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ANALGESICS
Analgesics are drugs used to relieve pain due to multiple causes.

Classification of Analgesics

Non-Opioid analgesics Opioid analgesics

Used in mild to moderate pain Used in moderate to severe pain
- Non-Steroidal Anti-inflammatory drugs - Morphine
- Paracetamol - Synthetic Opioids.

Non-Steroidal Anti-inflammatory Drugs and Paracetamol

• NSAIDs are a group of heterogeneous agents that share in common the capacity
to induce Anti-inflammatory, Analgesic and Antipyretic effects.
• Paracetamol is an Analgesic-Antipyretic with No Anti-inflammatory action.

Cyclo-oxygenase (COX) enzymes:

• Cyclo-oxygenase (COX) enzyme catalyses the conversion of Arachidonic acid to
Endoperoxides: This result in Prostaglandin (PG) and Thromboxane-A2
production.
• There are two types of cyclo-oxygenase enzymes:
- COX-1 is constitutive (present normally in tissues regulating its physiological
functions). It is responsible for forming protective PGs in GIT and Kidney.
- COX-2 is inducible (formed during inflammation).

Mechanism of action of NSAIDs and Paracetamol:

• Acetyl Salicylic acid (Aspirin), the prototype NSAID induces irreversible
inhibition (acetylation) of both COX-1 and COX-2 enzymes.
• Other NSAIDs cause competitive reversible inhibition of COX enzymes.
• Celecoxib and Rofecoxib are selective COX-2 inhibitors.
• Paracetamol inhibits PG synthesis in CNS resulting in Analgesic and Antipyretic
effects but is a weak inhibitor of PG in periphery. Thus, Paracetamol has No
Anti-inflammatory effect.

Acetyl Salicylic acid (Aspirin)

Pharmacological actions and Therapeutic uses of Aspirin:
1- Anti-inflammatory:
1) Decreases vasodilator PGE2 and PGI2 thus reducing the vasodilatation and
edema of inflammation.
2) Anti-oxidant effect (free radical scavenger).
Uses: - Rheumatic fever, Rheumatoid arthritis, Bursitis
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2- Analgesic effect:
1) Peripheral effect: Through its anti-inflammatory effect, it decreases PGs
which sensitize nerve endings to Kinins (released during inflammation)
thus increasing pain threshold.
2) Central effect: Decreases PGs thus inhibiting pain stimuli at sub-cortical
sites.
Uses: - Mild to moderate pain especially secondary to inflammation; Arthritis,
Dental pain, Headache (decreases cerebral vasodilator effect of PGs), Dysmenorrhea
and Postpartum pain.
3- Antipyretic effect:
1) Decreases PGE2, which is generated in response to inflammatory pyrogens
(e.g. Interleukin-1) and which is responsible for elevating the
hypothalamic set point for temperature control.
Uses: - Antipyretic (Lowers body temperature) in fever.
4- Antiplatelet effect:
1) Irreversible inhibition of COX enzyme in platelets results in inhibition of
TXA2 synthesis and inhibition of platelet aggregation.
Uses: - Prophylaxis against Transient Ischemic Attacks, Myocardial infarction and
Unstable Angina.

Pharmacokinetics of Aspirin:
• Aspirin is given orally and is rapidly absorbed since it is largely unionized in the
acidic medium of stomach.
• Bound to albumin and displaces other bound drugs, thereby potentiates Warfarin
anticoagulant effect.
• 75% metabolized in liver.
• Alkalanization of urine increases its excretion (useful in toxicity).
• Elimination follows first order kinetics with low doses (600mg); (t1/2 = 4hrs) and
follows saturation kinetics with higher doses (t1/2 >15hrs).

Dosages:
• Anti-platelet effect: - 150 (75 – 325) mg/day.
• Analgesic and Antipyretic: - 300 mg, 1-2 tablets when necessary.
• Anti-inflammatory: - 4-8 grams/day.

