Analgesic and Antipyretic by Dr DuryabDDuryab

1. • Dr Duryab Jamil
• Analgesic and Antipyretic

2. ANALGESIC AND ANTIPYRETIC:
The antipyretic analgesics are so named because they combine an analgesic action with
the ability to lower body temperature in fever (pyrexia). In fact, most drugs in this group
combine analgesic and antipyretic properties with anti-inflammatory properties. All of the
NSAIDs are antipyretic analgesics.
The most common antipyretics in the United States are ibuprofen and aspirin, which are
nonsteroidal anti-inflammatory drugs (NSAIDs) used primarily as analgesics (pain
relievers), but which also have antipyretic properties; and paracetamol
(acetaminophen), an analgesic with weak anti-inflammatory properties.
 ANALGESICS: Are a class of drugs used to relieve pain by
selectively inhibiting the perception of the pain.
 ANTIPYRETICS: An antipyretic is a type of medication that will
reduce fever by lowering temperature from a raised state.

3. PARACETAMOL:
Paracetamol (acetaminophen) is a pain reliever and a fever reducer. The
exact mechanism of action of is not known.
Paracetamol is used to treat many conditions such as headache, muscle
aches, arthritis, backache, toothaches, colds, and fevers. It relieves pain
in mild arthritis but has no effect on the underlying inflammation and
swelling of the joint.
Paracetamol may also be used for other purposes not listed in this
medication guide.
STRUCTURE

4. STRUCTURE ACTIVITY RELATIONSHIP:
SAR of Acetaminophen can be summarized as follows:
Aminophenols are less toxic than corresponding aniline.
Etherification of the phenolic function with methyl or propyl groups results in the derivatives
having greater side effects than with ethyl groups.
Substitution on the nitrogen with such groups that decreases the basicity also reduces the
activity of the drug.
Amides derived from aromatic acids are less active or inactive.
PHYSICAL PROPERTIES:
Color: White
State/Form: Solid-crystals
Description:
Melting point 169 to 170.5
Solubility in water: very slightly soluble in cold water but greater solubility in hot water.
Solubility in organic solvents: soluble in methanol, Ethanol, dimethylformamide, ethylene
dichloride, Acetone, ethyl acetate. Slightly soluble in ether.
Insoluble in petroleum ether, pentane, benzene.

5.  SIDE EFFECTS:
 Side effects of Acetaminophen are:
 Nausea
 Vomiting
 Allergic reactions
 Insomnia
 You get tightness in the chest or throat.
 You have trouble breathing or talking.
 Your mouth, face, lips, tongue or throat start swelling.
MODE OF ACTION:
Paracetamol is a p-aminophenol derivative that exhibits analgesic and antipyretic activity. It does not
possess anti-inflammatory activity. Paracetamol is thought to produce analgesia through a central
inhibition of prostaglandin synthesis.
Acts primarily in the CNS -increases the pain threshold by inhibiting both isoforms of
cyclooxygenase, -COX-1, COX-2 and COX-3 enzymes involved in prostaglandin (PG) synthesis.

6. KINETIC PROPERTIES:
Paracetamol is readily absorbed from the gastrointestinal tract with peak plasma
concentrations occurring about 10 to 60 minutes after oral administration. Paracetamol is
distributed into most body tissues.
INDICATION:
In general, acetaminophen is used for the treatment of mild to moderate pain and reduction of
fever. It is available over the counter in various forms, the most common being oral forms.
Acetaminophen injection is indicated for the management of mild to moderate pain, the
management of moderate to severe pain with adjunctive opioid analgesics, and the reduction
of fever.
Because of its low risk of causing allergic reactions, this drug can be administered in patients
who are intolerant to salicylates and those with allergic tendencies, including bronchial
asthmatics. Specific dosing guidelines should be followed when administering acetaminophen
to children.

