eg- morphine, codeine, hydromorphone, meperidine, propoxyphene & methadone) produce analgesia by binding to CNS opiate receptors.

• Agonist-Antagonist - (eg- buprenorphine, butorphanol, nalbuphine, pentazocine) produce analgesia by binding to CNS receptors.

Morphine & Related Drug

• Morphine is a potent opiate analgesic psychoactive drug. It is considered to be the prototypical opioid. Clinically, it is the gold standard of analgesics & is used to relieve severe pain & suffering.

• Morphine similar to other opioids (eg- oxycodone, hydromorphone, diacetylmorphine (heroin)) relieves pain by directly acting on the CNS. Morphine has a high potential for addiction. Tolerance & physical & psychological dependence both develop rapidly.

• Morphine analogues are closely related to morphine and are even synthesised from it. They may be agonist (morphine, diamorphine, codeine) or partial agonist (nalorphine & levallorphan) or antagonist (naloxone).

• Morphine is therapeutically used us.
  • Analgesia
  • Diarriea
  • Relief of Cough
  • Anaesthesia & Pre-anaesthesia
  • It cardiovascular shock caused by our injury basis etc...

SAR of Morphine

[Image description: Chemical structure of Morphine highlighting the Tertiary nitrogen, Alicyclic unsaturated linkage, Alcoholic hydroxyl group, Ether bridge, and Phenolic hydroxyl group]

(1) Modification on alicyclic ring

• The alcoholic hydroxyl group at C-6 when methylated, esterified, oxidized, removed or replaced by halogen, the analgesic activity as well as toxicity of the compound increased.
• The reduction of C-6 Keto Group to C-6 $\beta$ hydroxyl in oxymorphone gives nalbuphine it show antagonistic action on $\mu$ receptor.
• The saturation of the double bond at 6-7 position gives more potent compound.
  Eg- Dihydromorphine & Dihydrocodeine.
• Bridging of C-6 & C-14 through ethylene linkage gives potent derivative.

(2) Modification of phenyl ring

• An aromatic phenyl ring is essential for activity. Modification on phenolic hydroxyl group decreases activity.
• Any other substitution on phenyl ring diminishes the activity.

(3) Modification of nitrogen

• A tertiary amine is usually necessary for good opioid activity. The size of the N substitution can dictate the compound's potency & its agonistic & antagonistic activity.
• The N-methyl substitution is having good agonistic property & when increased the size of the substitution by 3-5 carbon results in antagonistic activity.
• N-allyl & N-cyclo alkyl group leads to narcotic antagonistic property.

(4) Epoxide Bridge

• Removal of 3,4 epoxide bridge in morphine structure results in the compound that is known as morphinans.
• The morphinans are prepared synthetically. As the synthetic procedure yielded compound is a racemic mixture, only levo isomer possesses opioid activity while the dextro isomer has useful antitussive activity.
• Eg. Levorphanol & Butorphanol. Levorphanol is a more potent analgesic than morphine.

Morphine Sulphate

• It is a principal alkaloid in opium & prototype opiate analgesic & narcotic.
• It has extensive effects on the CNS & on smooth muscle.

[Image description: Chemical structure of Morphine Sulphate]

Mechanism of Action

• The exact mechanism of action of morphine is not known. But, specific CNS opiate receptors have been recognised which are responsible for the analgesic effects of morphine.

Uses

• It is used for treating & relieving severe pain.

Codeine

• It is a morphine related opioid analgesic with less potent analgesic properties & mild sedative effects.
• It also suppresses cough by acting centrally.

[Image description: Chemical structure of Codeine]

Mechanism of Action - Opiate receptors bind to G-protein receptors & serve as positive & negative regulators of synaptic transmission via G-proteins which activate effector proteins.

Uses - It is used for treating & managing pain & as an antidiarrheal & cough suppressant.

Meperidine Hydrochloride - It is a narcotic analgesic.

It may cause morphine dependence on prolonged uses.