Adverse effects (Common particularly in the elderly):

- Gastro- intestinal side effects: - Dyspepsia, nausea, vomiting, gastritis, ulceration
with risk of hemorrhage (due to direct irritant effect on the mucosa and decreased
protective PGs).
- Renal damage (Analgesic nephropathy): due to decreased renal vasodilator PGs.
- Hypersensitivity reactions: Skin rash, Rhinitis, Asthma especially in asthmatics
and patients with nasal polyps (Aspirin diverts arachidonate metabolism from
cyclo-oxygenase to lipoxygenase pathway increasing chemotactic LTB4 and
spasmogenic LTs).
- Hyper-uricemia in patients with Gout (in low doses): Competes with uric acid for
excretion by organic acid secretory mechanism in renal tubules.
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- Reye’s syndrome (Encephalopathy and liver damage) in children with fever due
to viral infection.
- Increased bleeding tendency: Anti-platelet effect.
- Chronic toxicity (Salicylism): Large doses used for long periods lead to dizziness,
tinnitus and gastric upset.
- Acute toxicity: Respiratory alkalosis (hyperpnoea and washing out of CO2)
followed by respiratory acidosis due to respiratory depression and metabolic
acidosis (due to accumulation of acidic metabolites).

Other NSAIDs

Ibuprofen
• Effective and better tolerated (decreases incidence of side effects than other
NSAIDs).
• First choice in inflammatory joint disease.

Naprofen
• It is related to Ibuprofen, more potent with moderate risk of side effects.
• It is longer acting (given twice daily).

Piroxicam
• Potent and long acting (t1/2 = 45 hours); given once daily.
• No accumulation in the elderly or in patients with renal impairment.
• 20% of patients develop side effects e.g. GIT bleeding.

Diclofenac
• It is very potent and used in:
1) Long-term treatment of chronic inflammatory musculoskeletal disorders e.g.
Rheumatoid arthritis, Osteoarthritis and Ankylosing Spondylitis.
2) Renal colic and Post-operative pain.
3) An ophthalmic solution is used for post-operative inflammation.

Indomethacin
• Potent, but due to its serious adverse effects, its use is limited to:
1- Acute Gouty arthritis.
2- Rheumatoid arthritis, Ankylosing Spondylitis.
3- Post-operative pain.
4- Patent ductus arteriosus (inhibits PG synthesis closing the ductus).
Adverse effects of Indomethacin:
1) GIT: Nausea, vomiting, ulcer, bleeding.
2) CNS: Dizziness, confusion, ataxia, severe headache (cerebral vasodilatation).
3) Salt and water retention (antagonize antihypertensives) and hyperkalemia. It
aggravates pre-existing renal failure.
4) Aplastic anemia.
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Selective COX-2 inhibitors: Colecoxib and Rofecoxib

• Colecoxib and Rofecoxib are selective COX-2 inhibitors that spare COX-1, thus
they do not inhibit synthesis of protective PGs in the GIT. Hence they have less
GIT side effects.
• Colecoxib is structurally related to Sulphonamides. Therefore its use might be
associated with development of skin rash.

Paracetamol (Acetaminophen)

• Analgesic-Antipyretic with No Anti-inflammatory action.

• Preferred to Aspirin in:
1.Patients allergic to Aspirin.
2.Peptic ulcer (No GIT disturbances).
3.Gout (Aspirin may cause hyper-uricemia).
4.Viral infection in children (to avoid Reye’s syndrome with Aspirin).
5.Bleeding disorders (does not affect platelet function).
• Paracetamol is ineffective in high fever because excess free radicals generated by
leucocytes antagonize Antipyretic effect of Paracetamol.
• Dose: - It is given orally (500mg 2-3 times daily) and is metabolized in the liver.

Paracetamol hepatotoxicity:
• Toxic doses (15 grams or more) cause nausea and vomiting, followed in 24-48hrs
by potentially fatal liver damage due to generation of a toxic metabolite.
• In toxic doses, saturation of normal conjugation enzymes results in conversion of
the drug by mixed function oxidases to a toxic metabolite (N-acetyl-p-
benzoquinone). If this toxic metabolite is not inactivated by conjugation with
Glutathione, it reacts with cell proteins and kills the cell.
• Treatment:
- Agents which increase Glutathione (N-acetylcysteine orally or I.V).
- Agents which increase conjugation reaction (Methionine) can prevent liver
damage if given early.

DRUG THERAPY OF GOUT

• Gout is a metabolic disorder characterized by increased body stores of uric acid.

• Hyperuricemia results in deposition of urate crystals in tissues (kidney and joints)
causing pain and inflammation.
• The inflammatory reaction involves migration of leucocytes that phagocytose the
urate crystals. This results in production of inflammatory mediators (PGs and
Chemotactic LTB4 that attracts neutrophils) and oxygen metabolites that induce
tissue damage.
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Treatment strategies include:

• Reducing inflammation during acute attacks: - Colchicine (specific anti-
inflammatory in Gout) or Indomethacin (non-specific anti-inflammatory).
• Increasing renal excretion of uric acid with Uricosuric drugs (Probenecid,
Sulphinpyrazone).
• Inhibiting the synthesis of uric acid by Xanthine oxidase inhibitors (Allopurinol).

v Acute Gout: - Indomethacin or Colchicine.

v Chronic Gout: - Allopurinol or Uricosurics.

