3.

2 Non-steroidal anti-inflammatory agents, Anti-gout drugs,

Antirheumatic drugs

SNO Topic Page No

1 Nonsteroidal anti inflammatory drugs
2 Self assessment questionnare
3 Anti rheumatoid drugs
4 Self aseessment questionnare
5 Anti Gout Drugs
6 Self assessment questionnare
7 Summary
8 Answer to key
9 Terminal Questions and Activity
10 External Link

3.2.1 Non-Steroidal Anti-inflammatory Drugs and Antipyretic – Analgesic drug.

Classification of NSAID

Non selective Preferential Selective Analgesic

Coxinhibitors COX2- COX2- Antipyretic
inhibitors inhibitors

Eg :- Aspirin Nimesulide Celecoxib Paracetam

Ibuprofen Diclofenac Etoricoxib

Mefanamic

Acid

Syclooxygenase enzyme exists in two isoforms COX1 and CoX11

CoXI enzyme is involved in Cytoprotective, cell signaling and protective mechanism.
COXII generates prostaglandins at the site of inflammation.

Inhibition of PG Synthesis Causes

1. Closing of ductus arteriosus in neonate

2. Anti thrombotic effect

3. Analgesic effect

4. Anti-pyretic effect

Inhibition of PG synthesis can generate toxicity signs like

1. Damage to gastric mucosal lining

2. Inhibition of aggregation of platelets

3. Retention of water and salt

4. Asthmatic attacks

5. Anaphylactic reactions.

Pharmacological actions of Aspirin:-

1. Aspirin reduces the sensitivity of pain receptors in sensory nerve endings and
has therefore exhibit analgesic action. But analgesic action of aspirin is weaker
than that of morphine.

2. Aspirin causes heat loss by sweating and vasodilatation and hence has
antipyretic effect.

3. Low dose of aspirin is sufficient to produce analgesic and antipyretic. High

doses of aspirin is required to produce anti inflammatory effect signs of
 inflammation are restrained by inhibiting COX enzyme and also due to its
antioxidant potential

4. Cellular metabolism is enhanced at high doses of aspirin long term usage shifts
the nitrogen balance to negative.

5. Respiratory depression is observed in Salicylate poisoning. Effects on

respiration are generally dose dependent.

6. Salicylate poisoning causes increase in loss of water and electrolytes and leads
to dehydration. High doses of aspirin causes significant change in acid-base
balance.

7. There is no direct effect of Aspirin on the heart or blood vessels at normal

therapeutic doses.Effects of aspirin on CVS is dose –dependent.

Dose Effect

1. Therapeutic dose No direct effect on heart

2. High dose Increase cardiac out put

3. Toxic dose Depress Vasomotor centre.

8. Aspirin is not drug of choice in chronic goit condition. High dose of aspirin
>5g/day increases excretion of uric acid.

9. Low dose of Aspirin inhibits TXA2 syntheses by platelets and interferes with
functioning of platelets.

Side effects :-

1. Nausea 2. Emesis 3. Blood loss in stools,

4. Gastric bleeding 5. Hypersensitivity.

High doses causes :- 1) Salicylism syndrome 2) Liver damage in children

3) Reye’s syndrome

Symptoms of Acute Salicylate poisoning :-

This occurs when the serum levels of aspirin is greater than 50mg/dl.

Electrolyte imbalance ; high body temperatures, fall in glucose levels; emesis;

dehydration; death due to respiratory failure.

Uses :-

1. It is used as analgesic

2. It is indicated in fever

3. It is indicated in acetic rheumatic fever.

4. High dose of aspirin is indicated in Rheumatoid Arthritis.

5. Aspirin gives symptomatic relief in Osteoarthritis

6. It is indicated in post myocardial infarction and poststroke patients.

Propionic acid derivatives :-

Mechanism of action :- Inhibition of Arachidoni Acid ( AA) metabolism.

Side effects:- All are better tolerated drugs.

GI abnormalities ; headache, blurred vision Rashes

Ibuprofen is Contraindicated in pregnant women

Uses:-

1. It is indicated in dysmenorrhoea.

2. It is used in the treatment of rheumatoid arthritis; osteo arthritis and other

musculoskeleted disorders.

3. It is indicated to suppress swelling and inflammation after surgery or after

delivery.

Anthranlic acid derivative:-

Mefanomic acid:-

Mechanism of action :- Inhibits synthesis of Prostaglandins

Side effect :- The most important dose related side effect is diarrhea.

 There is no occurrence of significant gastric bleeding

 Skin rashes, CNS side effects.
 Haemolytic anaemia

Use :- It is used as analgesic in soft tissue pains.

