HOW THE ANALGESIC AND ANTIPYRETIC WORK ON THE HUMAN BODY(Non-opioid analgesics, NSAID).
•Analgesic:-
Antipyretic can produce relief of pain and lowering of body temperature. These drugs relieve pain of lesser intensity, like toothache and muscle pain. But they do not relieve severe pain like visceral pain, which is facilitated by opioid analgesics. Also, these drugs do not produce addiction. All these drugs have an anti-inflammatory effect. So they are called as non - steroidal anti-inflammatory drugs (NSAID). Since they act without interacting with opioid receptors, they are called non-opioid analgesics.
•NSAID and prostaglandin synthesis:-
The three significant actions of NSAID (analgesic, antipyretic and anti-inflammatory) are mediated through prostaglandin (PG) synthesis inhibition.
Phospholipid ( of cell membrane) >>>>Arachidonic acid >>COX-I cox-2>> Prostaglandins>> INFLAMMATION
l. During pain, fever and inflammation, arachidonic acid (AA) is liberated from phospholipid fraction of cell membrane.
2. The enzyme cyclooxygenase (COX) converts arachidonic acid to prostaglandins. The prostaglandins formed are responsible for inflammation.
3. There are two forms of the enzyme cyclooxygenase viz. Cyclooxygenase -l (COX-I) and Cyclooxygenase -2. (COX-2). COX-I is always present and it is found in blood vessels, stomach and kidney. But COX-2 is induced only during inflammation.
4. Drugs like aspirin are non - selective COX inhibitors, inhibiting both COX-I and COX-2. Aspirin inhibits COX irreversibly by acetylation of this enzyme.
5. Certain drugs inhibit COX-2 selectively e.g.Celecoxib Rofecoxib and valdecoxib.
•HOW MANY TYPE OF CLASSIFICATION OF ANALGESIC AND ANTIPYRETIC.
These are six types of classification with their subparts
1. Salicylates and congeners | Asprin.
2. Para - aminophenol derivative:-
Paracetamol.
3.Propionic acid derivative:- Ibuprofen
Ketoprofen
Flurbiprofen
4.Aryl - acetic acid derivative
Diclofenac
Acelofenac
5. Oxicam derivative
Proxicam
6.Indole derivative
Indomethacin
•HOWS THE SALICYLATES WORK (Asprin as the prototype) •Pharmacological actions : The pharmacological actions mentioned are those Of salicylates in general and those of aspirin in particular.
1. Analgesic effect:- Salicylates are effective only in dull - aching pain of low intensity. They do not relieve severe pain like visceral pain. They act by preventing the integration of pain sensation in the thalamus. But they do not alter the emotional reaction to pain•
2. AAntipyreticeffect:- Salicylates do not lower average temperature. Only the elevated temperature is lowered.
Mechanism:
a) The hypothalamic heat-regulating center (thermostat of the body) is set for a higher temperature in fever. This is reset fora lower temperature by salicylates
b) Salicylates produce sweating which also lowers body temperature.
3. Respiration: Salicylates stimulate respiration a) directly by stimulating the respiratory center b) indirectly through carbon dioxide (produced by increased oxygen utilization of skeletal muscles).
4. Gastrointestinal tract Salicylates produce nausea and vomiting due to a) direct irritation b) stimulation of chemoreceptor trigger zone. Salicylates can also cause gastric ulceration and bleeding.
5. Anti-inflammatory and anti-rheumatic effects: Salicylates have powerful anti-rheumatic effects. This effect is produced by reducing pain and inflammation of the joints.
6. Immunological effect: Salicylates inhibit the antigen-antibody reaction, and so prevent the release of histamine.
7. Uricosuric effect: Salicylates promote the excretion of uric acid. This effect is produced by inhibiting the reabsorption of uric acid in the proximal tubule.
8. Cardiovascular system: No effect at the usual dose. Toxic doses produce paralysis of the vasomotor center.
9. Blood : Salicylates lower erythrocytic sedimentation rate (ESR) which is high in rheumatic fever. They also decrease the prothrombin level of plasma.
10. Antiplatelet action: Platelet aggregation is inhibited significantly by Asprin. This effect helps prevent myocardial infarction.
11. Endocrines: Salicylates stimulate the release of adrenaline from the adrenal medulla. They also stimulate the release of adrenocorticotrophic hormone (ACTH). They interfere with the binding Of thyroxine with plasma proteins. This free thyroxine depresses the secretion of thyroid-stimulating hormone (TSH).
12 Metabolic effect. Salicylates produce uncoupling of oxidative phosphorylation. They have hyperglycen1ia and glycosuria. They inhibit the synthesis but enhance the breakdown of fatty acids.
13. Local actions : Salicylates (especially salicylic acid and methyl salicylate) have antiseptic, fungistatic and keratolytic effects.
Absorption, fate and excretion : Salicylates are absorbed from the stomach and small intestine. They are bound to plasma proteins. They are mainly concentrated in the liver, heart, muscle and brain. They are metabolised in liver by conjugation with glycine and glucuronic acid. The metabolic products are primarily excreted through urine.