[Image description: Chemical structure of Meperidine Hydrochloride]

Mechanism - They having local anaesthetic effects is an agonist of \mu$-opiate receptor. Its affinity for $\kappa receptor is much more than morphine.

Uses - It is used for controlling moderate to severe pain.

Anileridine Hydrochloride - It is a synthetic opioid & a strong analgesic, narcotic pain reliever & treats moderate to severe pain.

[Image description: Chemical structure of Anileridine Hydrochloride]

Mechanism of Action - Same as codeine.

Uses - It is used for treating & managing pain & also used as an adjunct in anaesthesia.

Diphenoxylate Hydrochloride - It is a meperidine congener used with atropine as an antidiarrhoeal. It acts like morphine at higher doses.

[Image description: Chemical structure of Diphenoxylate Hydrochloride]

Mechanism of Action - It is an opiate receptor agonist which constricts the sphincters & decreases peristalsis by stimulating the $\mu$-receptor in GIT.

Uses - It is used as an adjunctive therapy in managing diarrhoea.

Loperamide Hydrochloride - It is a long-acting synthetic antidiarrhoeal, which is not absorbed from the gut.

[Image description: Chemical structure of Loperamide Hydrochloride]

Mechanism of Action - In vitro & animal studies suggest that loperamide slows down intestinal motility & affects water & electrolyte movement through the bowel.

Uses - It is used for controlling & relieving the symptoms of acute non-specific diarrhoea & chronic diarrhoea related to inflammatory bowel disease & gastroenteritis.

Fentanyl Citrate - It is a potent narcotic analgesic which results in addiction when abused. It is a $\mu$-opioid agonist.

[Image description: Chemical structure of Fentanyl Citrate]

Synthesis -

N-(2-phenylethyl)-4-piperidone reacts with aniline to form an intermediate imine, which is reduced to an N-(4-piperidyl)-aniline derivative, then condensed with propionyl chloride to form Fentanyl, which is then reacted with Citric acid to form Fentanyl Citrate.

Mechanism of Action - Same as codeine.

Uses - It is used in a regular narcotic therapy for treating cancer patients having severe pain.

Methadone Hydrochloride

• It is a synthetic opioid agonist & a narcotic analgesic which is structurally similar to morphine. * It exhibits actions & uses similar to morphine.

[Image description: Chemical structure of Methadone Hydrochloride]

Synthesis

Diphenylacetonitrile + 1-chloro-2-dimethylamino propane $\xrightarrow{NaNH_{2}}$ 4-(Dimethylamino)-2,2-diphenyl-valeronitrile $\xrightarrow{C_{2}H_{5}MgBr}$ $\xrightarrow{H_{2}O, HCl}$ Methadone Hydrochloride.

Mechanism of Action

• It is a $\mu$ agonist & a synthetic opioid analgesic which acts on the CNS & organs composed of smooth muscle similar to morphine.
• Its main therapeutic uses are analgesia & detoxification & maintenance of opioid addiction.

Uses - It is used for treating dry cough, pain, drug withdrawal syndrome & opioid drug dependence.

Propoxyphene Hydrochloride

• It is a mild opioid analgesic.
• It was manufactured & patented (1955) by Eli Lilly & Company.

[Image description: Chemical structure of Propoxyphene Hydrochloride]

Mechanism of Action

• It is a weak agonist of OP1, OP2, OP3 opiate receptors in the CNS.
• It acts as both positive & negative modulator of synaptic transmission via G-proteins which activate effector proteins by mainly affecting OP3 receptors coupled with G-protein receptor.

Uses

• It is used for relieving mild to moderate pain.

Pentazocine

• It has mixed agonist/antagonist effect.
• Analgesic effect is the 1st kind to be marketed.

[Image description: Chemical structure of Pentazocine]

Mechanism of Action

• A large no. of evidence shows that pentazocine competes for the same receptor sites, especially opioid $\mu$-receptor & antagonises the opioid effect.

Uses

• It is used for relieving moderate to severe pain.
• It is a narcotic analgesic which may be addictive. Its effectiveness on oral administration is almost the same as by injection.

