Analgesic and

Antirheumatic Drugs
 I General Consideration
• Inflammation is a protective response to tissue injury.
• Inflammation is triggered by the release of chemical
mediators from injured tissues and migrating cells.
• Specific chemical mediators include histamine, 5-HT,
PGs, LTs, brandykinin, interleukin-1. LTs "leukotrienes", PGs "prostaglandins"
• nonsteroidal anti-inflammatory drugs(NSAID) or non-
narcotic analgesics. Non-Narcotic: don't trigger sleeping
• effects: antipyretic, analgesic and anti-inflamatory
activities. analgesic "pain killer"

• mechanisms of actions: reduction of PG biosynthesis by

inhibition of cyclooxygenase.*

Non-steroidal= anti-cyclooxygenase enzyme

 COX
COX-1: gastrointestinal tract, kidney, platelet
COX-2: inflammation.
COX-3: present in CNS
1. antipyretic effects:
Effect:
• reduction of body temperature in patients with
fever
• no effect on normal body temperature
Mechanism:
reduction of PGs biosynthesis via inhibition of
cyclo-oxygenase pathway for PGs synthesis to
lower body temperature in patients with fever. *
 pathogens or toxins
↓(+)
PMNs
↓
pyrogen release
↓(+)
hypothalamus
↓
PG E2 synthesis and release
↓(+)
body temperature-regulating center in hypothalamus
↓
set point for body temperature↑
↓
heat production↑and heat dissipation↓
↓
body temperature↑(fever)
Use: high fever.

• Antipyretics decreases only high body

temperature by inhibition of PGs biosynthesis
and has no effect on normal body temperature.
2. analgesic effect
Effect:
• weak, only effective on mild to moderate dull
pain
• little effect on colicky pain and sharp pain
(intense pain)
• no narcotic.
Mechanism:
• relieving pain via inhibition of PGs
biosynthesis*
Use:
• common dull pains.
e.g. headache, toothache, neuralgia, muscular
pain, arthralgia and dysmenorrhea etc.

Arthralgia: joint pain

Neuralgia: Nerve Pain
Dysmenorrhea: pain caused by menstrual periods
3. anti-inflammatory effect
Effect:
relieving inflammatory symptoms
(pain and swelling).
Mechanism:
inhibition of PG synthesis.*
• Classification:
A) Non-selective COX-Inhibitors: Most NSAIDs as:
1-Salicylates: Aspirin
2-Pyrazolones: Azapropazone
3- Propionic acid derivatives: Naproxen, ibuprofen, ketoprofen
4- Indoles: Indomethacin, sulindac
5- Fenamates: Mefenamic acid
6- phenylacetic acid derivatives: Diclofenac
7- Oxicams: Piroxicam, tenoxicam
B) Selective COX-2 Inhibitors: celecoxib, rofecoxib
C) Selective COX-3 Inhibitors: Paracetamol
【classification I】
1. salicylates
aspirin
2. aminophenol derivatives
acetaminophen
3. pyrazolon
phenylbutazone
4. other organic acids
indomethacin etc.
【classification II】
1. non-selective COX inhibitors: aspirin etc.
antipyretic
analgetic
antiinflammatory
antiplatelet
2. COX-2 selective inhibitors:
celecoxib,etoricoxib,meloxicam
antipyretic
analgetic
antiinflammatory
 Ⅱ Salicylates
Acetylsalicylic acid (ASA, aspirin)
【pharmacokinetics】
• metabolized in liver by the hydrolyzation to
salicylate and acetic acid by esterases .
• half life is 3.5 h,
【pharmacologic effects】
• Aspirin is rapidly deacetylated by esterases in body,
producing salicylate which has anti-inflammatory,
analgesic,and antipyretic effects.
• Aspirin irreversibly acetylates cyclooxygenase to
inhibit the enzyme activity.
1. antipyretic action: rapid and moderate in potency.
2. analgesic effects: effective for mild, moderate dull pain.
3. antiinflammatory effects: to treat rheumatoid and
rheumatic arthritis, symptomatic relief.
[Link] effects: to inhibit platelet aggregation

Due to its irreversible inhibition of cyclooxygenase of cox 1

[Link] effects:

• increasing gastric acid secretion and

diminishing mucus protection to cause
epigastric distress, ulceration, hemorrhage
• resulting in retention of sodium and water to
cause edema and hyperkalemia
【therapeutic uses】
DOSAGE
1. hyperpyrexia: middle dose.
[Link] pain: e.g. headache, arthritis, dysmenorrhea
etc. middle dose.
[Link] fever and rheumatoid arthritis (first-line
drugs) in relatively large dose.
4. prevention of thromboembolism, stroke,
myocardial infarction in small dose. decreasing
incidence of transient ischemic attack and
unstable angina as well as that of coronary artery
thrombosis.
[Link] use of aspirin reduces incidence of
colorectal cancer.*
【adverse effects】
[Link] reaction: epigastric distress,
nausea, vomiting, gastric ulceration and bleeding.
taking aspirin with meal or with sodium
bicarbonate, taking enteric- coated aspirin.
2. hepatic damage: mild, reversible.
3. prolonging bleeding time due to inhibition of
platelet functions in small dose and reduction of
plasma prothrombin level in large dose.
[Link] or allergy.
[Link]’s syndrome:
• seen during viral infections fatal, especially in
children
• manifestations: fulminating hepatitis with
cerebral edema
• children should use acetaminophen instead.
[Link] toxication (salicylism):
• mild toxication: headache, mental confusion,
drowsiness, difficulty in hearing, vomiting
• severe toxication: hyperventilation, severe CNS
disturbulance, respiration depression and
marked alteration in acid-base balance
Medication: discontinuation of salicylates,
gastric lavage, relieving symptoms, intravenous
infusion of NaHCO3 and dialysis.
 Ⅲ Aminophenol Derivatives
Acetaminophen
Acetaminophen inhibits prostaglandin synthesis in
CNS,but less effect on peripheral cyclooxygenase.
• antipyretic and analgesic effects are similar to aspirin in
potency
• no anti-inflammatory activity.
Use: dull pain and hyperpyrexia., choice for children
with viral infections or chicken pox.
Adverse effects: skin rash and drug fever,
hypoglycemic coma, renal tubular necrosis and renal
failure in long-term administration, acute hepatic
necrosis in large dose.
 Ⅳ Other Organic Acids
Indomethacin
【pharmacologic effects】
• anti-inflammatory, analgesic and antipyretic effects
• more potent than aspirin as an anti-inflammatory agent
• inferior to the salisylates at dose tolerated by patients
with rheumatoid arthritis.
【therapeutic uses】
rheumatoid and rheumatic arthritis, not routinely for
analgesia and antipyresis because of its toxicity and
side effects.
【adverse effects】
35%-50% of patients report some adverse
effects and most adverse effects are dose-related.
1. gastrointestinal complaints.
2. CNS effects: frontal headache, dizziness, vertigo,
mental confusion etc.
3. hematologic effects: neutropenia,
thrombocytopenia, inpaired platelet functions, rare
aplastic anemia.
4. contraindication: in pregnancy or nursing women,
patients with psychiatric disorders, epilepsy,
parkinsonism, renal diseases, peptic ulcers

neutropenia: decrease of neutrophils

 Ibuprofen
• anti-inflammatory, analgesic and antipyretic activity.
• chronic treatment of rheumatoid and osteoarthritis.
• less intense of gastrointestinal effects than that of
aspirin.
 General Features &
Conditions to use antirheumatic
— Low doses are commonly used early in the course of
the disease
— Used when the disease is progressing & causing
deformities
— Used when the inflammatory disease is not
responding to NSAIDs
— Can not repair the existing damage , but prevent
further deformity
— Have no analgesic effects
— Slow onset their effects take from 6 weeks up to 6
months to be evident
 Hydroxychloroquine
Mechanism of action :

 Trapping free radicals

 Suppression of T lymphocyte cells

Pharmacokinetics
— Rapidly & completely absorbed following oral
administration.

— Penetrates into C.N.S. & traverse the placenta

— Metabolized in liver
 Adverse Effects
Pruritus pruritus: scraping Headaches

GIT upset Blurred

vision
Cinchonism: tinnitus, blindness, CNS manifestations

Discoloration
Irreversible
of nail beds
retinal
& mucous
damage
membranes
Methotrexate
— Immunosuppressant drug
— Used mainly as chemotherapy for cancer
treatment

— Doses of methotrexate as antirheumatic are

much lower than those needed in cancer
chemotherapy

— Given once a week

 Mechanism of action

 Inhibition of T-Cells ( cell-mediated immune

reactions)

folic acid inhibition

Nausea
Cytopenia

Liver Adverse Effects

cirrhosis

Acute
Mucosal pneumonia
–like
ulceration syndrome
Biologic disease modifiers
— Genetically engineered drugs that are used to
modify imbalances of the immune system in
autoimmune diseases.
— Some of these agents block, or modify the activity
of selected cells in the immune system, while
others –including tocilizumab work by blocking
certain messenger proteins known as cytokines ,
that send signals between those cells.
Classification of biologic disease
modifiers
 T-cell modulating drug ( abatacept )

 B-cell cytotoxic agent ( rituximab )

 Anti-IL-6 receptor antibody ( tocilizumab) IL-6: interleukin 6

 TNF- blocking agents ( infliximab)

Tocilizumab
— IL-6 receptor inhibitor
— Binds to membrane IL-6 receptors ,blocking the
activity of IL-6 in mediating signals
— Half-life is dose dependent (11-13 days )

— Given as monthly IV infusion

— Used as monotherapy in adult with rheumatoid
arthritis or in children over 2 years with systemic
juvenile arthritis
Cont.
— Can be given in combination with methotrexate

or other non biologic anti-rheumatic drugs in

patients with active rheumatoid arthritis .

Side effects
— Severe infusion reactions
— Serious infections ( bacterial,
tuberculosis ,fungal
— Increase in cholesterol level
— Increase in liver enzymes
— Decrease in WBCs

— Blood tests will be used monthly for increase in

cholesterol, liver enzymes & decrease in WBCs
Drug Interaction
— In combination of tocilizumab with some drugs such
as cyclosporine or warfarin

CYP450: Cytochrome P450

{IL-6 inhibits CYP450, this enzyme is essential for the
metabolism of cyclosporine or warfarin.
Tocilizumab which act as inhibitor for IL-6 ,resulting in
restoring the activity of the enzyme }
Tumor necrosis factor –α

(TNF-α ) blocking agents

 Infliximab

A chimeric antibody ( 25% mouse,

75% human)

chimeric antibody has 2 tails: one tail linked to

rheumatoid, and the other tail is free
Mechanism of action
— Binds to human TNF-α resulting in inhibition of
its action as a mediator in inflammatory diseases

Exam questions: mechanism of actions, side effects, drug interactions

Comparison between NSAIDs &
DMARDs
DMARDs NSAIDs
— Slow onset of action used in — Rapid onset of action used in
chronic cases when acute cases to relief
deformity is exciting inflammation & pain

— Arrest progression of the — No effect

disease
— Can not stop formation of
— Prevent formation of new new deformity
deformity
Thank you