7. ADVERSE DRUG REACTION:
Side effects of paracetamol are rare and usually mild, although hematological reactions have
been reported. Skin rashes and hypersensitivity reactions occur occasionally. Over dosage
with paracetamol if left untreated can result in severe, sometimes fatal liver damage and
rarely, acute renal tubular necrosis.
INTERACTION:
Despite its frequent coadministration with other drugs and widespread use, very few clinically
significant drug interactions have been documented with paracetamol. Drugs that alter gastric
emptying can alter paracetamol pharmacokinetics, but this does not result in toxicity in
therapeutic use. A total of 116 drugs are known to interact with Paracetamol (acetaminophen).
8 major drug interactions, 73 moderate drug interactions, 35 minor drug interactions
Interaction reports for Paracetamol (acetaminophen) and the medicines listed below.
amitriptyline, amlodipine, aspirin, atorvastatin

8. CONTRAINDICATION:
Caloric under nutrition.
Acute liver failure.
Liver problems.
Severe renal impairment.
A condition where the body is unable to maintain adequate blood flow called shock.
Acetaminophen overdose.
Acute inflammation of the liver due to hepatitis C virus.

9. SALICYLIC ACID ANALOGUES:
Salicylic acid (from Latin Salix, "willow tree") is
a lipophilic monohydroxybenzoic acid, a type of phenolic acid, and
a beta hydroxy acid (BHA). This colorless crystalline organic acid is
widely used in organic synthesis, and functions as a plant hormone. It is
derived from the metabolism of salicin.
Several kinds of salicylic acid (SA) analogues administered orally with a
stomach tube. Aspirin, sodium salt of o-hydroxybenzoic acid (Na-
salicylate), sodium salt of m- and p-hydroxybenzoic acid (HBA), 2, 5-
dihydroxybenzoic acid (DHBA), PAS sodium dihydrate (PAS-Na),
salicylamide (SAM) and 2% CMC control were used.

10. ASPIRIN
Aspirin is an ester. Aspirin is the common name for (ASA) acetylsalicylic acid and belongs
to a group of drugs called salicylate.
It is a white, crystalline, weakly acidic substance.
Aspirin is a medicine that relieves pain and reduces fever.
PHYSICAL PROPERTIES:
Aspirin, an acetyl derivative of salicylic acid, is a white, crystalline, weakly acidic substance,
with a melting point of 136 °C (277 °F), and a boiling point of 140 °C (284 °F). Its acid
dissociation constant (pKa) is 3.5 at 25 °C (77 °F).
MODE OF ACTION:
Aspirin blocks the effects of an enzyme, cyclooxygenase which in turn prevents the
synthesis of prostaglandin. This gives it its pain-relieving and anti-inflammatory properties.
It also has an effect on the way platelets stick together which helps it to prevent blood clots
from forming in the heart. It is a type of nonsteroidal anti-inflammatory drug (NSAID).

11. Substitution on carboxyl groups may affect the potency and toxicity.
Reducing the acidity of the –COOH, retains the analgesic action of
salicylic acid, but it is devoid of the anti- inflammatory properties.
Placing the phenolic hydroxyl group, meta or para to the carboxyl group
abolishes the activity.
Substitution of halogen atoms on the aromatic ring enhances potency
and toxicity.
Substitution of aromatic rings at the 5 position of salicylic acid increases
anti-inflammatory activity.

12. KINETIC PROPERTIES:
Aspirin is absorbed rapidly from the stomach and intestine by passive diffusion.
Aspirin is a prodrug, which is transformed into salicylate in the stomach, in the
intestinal mucosa, in the blood and mainly in the liver.
INDICATIONS:
Some of the indications for aspirin use are as follows:
Angina pectoris.
Angina pectoris prophylaxis.
Ankylosing spondylitis.
Cardiovascular risk reduction.
Colorectal cancer.
Fever.
Ischemic stroke.
Ischemic stroke: Prophylaxis.