Levorphanol Tartrate

[Image description: Chemical structure of Levorphanol Tartrate]

Mechanism of Action

• Like other $\mu$ agonist opioids, Levorphanol acts at receptors in the periventricular & periaqueductal grey matter in the brain & spinal cord for altering the transmission & perception of pain.

Uses

• It is used for managing moderate to severe pain or as a pre-operative drug when an opioid analgesic is suitable for use.

Narcotic Antagonist

Nalorphine Hydrochloride

• It is an opioid agonist-antagonist which acts at two opioid receptors.

[Image description: Chemical structure of Nalorphine Hydrochloride]

Mechanism of Action

• It produces partial agonist effect and antagonises effect of morphine, methadone, meperidine, levorphanol.
• However, it does not have any antagonistic effect against barbiturates or general anaesthetic depression.
• It acts upon circulatory & respiratory depression & reverses the morphine effects.

Uses

• It is used for reversing opioid overdose.

Levallorphan Tartrate

• It is an opioid antagonist having properties similar to naloxone also possessing some agonist properties.

[Image description: Chemical structure of Levallorphan Tartrate]

Mechanism of Action

• They competes for the same sites & antagonises the opioid effects.
• It binds with the opioid $\mu$-receptor & the nicotinic Ach receptor.

Uses

• It is used for completely or partially reversing respiratory depression by opioids.

Naloxone Hydrochloride

• It is an opioid antagonist used for reversing or blocking the effects of opioid drugs.

[Image description: Chemical structure of Naloxone Hydrochloride]

Mechanism of Action

• Mechanism of action is not understood but the majority of evidence shows that it competes for sites & antagonises the opioid effect.
• Recently, it has been suggested that it can bind to all 3 opioid receptors but strongly binds to the $\mu$-receptor.

Uses It is used for completely or partially reversing respiratory depression by opioids.

Non-Narcotic Analgesics or Anti-inflammatory agents

• Non-narcotic analgesics include the NSAIDs (Non-steroidal anti-inflammatory drugs) (eg- aspirin, naproxen, ibuprofen, phenylbutazone, etc.) & acetaminophen.
• They exhibit antipyretic, analgesic & anti-inflammatory properties.
• These drugs have different chemical structures thus have different onset of actions, duration of effect & metabolism & excretion method.
• They are used in mild to moderate pain.
• In combination with small doses of narcotic analgesics, they can be used for relieving moderate to severe pain.
• NSAIDs are used for treating inflammation, mild to moderate pain & fever.

Sodium Salicylate

• It is an NSAID which effectively relieves pain & reduces fever.

[Image description: Chemical structure of Sodium Salicylate]

Mechanism of Action

• It is the sodium salt of salicylic acid.
• It reduces inflammation & pain by inhibiting prostaglandin synthesis through the irreversible acetylation of COX-1 & COX-2 enzymes.

Uses

• It is used as an analgesic & antipyretic.
• It induces apoptosis in cancer cells & necrosis.
• It can be used as a substitute for aspirin in aspirin-sensitive patients.

Aspirin

• It is produced by the acetylation of salicylic acid with acetic anhydride.

[Image description: Chemical structure of Aspirin]

Mechanism of Action

• Its action is to inhibit the activity of the enzyme called cyclooxygenase (COX) which leads to the formation of prostaglandins (PGs) that cause inflammation, swelling, pain & fever.

Uses

• It reduces pain & swelling by blocking certain natural substances in the body.
• It can be used for reducing pain & swelling in arthritis.
• It can prevent blood clotting in low doses.

Mefenamic Acid -

• It is an NSAID with analgesic, anti-inflammatory & antipyretic properties.
• It inhibits cyclooxygenase.

[Image description: Chemical structure of Mefenamic Acid]

Synthesis

• o-chlorobenzoic acid + 2,3-dimethylaniline $\rightarrow$ Mefenamic acid.

