Learning Objectives:

Classify NSAIDs.
Describe their mechanisms of action. List their therapeutic uses, side effects,

contra-indications and toxicity.

Discuss Paracetamol.

PAIN
It is an unpleasant sensation that can be acute or chronic.

It is subjective, so physicians must rely on the patients

perception & description of his or her pain.

ANALGESICS
It is a Greek word that means - an = without. - algesia = Pain Drugs that relieve pain due to multiple causes.

They are classified into 2 major groups:

Opioid or narcotic analgesics.

Non-opioid or analgesics/antipyretics.

ANALGESICS
Groups of drugs that can be used to combat pain but they are not classified as analgesics; e.g.: o Ergot alkaloids (Ergotamine) used for migraine.

o Nitrates (Nitroglycerine) used for angina pectoris.

Analgesic Antipyretics
Mild analgesics that works on subcortical centers,
they include: 1. Non-Steroidal Anti-inflammatory Drugs (NSAIDs) (Acetyl salicylates, Ibuprofen ..) 2. Paracetamol.

I. Non-steroidal antiinflammatory drugs NSAIDs

NSAIDs are group of drugs that share in common the capacity to induce: Analgesic effect.

Antipyretic effect.
Anti-inflammatory effect.
Peripheral action

Central action

3A

Non-steroidal anti-inflammatory drugs NSAIDs

Classification of NSAIDs:
Non-selective COX inhibitors

Selective COX-2 inhibitors

20 %

80 %

TXA2

PGI2

INFLAMMATION

NSAIDs
Mechanism of action of NSAIDs:
Acetyl salicylic acid causes irreversible inhibition

of both COX-1 and COX-2 enzymes.

Other NSAIDs cause competitive reversible

inhibition of COX enzymes.

Celecoxib is a selective COX-2 inhibitor.

NSAIDs
Non-selective COX inhibitors
1. Salicylates, e.g. acetyl salicylic acid.
2- Other NSAIDs:
Propionic acid derivatives e.g. Ibuprofen & naproxen.
Oxicams e.g. piroxicam (Feldene)

Diclofenac (Voltaren).
Indole derivatives e.g. Indomethacin .

Salicylates
Local action
Salicylic acid:
keratolytic.

Systemic action
Acetyl salicylic acid

Salicylic acid

Salicylates
Pharmacokinetics:
Salicylates are weak organic acid 1. They are rapidly absorbed from stomach & upper SI. 2. They are highly bound to plasma proteins (albumin). (CI: Warfarin) 3. Their rate of renal excretion is enhanced by alkalinization of urine.

Salicylates
Sodium Salicylate & Acetyl salicylic acid

Pharmacological Actions:
1. Analgesic action: (Subcortical level)
a) By raising the threshold to painful stimuli at the

level of the thalamus (central action)

b) Anti-inflammatory action (peripheral action)

(Anti-PGs that are mediators of pain & inflammation)

Salicylates
Sodium Salicylate & Acetyl salicylic acid

Pharmacological Actions: 2. Antipyretic action:

a) Inhibiting PGs synthesis (centrally- PG E1, PGE2 & IL-1).

b) Acting on heat regulating center in the hypothalamus promoting loss of heat by: - Vasodilatation of cutaneous BVs stimulating radiation - Increasing sweating & encouraging evaporation

Salicylates
Sodium Salicylate & Acetyl salicylic acid

Pharmacological Actions:
3. Anti-inflammatory & anti-rheumatic:
Relieve of most types of pain; muscular, joint, mainly through:
(******)

Decrease PGs Synthesis

Inhibition of chemotaxis
Decrease Interleukin-1 production

Salicylates
Sodium Salicylate & Acetyl salicylic acid

Pharmacological Actions: 4. Action on the GIT: Nausea & vomiting

Direct due to irritation of gastric mucosa by

salicylic acid

Decrease protective PGs Synthesis

Salicylates
Sodium Salicylate & Acetyl salicylic acid

Pharmacological Actions: 4. Action on the GIT:

Gastric ulceration & bleeding

Na HCO3

Salicylates
Sodium Salicylate & Acetyl salicylic acid

Pharmacological Actions:
5. Uricosuric action:

Small doses: (less than 5 g /day) Uric acid retention due to competition with its
secretion in PCT .