13. ADVERSE DRUG EFFECT:
Severe nausea, vomiting, or stomach pain; bloody or tarry stools, coughing up blood or
vomit that looks like coffee grounds; fever lasting longer than 3 days; or Swelling, or
pain lasting longer than 10 days.
INTERACTION:
Aspirin can interact with many drugs. Some of these include: Anti-inflammatory
painkillers: Examples include such as diclofenac, ibuprofen, and naproxen. Combined
with aspirin, these types of drugs can increase the risk of stomach bleeding.
Severe interactions of Aspirin include: Dichlorphenamide, mifepristone
Serious interactions of Aspirin include: benazepril, captopril
CONTRAINDICATION:
Aspirin is contraindicated in patients with known allergy to NSAIDs and in patients with
asthma, rhinitis, and nasal polyps. It may cause anaphylaxis, laryngeal edema, severe
urticaria, angioedema, or bronchospasm (asthma).

14. QUINOLINE:
Any of a class of aromatic heterocyclic compounds containing a benzene ring fused with aring of five
carbon atoms and a nitrogen atom; especially the simplest such compound, C 9H7N. Quinoline is a
heterocyclic aromatic organic compound with the chemical formula C9H7N. Itis a colorless hygroscopic
liquid with a strong odor . Aged samples, if exposed to light,become yellow and later brown. Quinoline is
only slightly soluble in cold water but dissolvesreadily in hot water and most organic solvents. Quinoline
itself has few application, butmany of its derivatives are useful in diverse applications. A prominent example
is quinine, whichis found naturally in plants as alkaloids. 4-Hydroxy-2-alkylquinolines (HAQs) are involved
inantibiotic resistance.
STRUCTURE:

15. PRDEPERTY OF QUINOLINE:
Quinoline is a hygroscopic liquid with a penetrating odor.
It absorbs as much as 22 percent water andis volatile with steam.
Quinoline is slightly soluble in cold water, more easily in hot water; and misciblewith alcohol, ether,
and carbon disulfide.
It dissolves sulfur, phosphorus, and arsenic trioxide .
Quinoline is a colourless liquid ,bp238°c,having disagreeaceble, pyridine -like odour.chemically it
gives all the reaction of pyridine and electrophilic substitution reaction of thebenzene ring
MECHANISM OF QUINOLINE:
FQ’s are resisted due to chromosomal mutation and producing a DNA gyrase or topisomerase IV
with reduced affinity. Due to reduced permeability.( increased efflux of these drugs across bacterial(
membranes. Increasing resistance has been reported among salmonella, pseudomonas,
staphylococci, gonococci and pneumococci.
DEUALINIUM
is a quaternary ammonium cation antimicrobial agent used to treat common infections of the
mouth and throat that has been studied in the treatment of vaginal candidiasis.

17. MECHANISM OF ACTION:
Dequalinium has a multiple mode of action. It disrupts the cell permeability of the bacteria by
absorbing onto the bacterial cell surface and diffusing across the membrane. It also binds to the
cytoplasmic membrane with subsequent formation of complexes and protein precipitation and lyses
the membrane in adequate concentrations, perturbing osmotic exchange. Loss of normal enzymatic
activity is achieved through several different processes. Denaturation of proteins results in inhibition of
bacterial cell metabolism. Disruption of bacterial energy production is mediated through inhibition of
glucose metabolism and inhibition of mitochondrial ATP synthesis via inhibition of bacterial F1-
ATPase. Protein synthesis is also terminated at the level of ribosomes. Bacterial nucleic acids are also
affected through direct binding of the drug to DNA in vitro, and precipitation of cytoplasmic material
with nucleic acids being the most sensitive. The cationic form of dequalinium accumulates in the
mitochondria and promotes anticancer activity in human leukemia cells. It mediates a cytotoxic effect
by altering redox balance in cells and downregulating Raf/MEK/ERK1/2 and PI3K/Akt signaling
pathways in these cells which leads to cell death by apoptosis and/or necrosis. Dequalinium inhibits
mycothiol ligase activity in Mycobacterium tuberculosis strains .