•Adverse reactions :
l. Gastrointestinal disturbances like nausea, vomiting, and diarrhea. Also ulceration, perforation and hemorrhage are produced.
2. Intolerance leading to skin rashes of various types.
3. Bone marrow depression leading to agranulocytosis, thromboplastin anemia.
4. Fatty infiltration of liver and kidney.
5. Salicylism is characterized by headache, tinnitus—Difficulty in hearing, drowsiness, lethargy and confusion.
•Preparations and dose :
Asprin tablets-300 to 600 mg. every 6 to 8 hrs. for analgesic effect; 4 to 6 e. 0 per day for anti-inflammatorv effect: 75 to 30() mg. daily for antiplatelet action. Therapeutic uses :
1. As an analgesic for light and moderate pain.
2. As an antipyretic in case of fever.
3. As an anti-rheumatic.
4. In osteoarthritis.
5. For post-myocardial infarction.
•PARACETAMOL :
It is a para-amino phenol derivative. It has analgesic and antipyretic effects like salicylates. But it does not have anti-inflammatory and uricosuric effects. Also it does not produce gastrointestinal irritation and ulceration. Paracetamol is well absorbed on oral administration. It is metabolised in liver and excreted in urine in a conjugated form.
•Dose: 300 to 600 mg. as tablets. Maximum dose 2.5 g. Paracetamol overdosage is treated with N-acetyl cysteine.
•INDOMETHACIN
: It is a derivative of indole acetic acid. It has an analgesic, antipyretic and anti-inflammatory activity. It is much effective in the treatment of rheumatoid arthritis and gout. It is administered at a dose of 50 to 150 mg.-daily in divided doses. It is commonly used for medical closure of patent ductus arteriosus (PDA). Sulindac is a fluorinated derivative of indomethacin.
•IBUPROFEN (Brufen):
It is a synthetic compound having analgesic and mild anti-inflammatory effects. It produces less gastric irritation than aspirin. Dose : 0.4 to 0.6 g. three times daily by oral route.
•MEFENAMIC ACID :
It is a derivative of anthranilic acid. It has a weak analgesic efféct. It produces toxicities like gastrointestinal disturbances, skin rashes and blood dyscrasias.
•PIROXICAM :
It belongs to the group of oxicams. It has an analgesic, antipyretic and anti-inflammatory effect. But it does not produce gastric irritation. It is well absorbed on oral administration. Also, it has a prolonged effect. It is used in rheumatoid arthritis and acute gout. Dose: 20 mg. once daily.
•DICLOFENAC :
It is an aryl acetic acid derivative. It is an analgesic, antipyretic and anti-inflammatory drug. Il inhibits prostaglandin synthesis. Also, it has a fast antiplatelet action. Since it accumulates in synovial fluid it has more prolonged activity. It is used in rheumatoid arthritis and osteoarthritis.
•KETOROLAC :
It is a pyrrolo-pyrrole derivative. It has a pontent analgesic and moderate anti-inflammatory activity It inhibits prostaglandin synthesis. Also, it inhibits platelet aggregation for short periods. It is helpful in post-operative pain and acute musculoskeletal pain—selective COX -2 inhibitors.
•CELECOXIB :
It is a selective COX-2 inhibitor. It has anti-inflammatory, analgesic, and antipyretic effects. But ulcerogenic effect is more negligible. Also, it does not have antiplatelet action. It is metabolised in liver. Hepatic impairment increases its plasma concentration. It has a plasma half-life of 11 hours. Adverse effects: hypertension oedema, abdominal pain, dyspepsia and mi Id diarrhoea. Use: Osteoarthritis, rheumatoid arthritis, dysmenorrhea, dental and post-operative pain.
•ROFECOXIB :
It is a more potent COX-2 inhibitor than celecoxib. Similar to celecoxib, it has no antiplatelet action. Like celecoxib, it is helpful in osteoarthritis, rheumatoid arthritis, dysmenorrhea, dental and post-operative pain. It has a plasma half-life of 17 hrs: adverse effects headache, dizziness, gastrointestinal disturbances, oedema and hypertension.
•VALDECOXIB :
It is a newer selective COX-2 inhibitor. Its efficacy is similar to rofecoxib. It has a plasma half-life of 8 to Il hrs. It is helpful in osteoarthritis, rheumatoid arthritis, dysmenorrhoea, and post-operative pain.
•NIMESULIDE:
It is an NSAID with a more negligible COX-2 inhibiting effect. It has analgesic, antipyretic and anti-inflammatory effects. Also it has mild antihistaminic and antiplatelet actions. It can cause gastrointestinal disturbances. Advantage It can be used in patients allergic to aspirin or other N SAID's.
•Dose: 200 to 300 mg, daily in divided doses.
•PSYCHOPHARMACOLOGICAL AGENTS
The psychopharmacological agents are broadly classified into antipsychotics, anti-anxiety agents, anti-depressants and psychotogenic drugs. Each of these groups are discussed in the succeeding chapters.
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