Large doses: (greater than 5 g/day) - Inhibit the renal reabsorption by PCT.
- Increasing uric acid excretion, - Decreasing its plasma level

Uricosuric action
This effect is enhanced if the urine is made alkaline.

Salicylates
Sodium Salicylate & Acetyl salicylic acid

Pharmacological Actions:
6. Effect on the blood:

Erythrocyte sedimentation rate (ESR). Small dose: (-) platelet aggregation as

(-) of platelet COX-1
Reduces production of TXA2

Prolongation of bleeding time

Anti-platelet

Salicylates Therapeutic Uses:

Prophylaxis & treatment of vascular

thrombosis, as myocardial

infarction & TIA: Aspirin in low dose

(75 - 300 mg/ day ) inhibits platelet aggregation i.e. anti-platelet (anti-thrombotic)

Very important use

Salicylates Therapeutic Uses:

Acute rheumatic fever [6-12g/day]
(to relieve fever, arthritis but not the cardiac complications).

Salicylates Therapeutic Uses:

Antipyretic in fever (non-specific). Analgesic (headache, toothache, myalgia &
arthralgia, mild surgical pain.).

Common cold (lowers fever, relieves

headache & muscle aches).

Salicylates Side effects & Toxicity:

GIT:
Gastric irritation, bleeding & ulceration.

Hypersensitivity:
(Inhibition of COX & shift to LTs) bronchoconstriction, urticaria, angioneurotic oedema.

CNS:
1.
disturbance, N, V, D, sweating). 2. Reye's syndrome: severe hepatic injury & encephalopathy in viral infections in both children and adolescents.

Salicylism (Headache, mental confusion, ringing of ears, visual

Kidney : Chronic use

Nephropathy

Acute salicylate poisoning

Salicylates
Acute salicylate poisoning :
Clinical picture:
G.I.T: Nausea, Vomiting. C.N.S: Restlessness, Tremors, Convulsions, Coma. Hemorrhages. Acid/ base imbalance.

Salicylates
Acute salicylate poisoning :
Treatment:
Gastric lavage with NaHCO3

Alkalinization of urine by intravenous

injection of Na HCO3 to increase the excretion of salicylates. For hemorrhage: Vitamin K or blood transfusion

Hemodialysis in severe cases.

Contraindications:
Patients with peptic ulcer.

Salicylates

Patients having hypersensitivity reactions to salicylates. Bleeding tendency. Patients taking anti-coagulants. Children with viral infections e.g. chicken pox or

influenza. Gout: in small dose.

Selective COX-2 Inhibitors

Celecoxib (Celebrex):
It is a selective COX-2 inhibitor that spares COX-1, thus it does not inhibit synthesis of protective PGs in the gut in usual therapeutic doses.
- Hence, its anti-inflammatory effect is associated

with less GI adverse effects.

- Has no anti-platelet action

Analgesic Antipyretics
II. Paracetamol
A. A. with No anti-inflammatory action.

WHY ??
It effectively inhibits PG synthesis in the CNS resulting in analgesic & antipyretic effects But it is a weak PG inhibitor in peripheral tissue thus has no or weak antiinflammatory effect.

Paracetamol
Mechanism of action:

Analgesic, antipyretic: as it inhibits

COX enzyme centrally

No (weak) anti-inflammatory action (doesnt inhibit COX peripherally)

No uricosuric action

Paracetamol
Commonly used instead of aspirin in
cases of:
- Peptic or gastric ulcers (it causes no GIT disturbances)
- Bleeding tendency (it does not affect platelet function)

- Allergy to salicylates.
- Viral infections in children (to avoid Reyes

syndrome).
- Pregnancy.

Paracetamol

Pharmacokinetics:
Hepatic metabolism

Liberation of free radicals scavenged by Glutathione.

Paracetamol
The usual dosage for adults and children aged 12 and over is 325 650 mg every 6 hours as needed

No more than 4 g (4,000 mg) should be taken in

24 hours, to avoid toxicity in the form of: - Liver damage (with acute over dosage). - Nephropathy (long use)
In case of acute paracetamol poisoning,

N-acetyl cysteine
is a specific antidote and should be given as early (it contains -SH group)

as possible