Piroxicam :-

1. It is a long acting NSAID

Mechanism of action:- It is inhibits COX enzyme reversibly and is non-selective. It
also decreases the production of Ig M antibodies in rheumatoid arthritis

Side effects:-

1. Gastric intestinal abnormalities

2. Edema ; Elevated levels of urea.

Uses :-

1. It is not the medication of choice due to its toxicity signs.

2. It is suitable to use as anti- rheumatic drug or anti-gout drug.

Ketorolac :-

Mechanism of action:- By a peripheral mechanism it inhibits synthesis of

prostaglandius and relieves pain

Side effects:- Emesis; gastric pain; CNS effects, Retention of fluid

Ketorolac is contraindicated in patients on anti coagulant therapy

Use :- It is indicated in Post surgical pain, musculo skeleted and dental pains

Indomethacin :-

MOA :- It is highly potent PG synthesis inhibitor. It also decreases the motality of

neutrophil
Side effects:- Irritation of gI tract Emesis; Loss of appetite

CNS side effects; Decrease in leukocytes; hypersensitivity reactions, Impaired

coordination.

Uses:-

1. It is indicated as a reserve drug in conditions like ankylosing spondylytis,

psoriatic arthritis

2. It is the drug of choice for medical closure of patent ductus arteriosus

Pyrazolones:-

Dipyrone and propiphenazone had reported toxicity signs.

Preferential COX 2 – inhibitors:-

Nimesulide : Diclofenac come under this category

Mechanism of action:- These drugs preferably inhibit COX-2 enzyme

Side effects:- Nimesulide causes gastro intestinal abnormalities, rashes, hepatic

failure gastric ulceration and gI bleeding is less with Diclofenac. Diclofenac can
increase the risk of cardiac attack

Uses:- Etodolacis approved for its use in osteu and rheumatoid arthritis and
musculoskeletal pain.
Selective COX2-Inhibitors

MOA :- These drugs selectively inhibit COX-2 enzyme.

These drugs are contraindicated in patients with ischaemic head disease.

Side effects:-

Celecoxib causes rashes, edema and increase in Blood pressure.

Etoricoxib causes abdominal discomfort, dry mouth, parasthesia, edema.

Uses :-

Celecoxib is the approved drug in conditions like osteo arthritis and Rheumatoid
arthritis

Para aminophenol derivative :-

Paracetamol:-

Mechanism of action :- It increases through hold potential of pain. Its actions are more
prominent in central COX enzyme

Side effects:- It is safe and tolerated drug

Use:- It is one of the over the counter drug. It is the drug of choice in rheumatoid
arthritis.

Self assessment Questionnaire

1. Identify a non-selective COX – inhibitor

A) Aspirin b) Nimesulide

c) Celecoxib d) Paracetamol
2. Which one of the following causes “Reyes Syndrome “?

a) Paracetamol b) Aspirin

c) Ketoralac d) All the above

3. Which one of the following is a preferential COX2 inhibitor

a) Diclofenac b) Aspirin c) Paracetomol d) none

4. Piroxicam is a short acting NSAID ( True/False)

5. Match the following

1. Aspirin a Preferential COX-2 inhibitor

2. NImesulide b Selective COX-2 inhibitor

3. Celecoxib c Non- selective COX-2 inhibitor

3.2.1 ANTI RHEUMATOID DRUGS.

3.2.1.i Classification of Anti rheumatoid drugs

1. Disease modifying (ii) Adjuvant drugs

antirheumatic drugs Eg:- Corticosteroids

Non biological Biological

Eg:- Methotrexate
Azathiopoine TB – inhibitors IL-1

Sulfasalazine Eg :- Eanercept Eg : Anakinra

Chloroquine

Leflunomide.

Methtrexate :-

Mechanism of Action :- It is dihydrofolate reductase inhibitor.

Side effects:-

Non biological DMARDS are indicated in individuals with Acute Flare.

Methotrexate is a folic acid analogue that inhibitor dihydrofolate reductase an

enzyme that inhibits the synthesis of tetra hydrofolate synthesis which in turn
inhibits the synthesis of DNA,RNA and proteins.

In RA it is not the main mechanism of action there are other multiple other
mechanisms including inhibition of the immune system.

Side effects :-

Pulmonary fibroses

Liver toxicity

Stomatitis or mouth ulcers

A Renal toxicity

Folate deficiency and causes megaloblastic anaemia

Myclosuppression

Teratogenicity

Leflunomide:- This drug is indicated in patients where methotrexate is

contra indicated

Mechanism of action :- It suppresses T cell proliferation.

Side effects:- Diarrhea, hypertension, Hepatotoxicity, Teratogenicity.

Hydroxy Chloroquine:-

It is the safest DMARD.

It is indicated in pregnant individuals

Mechanism of action :- It inhibits Immune system by multiple mechanism.