18. INDICATION: Effective local treatment as vaginal tablets for infections such as fluor vaginalis,
bacterial vaginosis, aerobic vaginitis, vulvo-vaginal candidiasis and trichomoniasis. Used as a topical
antimicrobial agent.
CONTRAINDICATION: Dequalinium should not be used in patient allergic to ammonium compounds
or to the drug itself. It should not also be used in children
SIDE EFFECTS: common or very common. Increased risk of infection; vulvovaginal disorders.
Uncommon. Haemorrhage; headache; nausea.
Frequency not known. Cystitis; fever.
PHYSICAL PROPERTIES:
It is most commonly available as a dichloride salt but is available as other various salts as well.
It is used in wound dressings and mouth infections and may also have antifungal action, but may
associate with skin ulceration.
KINETIC PROPERTIES:
The degree of absorption is minimal in case of topical or vaginal administration thus systemic
exposure is negligible. <0.1 % is absorbed systemically after oral administration.

19. ADVERSE DRUG INTERACTION:
Gastrointestinal disorders: Glossodynia (oral).
Reproductive system and breast disorders: Vaginal discharge, vulvovaginal pruritus, vulvovaginal burning
sensation.
PYRAZOLONE:
Pyrazolone is 5-membered heterocycle containing two adjacent nitrogen atoms. It can be viewed as a
derivative of pyrazole possessing an additional carbonyl (C=O) group. Compounds containing this functional
group are useful commercially in analgesics and dyes.
STRUCTURE:
Pyrazolone can exist in two isomers: 3-pyrazolone and 4-pyrazolone.

20. SYNTHESIS:
These isomers can interconvert via lactam–lactim and imine–enamine tautomerism; these
conversion often display photochromism. For pyrazolone derivatives, the 3-pyrazolone isomer can
be stabilized with N-alkyl or N-aryl substituents.
APPLICATION:
Pyrazolones are amongst the oldest synthetic pharmaceuticals, starting with the introduction of
antipyrine (phenazone) in 1880s. The compounds generally act as analgesics and include dipyrone
(Metamizole), aminopyrine, ampyrone, famprofazone, morazone, nifenazone, piperylon and
propyphenazone, aminophenazone. Of these dipyrone is perhaps the most widely used. Edaravone
is useful for prevention and/or therapy of arterial wall injury.[6] Eltrombopag is used to address low
blood platelet count.
PYRAZOLONE DERIVATIVES:
the pyrazolone derivatives, which include dipyrone, antipyrine, aminopyrine and
propyphenazone, are widely used analgesics. Dipyrone, the most widely used pyrazolone, has
been the most studied.

21. DIPYRONE:
OTHER NAME: METAMIZOLE
Metamizole, or dipyrone, is a painkiller, spasm reliever, and fever reliever that also has anti-inflammatory
effects. It is most commonly given by mouth or by injection.
Although it is available over-the-counter in some countries, it is prescription or banned in other countries,
due to its potential for adverse events, including agranulocytosis. A study by one of the manufacturers of
the drug found the risk of agranulocytosis within the first week of treatment to be a mere 1.1 in a million,
versus 5.92 in a million for diclofenac. It is in the ampyrone sulfonate family of medicines.
STRUCTURE:

22. MECHANISM OF ACTION:
I ts precise mechanism of action is unknown, although it is believed that inhibiting brain and
spinal cord prostaglandin (fat-like molecules that are involved in inflammation, pain and
fever) synthesis might be involved. Recently, researchers uncovered another potential
mechanism involving metamizole being a prodrug. In this proposal, not yet verified by other
researchers, the metamizole itself breaks down into other chemicals that are the actual
active agents. The result is a pair of cannabinoid and NSAID arachidonic acid conjugates
(although not in the strict chemical meaning of the word) of metamizole's breakdown
products. Despite this, studies in animals have found that the CB1 cannabinoid receptor is
not involved in the analgesia induced by metamizole. Although it seems to inhibit fevers
caused by prostaglandins, especially prostaglandin E2, metamizole appears to produce its
therapeutic effects by means of its metabolites, especially N-methyl-4-aminoantipyrine
(MAA) and 4-Aminoantipyrine (AA).