Mechanism of Action

• It inhibits the action of prostaglandin synthetase by binding to the prostaglandin synthetase receptors COX-1 & COX-2.

Uses

• It is used in rheumatoid arthritis, osteoarthritis, dysmenorrhea, mild to moderate pain, inflammation & fever.

Meclofenamate

• It is an NSAID which inhibits prostaglandin biosynthesis & exhibits antipyretic & anti-inflammatory activities.

[Image description: Chemical structure of Meclofenamate]

Mechanism of Action

• The mechanism of action is not known.
• Animal studies have shown that meclofenamic acid inhibits prostaglandin synthesis & competes for binding at the prostaglandin receptor site.

Uses

• It is used in primary dysmenorrhea, idiopathic heavy menstrual blood loss, & for relieving mild to moderate pain, signs & symptoms of acute & chronic rheumatoid arthritis & osteoarthritis.

Indomethacin

• It is a non-steroidal anti-inflammatory agent exhibiting analgesic & antipyretic activity.

[Image description: Chemical structure of Indomethacin]

Mechanism of Action

• It is a cyclooxygenase inhibitor which acts on prostaglandin COX-1 & COX-2.
• These enzymes catalyse arachidonic acid to prostaglandins, which are involved in fever, pain, swelling, inflammation & platelet aggregation.

Uses

• It is used in moderate to severe rheumatoid arthritis such as acute flares of chronic disease, acute gouty arthritis, acute painful shoulders, Ankylosing spondylitis.

Sulindac

• It is a prodrug which is derived from sulfinyl indene.
• It gets converted in vivo by liver enzymes into an active sulfide compound.

[Image description: Chemical structure of Sulindac]

Mechanism of Action

• The exact mechanism of action is not known. Inhibition of COX-1 & COX-2 leads to the inhibition of prostaglandin synthesis, and this is the reason for the anti-inflammatory effects of the drug.

Uses

• It is indicated for acute or long-term use in relieving the signs & symptoms of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute gouty arthritis, acute painful shoulder.

Tolmetin

• It is an NSAID with mechanism of action similar to indomethacin.

[Image description: Chemical structure of Tolmetin]

Mechanism of Action

• The mechanism of action is unknown.
• It reduces the plasma level of prostaglandin E in humans by inhibiting prostaglandin synthetase.

Uses

• It is used for relieving the signs & symptoms of rheumatoid arthritis & osteoarthritis, for long term management of acute flares.
• It is used in juvenile rheumatoid arthritis.

Zomepirac

• It is an analgesic & anti-inflammatory.

[Image description: Chemical structure of Zomepirac]

Mechanism of Action

• Clinical studies show that a 25-50 mg dose of zomepirac provides relief equivalent to that of 650 mg aspirin.
• In advanced cancer subjects, 100-200 mg of oral dose of this drug is as effective as moderate doses of morphine.

Uses

• It is prescribed for managing mild to severe pain.

Diclofenac

It is an NSAID with antipyretic & analgesic action.

[Image description: Chemical structure of Diclofenac]

Mechanism of Action

• The anti-inflammatory effects of diclofenac are because of the inhibition of leukocyte migration & COX-1 & COX-2 enzymes.
• Its antipyretic effects are because of its action on hypothalamus, causing peripheral dilation, increasing cutaneous blood flow & heat dissipation.

Uses

• It is used for treating acute & chronic signs & symptoms of osteoarthritis & rheumatoid arthritis.

Ketorolac

• It is a pyrrolizine carboxylic acid derivative that is structurally related to indomethacin & tolmetin.

[Image description: Chemical structure of Ketorolac]

Mechanism of Action

• It is an NSAID that is chemically related to indomethacin having analgesic activity.
• The drug is in the form of ketorolac tromethamine as a racemic mixture of [-]S- and [+]R-enantiomeric forms.
• It is anti-inflammatory in nature as it inhibits COX-1 & COX-2 which further inhibits prostaglandin synthesis.

Uses

• The moderately severe acute pain which requires analgesia at the opioid level can be managed for a short term (~5 days) in a post-operative setting with ketorolac.