1. It increase lysosomal Ph in Antigen- Presenting cells/

2. It blocks Toll – like receptors on plasmocytoid dendritic cells ( Toll- like

receptors are surface proteins that play a role in recognizing pathogens.

Side effects :-

1. Eye toxicity

2. Hepato toxixity

3. Excessive coloring of skin

4. Nausen & Diarrhea.

Sulfosalazine :- It is a combination of Sulfa pyridine ( Antibiotic) and 5-
Amino salicylic acid can anti- inflammatory). It is activated by colonic bacteria

Side effects: - Malaise ; Emesis ; Sulfonamide toxicity ; Reversible

Oligospermia

Biological DMARDS

These are indicated in severe disease or resistant to combination therapy

Mechanism of action :- It suppress immune system. ABatacept suppresses T

cells and Rituximab suppresses B cells

Etanercept : It reduces TNF –α activity as DECOY Receptor preventing

cytokine from attaching to receptors on healthy tissues

Infliximab and Adalimulmab act as Anti- TNF-α monoclonal antibodies against

cytokines

Biological DMARD increases précis position to infection. They can cause

reactivation of latent tuberculosis. It is advised to test for latent TB before
starting TNF-α inhibitors

 They can also induce Drug induced lupus

Short term Medications:-

They act as analgesics and provide short term relief.

NSAIDS: - Naproxen

Glucocorticoids :- Prednisolone
These drugs are fast acting and offer symptomatic relief when compared to
DMARDS

“Rheumatoid arthritis is a chronic inflammatory auto immune disorder mostly

affects synovial joints.

Cause :- Genetic Predisposition of alleles HLA-DR1 and HLA – DR 4

Acetaminophen or paracetamol is mainly indicated.

COX-1 is constitutive It is also active enzyme and COX-2 is inducible It has to

be turned on enzyme.

Paracetamol :- Oral ; rectal ; Intravenously.

Note: - It is not considered as NSAID

It is coadministered with Ibuprofen or Morphine after surgical procedures.

 It is preferred drug in treatment of fever and pain in individuals with

Bleeding disorders

Peptic ulcers

Allergies to Aspirin

 It is first line therapy for Children with fever or Pain

 

Acetaminophen Toxicity

 It could occur with therapeutic doses in individuals with low glutathione

stores.
 Infants; Elderly; Individuals with malnutrition or with glutathione
synthesis deficiency.
 Chronic use of alcohol :- Increase Activity of cyp450

Early Symptoms: - Nausea,

Emesis

Abdominal pain

Worsening symptoms:- Jaundice,

 Coagulopathy ( excessive bleeding Claudine)

Hepatic encephalopathy

Acute renal failure

N – Acetyl cysteine  Replenishes Glutathione

Drug Interactions

Diuretics - ↓ Diuresis

Anticoagulants - ↑ risk of bleeding

Alcohol - ↑ risk of bleeding

Corticosteroids - ↑ risk of bleeding

Digoxin ; Lithium ; Amino glycosides - ↓ Renal excretion of the interacting

compound.

Self assessment Questionnare:

6.Which one of the following is safest Disease Modifying Anti Rheumatic Drug

A. Hydroxychloroquine B. Leflunomide

C. Sulfasalazine D. Rituximab

7.Side effects of sulphasalazine are

A.Malaise B.Emesis

C.Reversible Oligospermia D. All the above

8. Which one of the following is a short term medication used in rheumatoid

arthritis?

A.Naproxen B.Methotrexate
C. Leflunomide D.Sulphasalazine

9. Identify Dihydrofolate reductase inhibitor

A.Methotrexate B. Naproxen

C.Glucocorticoid D. Leflunomide

10.Sulphasalazine is a combination of sulphapyridine and 5-Aminosalicylic

acid(True/False)

3.2.2 Anti – Gout Medications:-

Gout is an inflammatory arthritis causes due to hypouricemia with

deposition of monosodium urate crystals

Purine  Hypoxanthine

Drugs used in Gout.

Gout is a metabolic disorder characterized by increase in levels of uric

acid in blood. Uric acid is the metabolic product of purine To the regions where
blood perfusion is low like meta tarsophalangeal point uric acid gets deposited
and leads to inflammatory responses.

Leukaemias, lymphomas, and drugs lay thiazides furosemide, ethambutol can

lead to secondary hyperurecemia.

Classification of anti gout drugs

Acute Gout Chronic gout

Eg : NSAIDS

COLCHICINE Uricosurices Synthesis inhibitors

CORTICOSTEROIDS Eg: Probenecid Eg : Allopurinol

Sulfinpyrazone Febuxostat

NSAIDS: - eg :- Naproxen

Piroxicam

Diclofenac

Indomethacin

Etoricoxib.

These are strong anti-inflammatory drugs which are given at high doses
and with repeated intervals. Prolonged usage of NSAIDS is not recommended.
Colchicines:-

Source :- Colchicum autumnal

Mechanism of action :-

It prevents migration of granulocytes to affected joints and inhibits of

glycoprotein there by reducing the inflammatory condition.