23. INDICATION:
It is primarily used for perioperative pain, acute injury, colic, cancer pain, other
acute/chronic forms of pain and high fever unresponsive to other agents. Its use in the
elderly and those with liver or kidney impairment is advised against, but if these groups of
people must be treated, a lower dose and caution is usually advised. Its use during
lactation is advised against, as it is excreted in breast milk
CONTRAINDICATION:
Previous hypersensitivity (such as agranulocytosis or anaphylaxis) to metamizole or any of
the excipients (e.g. lactose) in the preparation used, acute porphyria, impaired
haematopoiesis (such as due to treatment with chemotherapy agents), third trimester of
pregnancy (potential for adverse effects in the newborn), lactation, children with a body
weight below 16 kg, history of aspirin-induced asthma and other hypersensitivity reactions
to analgesics

24. SIDE EFFECTS:
Metamizole has a potential of blood-related toxicity (blood dyscrasias), but causes less
kidney, cardiovascular, and gastrointestinal toxicity than non-steroidal anti-inflammatory
drugs (NSAIDs Like NSAIDs, it can trigger bronchospasm or anaphylaxis, especially in
those with asthma.
Serious side effects include agranulocytosis, aplastic anaemia, hypersensitivity reactions
(like anaphylaxis and bronchospasm), toxic epidermal necrolysis and it may provoke acute
attacks of porphyria.
PHYSICAL PROPERTIES:
It is a sulfonic acid and comes in calcium, sodium and magnesium salt forms.[3]
Its sodium salt monohydrate form is a white/almost crystalline powder that is unstable in
the presence of light, highly soluble in water and ethanol but practically insoluble in
dichloromethane

25. ADVERSE DRUG INTERACTION:
ciclosporins decreased serum levels of ciclosporin.
methotrezate additive risk for haematologic (blood) toxicity.
Chlorpromazine additive hypothermia (low body temperature) may result.
Aryl acetic acid/Aryl propionic acid Derivatives:
Ibuprofen:
Analgesic, antipyretic and non-steroidal anti-inflammatory drug.
PHYSICAL PROPERTIES:
It is a colourless, crystalline stable solid
It has a characteristic odour
It’s boiling point is 1570C and melting point of 75-77.5oC.
It is readily soluble in most organic solvents and very soluble in alcohol.
MODE OF ACTION:
Ibuprofen work by non-selective reversible inhibition of cyclooxygenase enzyme COX 1 and COX
2.
STRUCTURE OF IBUPROFEN:

27. KINETIC PROPERTIES:
It is well absorbed orally and the peak spectrum
concentration can be attained in 1 to 2 hours after
extravascular administration.
Apparent volume of distribution of ibuprofen is 0.1L/kg.
Ibuprofen dosage is more than 99 % bind to plasma protein
and site II of purified albumin.
It is rapidly metabolized and bio transformed in the liver,
forming hydroxylated and carboxylated metabolites.

28. INDICATIONS OF IBUPROFEN:
Patent Ductus Arteriosus: it is a neonatal condition wherein the ductus arteriosus (blood vessel that
connects the main pulmonary artery to the proximal descending aorta) fails to close after birth causing
severe risk of heart failure.
Rheumatoid and osteo-arthritis: DOSING: 300 mg, 400 mg, 600 mg, or 800 mg PO q6-8hr; not to
exceed 3200 mg/day
Cystic fibrosis: DOSING: <4 years: Safety and efficacy not established
≥4 years: PO administration q12hr, adjusted to maintain serum levels of 50-100 mcg/mL; may slow
disease progression in younger patients with mild lung disease
Orthostatic hypertension:
Dental pain: DOSING: 1200 mg daily for 3 days or 2400 mg daily for 2 days significantly suppress
odema formation 48 hours after oral administration.

29. ADVERSE DRUG REACTIONS:
Most common includes diarrhea, nausea and vomiting.
Other adverse drug reaction includes;
Bloating, edema, hypertension or high blood pressure, ulcers in digestive system, worsening asthma
symptoms.
May rarely cause metabolic acidosis, abnormal hepatic function, renal failure, coma and apnea.
DRUG INTERACTIONS:
Acemetacin: The risk or severity of adverse effects can be increased when Ibuprofen is combined
with Acemetacin
Ammonium chloride: Ibuprofen may decrease the excretion rate of Ammonium chloride which could
result in a higher serum level
Zolmitriptan: The risk or severity of hypertension can be increased when Zolmitriptan is combined
with Ibuprofen