Ibuprofen

• It is a propionic acid derivative & a prototypical NSAID having analgesic & antipyretic properties.

[Image description: Chemical structure of Ibuprofen]

Synthesis

Isobutyl benzene $\xrightarrow{\text{acetylation with } (CH_{3}CO)_{2}O}$ p-isobutyl acetophenone $\xrightarrow{HCN}$ cyanohydrin intermediate $\xrightarrow{\text{(i) HI/P (ii) hydrolysis}}$ Ibuprofen.

Mechanism of Action

• The mechanism of action is unidentified.
• It non-selectively inhibits cyclooxygenase enzyme, involved in prostaglandin synthesis via the arachidonic acid pathway.
• It is pharmacologically active as it inhibits COX-2.

Uses

• It is used for symptomatic treatment of rheumatoid arthritis, juvenile rheumatoid arthritis & osteoarthritis.
• It is used in mild to moderate pain, gout & inflammation of pericarditis.

Naproxen

• It is an anti-inflammatory agent having analgesic & antipyretic properties.

[Image description: Chemical structure of Naproxen]

Mechanism of Action

• The mechanism of action of naproxen is related to cyclooxygenase inhibition.
• COX-1 inhibition is related with gastrointestinal & renal toxicity, while COX-2 inhibition gives anti-inflammatory activity.

Uses

• It is used in rheumatoid arthritis, osteoarthritis, ankylosing spondylitis & acute gout.
• It is used for relieving mild to moderate pain. Used for treating primary dysmenorrhea.

Piroxicam

• It is a cyclooxygenase inhibiting NSAID which is used to treat rheumatoid arthritis & osteoarthritis.

[Image description: Chemical structure of Piroxicam]

Mechanism of Action

• The reversible inhibition of cyclooxygenase which further causes peripheral inhibition of prostaglandin synthesis is responsible for the anti-inflammatory effect of piroxicam.
• The prostaglandins are produced by COX-1.

Uses

• It is used for treating osteoarthritis & rheumatoid arthritis.

Phenacetin

• It was the first NSAID & fever reducer to be marketed.
• It acts on the sensory tracts of the spinal cord & produce analgesic effect.

[Image description: Chemical structure of Phenacetin]

Mechanism of Action

• It produce analgesic effect by acting on the sensory tracts of the spinal cord.
• It is an antipyretic which decreases the temperature set point by acting on the brain.

Uses

• It is mainly used as an analgesic.

Acetaminophen - (Paracetamol)

• It exhibits analgesic & antipyretic effects therapeutically.
• It is similar to salicylates but has no anti-inflammatory, antiplatelet, & gastric ulcerative effects.

[Image description: Chemical structure of Paracetamol]

Mechanism of Action

• It acts in the CNS & increases the pain threshold.
• It inhibits COX-1, COX-2, COX-3 enzymes, therefore, increases the pain threshold.
• It has no peripheral anti-inflammatory effects as it does not inhibit cyclooxygenase in peripheral tissues but not in platelets & immune cells.
• Thus it is effective in the CNS & endothelial cells.

Uses

• It is used for temporary relief from fever, minor aches & pains.
• It is used as an analgesic & antipyretic given orally or as ear drops.

Antipyrine

[Image description: Chemical structure of Antipyrine]

Mechanism of Action

• It acts in the CNS & increases the pain threshold as it inhibits COX-1, COX-2 & COX-3.

Uses

• It is used as an analgesic & for testing the effects of other drugs or enzymes.

Phenylbutazone

• It exhibits anti-inflammatory, antipyretic & analgesic activities.

[Image description: Chemical structure of Phenylbutazone]

Mechanism of Action

• It binds with prostaglandin H synthase & prostacyclin synthase by peroxide mediated deactivation.
• The reduction of prostaglandin production further reduces inflammation of the surrounding tissues.

Uses

• It is used for treating backache, ankylosing spondylitis, rheumatoid arthritis & Reiter's syndrome.