Deposition of uric acid crystals in synovial joint

↓
Triggers inflammatory responses
 ↓
Formation of chemotactic factors
↓
Granulocyte migration to joints – co/CHICINE
↓
Engulf uric acid crystals

↓
Cause the release of glycoprotein

Decrease PH Release liposomal

which further causes enzyme and causes

accumulation of uric acid joint destruction

Note :- Colchicine’s binds to tubulin and decreases the cellular motility of

granulocytes.

Side effects and Toxicity:-

It is dose related

Nausea Emesis; Watery diarrhea; Abdominal

Cramps; Renal damage ; Intestine bleeding

Long term of therapy of colchicines is not advisable as it will lead to a plastic

anemia, agranulocytosis, myopathy and loss of hair.
Uses :- Acute gout

Prophylactic drug

Corticosteroids :- These are the reserved drugs for patients with kidney failure
or history of ulcers and in conditions. Where NSAIDS/Colchicines are not
tolerated.

Probenecid :-

It is a uricosuric drug. It blocks active transport of organic acid by OATP

in renal tubules. ( URAT-1, a member of OATP family)

Side effects :- Difficulty in digestion,

Rashes; Hypersensitivity reactions.

Toxicity signs :- Seizures ; Respiratory failure.

Uses :- It is used in chronic gout and hypercurecemia.

Allopurinol :- It is an analogue of hypoxanthine and is an inhibitor of

Xanthenes Oxidize enzyme.
→ →

Hypoxanthine Xanthine Xanthine Xanthine uric acid

Oxidase Oxidase

Allopurinol Xanthine Alloxanthine ……..> Inhibitioc

Oxidase

Side effects :-
1. Hyper sensitive reaction; fever, malaise; Muscle pain; rarely Steven –
Johnson syndrome; Gastric irritation.

Uses :- 1. Allopurinol is the drug of choice in chronic gout

1. Secondary hyperurecemia

Febuxostat :- It is non-purine xanthene’s oxidize inhibitor.

 It is an alternative drug of choice in the treatment of symptomatic gout.

Side effects :- Hepatotoxicity

Gastro intestinal disturbances

Recombinent urate oxidases

Eg :- Pegloticase ; Rasburicase

Mechanism of action :- These drugs oxidize uric acid to Allenton. Which is a

highly soluble product and will be excreted easily.

Side effects :- Anaphylactic reactions

Methemoglobinemia

Hemolytic (Especially in individuals with glucose 6- PO 4

dehydrogenase deficiency)

Point of interest:-

Colchicines are also indicated in Mediterranean fever

 First line treatment for acetic gout is with Non – Steroidal Anti –
Inflammatory Drugs.

Self assessment questionnaire:

11. Which one of the following is a uricosuric drug?

A.Probenecid B. Allopurinol

C. Colchicine D. All the above

12.Pegloticase is a

A. Uricosuric drug B.Recombinant Urate Oxidase

C.Cox Inhibitor D. None of the above

13.Colchicine is also indicated in

A.Mediterranean fever B.Rheumatic fever

C.Drug induced fever D. All the above

14. Febuxostat is

A. Non purine Xanthine Oxidase inhibitor

B. Purine xanthine oxidase inhibitor

C. Non purine Xanthine Oxidase promoter

D. Purine Xanthine Oxidase Promoter

15. Source of colchicine is colchicum autumn ale (True/False)

Summary :-

Non- Steroidal anti-inflammatory drugs can be classified as Non-

selective COX inhibitors, preferential COX2 inhibitors; selective COX 2
inhibitor .

Pharmacological effects of Aspirin are dose- dependent overdose of aspirin

causes Salicylate poisioning. Ibuprofen is a propionic acid derivative and
Mefanamic acid is an Anthranlic acid derivative piroxicam is a long acting
NSAID. Indomethacin is a potent PG synthesis inhibitor.

Anti rheumatic drugs are classified into disease modifying drugs and adjunct
drugs methotrexate, Azathioprine are non-biological drugs Etanerecpt;
anaconda are biological drugs corticosteroids are the adjunct drugs. Antigun
drugs are classified as drugs used in acute gout and chronic gout. NSAIDS are
indicated in acute gout. Probenecid and allopurinol are indicated in chronic
gout.

Answer Key:

QNo Answer
1 A
2 B
3 A
4 False
5 1-C,2-A,3-B
6 A
7 D
8 A
9 A
10 True
11 A
12 B
13 A
14 A
15 True

Terminal question :-

1. Explain Mechanism of action of Colchicines

2. Discuss Pharmacology of aspirin

Activity:- 5M

1. Give classification of anti- gout drugs

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