30. CONTRA-INDICATIONS:
Patients with known hypersensitivity issues.
Active gastrointestinal bleeding or peptic ulceration
Known hypersensitivity to aspirin or NSAIDs.
Naproxen:
Analgesic, anti-pyretic and non steroidal anti-inflammatory drug.
PHYSICAL PROPERTIES:
It is white to off-white crystalline powder.
It is sparingly soluble in alcohol and insoluble in water
It is practically odorless
It’s melting point varies from 152-1550C
It is available as a free acid and sodium salt.

31. MODE OF ACTION:
Works by reversibly inhibiting both COX 1 and COX 2 enzymes resulting in prostaglandin synthesis
inhibition therefore reducing inflammation and pain.
STRUCTURE OF NAPROXEN:

32. KINETIC PROPERTIES:
At comparable doses, they may differ slightly in their rates of absorption but otherwise they
are therapeutically equivalent.
Naproxen sodium achieves its peak plasma concentration after 1 hour and 2 hours with free
acid(naproxen).The mean Cmax ranges from 94 – 97.4 mcg/mL.
It has a volume of distribution of 0.16 L/kg
It is heavily metabolized in liver and undergoes both phase I and phase II metabolism.
Half life is reported to be 12-17 hours.

33. INDICATIONS OF NAPROXEN:
Ankylosing Spondylitis: DOSING: 250 mg to 500 mg (naproxen) or 275 mg to 550 mg
(naproxen sodium) orally twice a day
Ostero-arthritis: DOSING: 750 mg to 1000 mg orally once a day for controlled release and 375
mg to 500 mg orally twice a day for delayed release.
Acute gout: DOSING: Initial dose: 750 mg (naproxen) or 825 mg (naproxen sodium) orally once
on first day of attack
-Following initial dose: 250 mg (naproxen) or 275 mg (naproxen sodium) orally every 8 hours
until attack subsides
Bursitis: DOSING: 550 mg orally once, followed by 275 mg orally every 6 to 8 hours or 550 mg
orally every 12 hours as needed
-Maximum dose: Initial total daily dose not to exceed 1375 mg; thereafter, not to exceed 1100
mg/day

34. ADVERSE DRUG REACTIONS:
Indigestion, nausea, vomiting and stomach pain.
Bruising, itching rash
Ringing in your ears
Headache, dizziness and drowsiness
Lethargy, epigastric pain
DRUG INTERACTIONS:
Acetohexamide: The protein binding of Acetohexamide can be decreased when combined with Naproxen.
Amphotericin B: The risk or severity of nephrotoxicity can be increased when Amphotericin B is combined
with Naproxen.
Valganciclovir: Naproxen may decrease the excretion rate of Valganciclovir which could result in a higher
serum level.
Zuclopenthixol: The risk or severity of hypertension can be increased when Naproxen is combined with
Zuclopenthixol.
CONTRAINDICATIONS:
Patient with previously known hypersensitivity
3rd trimester of pregnancy

35. HETRO ARYL ACETIC ACID DERRIVATIVES:
Diclofenac:
It is a phenyl acetic acid derivative and non steriodial anti-inflammatory drug.
PHYSICAL PROPERTIES:
It is available in solid tablets, intravenous preparations and oral preparations.
It is a crystal from ether-petroleum-ether.
It’s melting point ranges from 283 – 285OC
It is soluble in water
MODE OF ACTION:
It also work by inhibiting COX 1 and COX 2 enzymes thereby inhibiting prostaglandin synthesis
STRUCTURE OF DICOLOFENAC:

36. KINETIC PROPERTIES:
It is completely absorbed from the GI tract but slightly undergoes first
pass metabolism with only 60% of drug reaching systemic circulation
unchanged.
It has total volume of distribution of 5 – 10 L
It is over 99.7% bound to serum proteins, primarily albumin.
It undergoes oxidative metabolism to hydroxyl metabolites as well as
conjugation to glucuronic acid, sulfate and taurine.
Half life is of approximately 2 hours.