N.B: Allopurinol or Uricosuric agents are of no value in acute Gouty Arthritis and may
precipitate an acute attack (lowering of serum uric acid causes its withdrawal from tissues
initiating an inflammatory reaction).

Pathophysiology &Treatment Strategies of Gout

Purines

Hypoxanthine

Xanthine oxidase (-)

Allopurinol
Xanthine
(-)
Xanthine oxidase

Uric acid

Deposition in tissues Renal excretion

(+)
Uricosuric agents
Inflammatory reaction eg. Sulphinpyrazone
Probenecid.

PGs Leukocyte migration LTB4

and Urate crystals Chemotactic
phagocytosis. attracts more
(-) leucocytes.
(-) (-)
Indomethacin Colchicine
Non-specific Specific anti-inflammatory
Anti-inflammatory in Gout.
in Gout.
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Colchicine
Mechanism of action:
1- It is a selective inhibitor of microtubule assembly reducing leukocyte migration
and phagocytosis.
2- It may also reduce production of leukotriene-B4 (chemotactic for neutrophils).

Indications:
1) Acute Gouty Arthritis: 1mg then 0.5mg/2hrs until pain is relieved or nausea
and diarrhea occur.
2) Mediterranean fever.

Toxicity:
1) GIT disturbances especially diarrhea.
2) Alopecia.
3) Liver and kidney damage.

Allopurinol
Mechanism: - Inhibits Xanthine oxidase enzyme which converts hypoxanthine to
xanthine and xanthine to uric acid. This results in decrease in uric acid synthesis
decreasing urate pools in the body.

Dose: 100 - 300mg/day orally.

Adverse effects:
1. Precipitating acute attacks of Gout.
2. GIT upsets.
3. Hypersensitivity reactions.
4. Peripheral neuritis (rare).

Uricosuric agents (Probenecid)

Mechanism: - Competes with uric acid in the renal tubule for reabsorption by the weak
acid carrier mechanism resulting in increased uric acid excretion.

Dose: 0.5 – 1mg/day.

Adverse effects:
1- Acute attacks of Gout.
2- GIT disturbances.
3- Hypersensitivity reactions.
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DRUG THERAPY OF RHEUMATOID ARTHRITIS

• Rheumatoid Arthritis is an auto-immune disease characterized by inflammation

and subsequent tissue damage. Progression of the disease results in deformities.
• The aim of therapy is to relieve pain, muscle spasm, joint stiffness and to suppress
inflammation:
A- First-line drugs: NSAIDs: - Analgesic and Anti-inflammatory.
B- Second-line drugs: Disease-modifying: slow acting agents: - Gold salts,
Penicillamine, Sulfasalazine, Antimalarial drugs and Methotrexate.
C- Third-line drugs: Corticosteroids: - They are too toxic for chronic use and should
be reserved for temporary control of severe exacerbation of inflammatory joint
conditions.

isease-modifying Anti-rheumatic Drugs (DMARDs): Slow-acting agents

I- Methotrexate: - It is an immunosuppressant cytotoxic drug that acts by

reducing the inflammatory response.
Adverse effects:
- Bone marrow suppression.
- Hepatotoxicity.
- Teratogenicity.

II- Gold salts: - They alter the activity of macrophages, inhibit lysosomal
enzyme activity and reduce Histamine release.
Adverse effects:
- Dermatitis.
- Bone marrow suppression.
- GIT disturbances with oral Gold compounds.

III- Antimalarial drugs (Chloroquine and Hydroxychloroquine):

• Interfere with T-lymphocyte activity.
• Decrease leukocyte chemotaxis.
• Stabilize lysosomal membranes.
• Interfere with DNA and RNA synthesis.
• Trap free radicals.
Adverse effects:
- Dermatitis.
- Bone marrow suppression.
- Retinal degeneration.

IV- Penicillamine: - It is a copper-chelating agent: The Penicillamine-copper

complex acts as superoxide dismutase inhibiting formation of toxic oxygen
metabolites.
Adverse effects: - Renal damage - Aplastic anemia.
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V- Sulphasalazine: - It is a scavenger of toxic oxygen metabolites produced

by neutrophils.
Adverse effects:
- GIT upset.
- Headache.
- Neutropenia.