37. INDICATIONS OF DICLOFENAC:
Rheumatoid Arthritis: DOSING: 50 mg PO q8hr or 75 mg PO q12hr
Osteoarthritis: DOSING: 50 mg PO q8hr or 75 mg PO q12hr
Ankylosing Spondylitis: DOSING: 25 mg PO 4 or 5 times daily
Dysmenorrhea: DOSING: 100 mg PO once, then 50 mg PO q8hr PRN
Mild to moderate Pain: DOSING: 100 mg PO once, then 50 mg PO q8hr PRN
Acute Migraine: Oral solution: 50 mg (1 packet) in 30-60 mL of water, mixed well and drunk
immediately
ADVERSE DRUG REACTIONS:
Upset stomach, nausea, vomiting and diarrhea
Headache, drowsiness and dizziness
Mild rash
Loss of appetite
Acute renal failure, respiratory depression and coma can rarely occur.

38. DRUG INTERACTIONS:
Abacavir: Diclofenac decrease the excretion rate of abacavir.
Abametapir: It increase the serum concentration of diclofenac
Abcimixab: The risk and severity of bleeding and hemorrhage increses when diclofenac
is combined with abcimixab.
Acebutolol: Diclofenac reduces the anti hypersensitivity activities of acebutolol.
CONTRAINDICATIONS:
Patient with known hypersensitivity
Hypertension
Pregnancy and lactation.

39. TOLMETIN
It is one of the hetero aryl acetic acid derivative and belong to the class of NSAIDs.
PHYSICAL PROPERTIES:
It is a solid crystalline compound from acetonitrile.
Its melting point ranges from 156 -157oC
It solubility value is 222mg/L
MODE OF ACTION:
Its mode of action is still unknown however test and laboratory studies on animals and men conclude
that it’s anti inflammatpry activity is not due to pituitary adrenal stimulation. It inhibits prostaglandin
synthetase in vitro and lowers the plasma level of prostaglandin E in men.
STRUCTURE OF TOLMETIN:

40. KINETIC PROPERTIES:
Rapidly and almost completely absorbed with peak concentration levels being reached
with 30 – 40 minutes after oral administration.
Essentially all of the dose is recovered from the urine in 24 hours either as an oxidative
metabolites or conjugates or tolmetin.
Biphasic elimination from the plasma consisting of a rapid phase with a half-life of one to 2
hours followed by a slower phase with a half-life of about 5 hours.
INDICATIONS FOR TOLMETIN:
For the treatment of rheumatoid arthritis, juvenile rheumatoid arthritis (JRA)/juvenile
idiopathic arthritis (JIA), or osteoarthritis.
NOTE: Tolmetin is indicated in the treatment of acute flares and in the long-term
management of both RA and OA.
Oral dosage

41. Adults
Initially, 400 mg PO three times a day. If needed, adjust dose upward or downward after
1—2 weeks.
Maintenance dosage is usually 600—1800 mg/day PO in 3—4 divided doses.
Symptomatic improvement may occur within 7 days, with progressive improvement during
successive weeks of therapy.
Children >= 2 years and Adolescents
20 mg/kg/day PO in 3—4 divided doses.
Maintenance dosage is usually 15—30 mg/kg/day PO in 3—4 divided doses, not to
exceed 1800 mg/day.
Children < 2 years: Safety and efficacy have not been established.
ADVERSE EFFECTS:
Indigestion, stomach pain, nausea, diarrhea, gas, headache, weakness,lethargy and
epigastric pain.

42. DRUG INTERACTIONS:
Reviparin: The risk or severity of bleeding and hemorrhage can be increased when
Tolmetin is combined with Reviparin
Sitaxentan: The therapeutic efficacy of Sitaxentan can be decreased when used in
combination with Tolmetin
Trimebutine: Tolmetin may decrease the excretion rate of Trimebutine which could
result in a higher serum level
Zolmitriptan: The risk or severity of hypertension can be increased when Zolmitriptan
is combined with Tolmetin.
CONTRAINDICATIONS:
Systemic mastocytosis
Increased risk of bleeding due to clotting disorder
Heart problem
Pregnancy and hypertension.

43. N-anthranilic Acid Derivative (Fenamates):
MEFENAMIC ACID:
It is an NSAIDs and belongs to the class of fenamates.It works as an analgesic, antipyretic and
non steroidal anti inflammatory drug.
PHYSICAL PROPERTIES:
It is available in white to off white crystalline powder.
Melting point ranges from 230 -231oC
Soluble in water, sparingly soluble in ether, chloroform and slightly soluble in ethanol
MODE OF ACTION:
Mefenamic acid binds the prostaglandin synthetase receptors COX-1 and COX-2, inhibiting the
action of prostaglandin synthetase. As these receptors have a role as a major mediator of
inflammation and/or a role for prostanoid signaling in activity-dependent plasticity, the symptoms of
pain are temporarily reduced.

44. STRUCTURE OF MEFENAMIC ACID

45. KINETIC PROPERTIES:
It is rapidly absorbed after oral administration.
Volume of distribution is 1.06 L/kg
It has 90% protein binding
Mefenamic acid undergoes metabolism by CYP2C9 to 3-hydroxymethyl mefenamic acid, and
further oxidation to a 3-carboxymefenamic acid may occur.
It has half life of 2 hours.
INDICATIONS FOR MEFENAMIC ACID:
Acute Pain
Initial 500 mg PO once, THEN
250 mg PO q6hr PRN usually not to exceed 7 days
Primary Dysmenorrhea
Initial 500 mg PO once, THEN
250 mg PO q6hr PRN usually not to exceed 3 days
Rheumatoid and osteoarthritis, pain, inflammation and fever.

47. Meclofenamic Acid:
It is an NSAID used to treat mild and moderate pain, inflammation and fever.
PHYSICAL PROPERTIES:
It is available in solid form
It’s melting point ranges from 248-257oC
It’s solubility value is 30mg/L
MODE OF ACTION:
The mode of action, like that of other nonsteroidal anti-inflammatory agents, is not
known. Therapeutic action does not result from pituitary-adrenal stimulation. In animal
studies, meclofenamic acid was found to inhibit prostaglandin synthesis and to compete
for binding at the prostaglandin receptor site. In vitro meclofenamic acid was found to be
an inhibitor of human leukocyte 5-lipoxygenase activity. These properties may be
responsible for the anti-inflammatory action of meclofenamic acid.

48. STRUCTURE OF MECLOFENAMIC ACID:

49. KINETIC PROPERTIES
Rapidly absorbed in man following single and multiple oral doses with peak plasma
concentrations occurring in 0.5 to 2 hours.
It has volume of distribution of 9.1 to 43.2 L
Greater than 99% bound to plasma proteins over a wide drug concentration range.
Meclofenamic acid is extensively metabolized to an active metabolite (Metabolite I; 3-
hydroxymethyl metabolite of meclofenamic acid) and at least six other less well
characterized minor metabolites.
A study in 10 healthy subjects following a single oral dose the apparent elimination half-life
ranged from 0.8 to 5.3 hours.
INDICATIONS FOR MECLOFENAMIC ACID:
It is indicated for acute gout arthritis, ankylosing spondylitis, fever, hypermenorrhea,
osteoarthritis, rheumatoid arthritis and supraspinatus tendinitis.

50. ADVERSE DRUG EFFECTS:
Stomach pain, nausea, vomiting,diarrhea
Headache, dizziness and drowsiness
Seizures and renal toxicity rarely occur
DRUG INTERACTIONS:
Acetylsalicylic acid: The therapeutic efficacy of Acetylsalicylic acid can be
decreased when used in combination with Meclofenamic acid.
Cefuroxime: Cefuroxime may decrease the excretion rate of Meclofenamic acid
which could result in a higher serum level.
Flurbiprofen: The risk or severity of adverse effects can be increased when
Flurbiprofen is combined with Meclofenamic acid.
CONTRA INDICATIONS:
Patient allergic or sensitive to NSAIDs.
3rd trimester of pregnancy
Chronic inflammation of GIT.