Non-Narcotic Analgesics

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Pharmacology Surgery Medicine




Analgesia—condition where there is relief of pain without loss of consciousness.

Analgesics—agents which cause analgesia.

Narcosis—a condition of CNS depression with varying degree of stupor from where the patient can be aroused with difficulty.{if without difficulty then it is hypnosis}


Classification of the Anti-Inflammatory drugs—

§    NSAID—non steroidal anti-inflammatory drugs (Aspirin)

§    SAID—steroidal anti-inflammatory drugs (Corticosteroids)

§    SAARD—slow acting anti-rheumatic drugs

§    DMARD—disease modifying anti-rheumatic drugs (Methotrexate)


Classification of Analgesics—

Narcotics / Narcotic Analgesics




o  Other—Acetaminophane (Paracetamol), Phenacetin


Narcotic analgesics—the analgesics that have CNS effect.

Non-Narcotics—the analgesics that do not have CNS effect.


Difference between narcotic and non-narcotic analgesics—

Narcotic Analgesics

Non-Narcotic Analgesics

Act centrally

Act peripherally

Cause addiction

Do not cause addiction

Produce CNS depression

Do not produce CNS depression

Do not produce gastric irritation

Produce gastric irritation

Has no anti-inflammatory effect

Has anti-inflammatory effect












Common characteristics of NSAID—

1.      They are non-steroidal

2.      They all are analgesics, anti-pyretic and anti-inflammatory drug.

3.      They act by inhibiting the cyclo-oxygenase pathway. (exception—Nimesulide)


Classification of NSAID—


o  Salicylic acid

o  Na-salicylates

o  Acetyl salicylic acid (Aspirin)

o  Methyl salicylate (topical use)

o  Benorylate

o  Deflonisol

Indole derivatives—

o  Indomethacin

o  Sulindac


o  Mefenamic acid


Propionic acid derivatives—

o  Ibuprofen

o  Ketoprofen

o  Florbiprofen

o  Fenoprofen

o  Naproxane

o  Oxaprozin (newest)

Oxicam derivatives—

o  Piroxicam


Phenyl acetic acid derivatives—

o  Diclofenac (Voltaren)


Pyrazolone derivatives—

o  Phenyl Butazone (not used anymore)



o  Nabumatone

o  Ketorolac

o  Roxicob (newest)

    (cyclo-oxygenase-B inhibitor)



o  It is an acetyl salicylic acid

o  Over the counter drug (OTC)—do not require prescription to buy. (also paracetamol, antacid, vitamins, minerals)

o  Most consumed drug

o  Mostly used in CVS disease and Rheumatoid arthritis

o  Not soluble in water but salts with Na+, Ca+ are soluble.


History and source—

o  First synthesized from Willow Bark—1829

o  First synthesized in pharmacology lab—1853

o  First used in—1899


Chemistry—It is Acetyl Salicylic acid. A weak organic acid. pKa—3.5 (so, within alkaline pH)



Mechanism of Action—

Aspirin irreversibly acetylates and blocks the enzyme cyclo-oxygenase which is responsible for the arachidonic acid metabolism and thereby inhibits the production of prostaglandin and thromboxane that are chemical mediators of inflammation. Other NSAID reversibly block the cyclo-oxygenase system.


Note :-

o  Cyclo-oxygenase pathway—produce PG, Thromboxane, Prostacycline (PGI2)

o  Lipoxygenase pathway—produce Leukotriens

§    Inhibition of PG synthesis in the injured tissue causes analgesia

§    Inhibition of PGE2, PGI2 and Thromboxane A2 (TBA2) is responsible for anti-inflammatory effect

§    Inhibition of PGE2 in hypothalamus causes anti-pyrexia

§    Inhibition of TBA2 is responsible for anti-platelet effect

We don’t use Aspirin in Asthma—

Because leukotriens is one of the mediators of bronchial asthma. So when aspirin inhibits the cyclo-oxygenase pathway arachidonic acid undergoes Lipoxygenase pathway and there is increased production of leukotriens.


Pharmacological effects—

§    Anti-inflammatory effect

§    Analgesic effect

§    Anti pyretic effect

§    Anti-platelet effect

{↑ these 4 are most important}

§    GIT effect

§    Renal effect

§    CNS effect

§    Effect on respiratory system

§    Hypoprothrmbinemia

§    Uricosuric effect


v     Anti-inflammatory action—


§    Inhibits granulocytic adherence to the damaged vasculature

§    Inhibits migration of neutrophils and macrophages to the site of inflammation

§    It stabilizes lysozome, so no enzyme is released

Mechanism—Aspirin inhibits PG and TBA2 synthesis, these are the chemical mediators responsible for inflammation.


v     Analgesic effect—Aspirin reduces mild to moderate type of pain and relieves mostly musculo-cutaneous pain of somatic origin.


Peripheral action—it reduces the sensitization of nerve endings to the action of Bradykinin and Histamine, released locally by inflammatory processes. Aspirin inhibits production of PGE and PGF that increases the sensitization of nerve endings and stimulates the secretion of Bradykinin and Histamine.

Central action—probably inhibits pain stimuli in the sub-cortical area.


v     Anti-pyretic effect—reduces the fever symptomatically, no action on underlying cause. It only reduces the fever but not the normal body temperature.

If the fever is due to an infection then it is usually produced in 2 ways—

        i.      Leukocyte produces pyrogen which stimulates PG production that elevates body temperature.

     ii.      Macrophages produce IL1 and TNF which stimulates the thermoregulatory center in the hypothalamus.


*** hypothalamus has a set point that is about 370c. If body temperature rises, blood becomes hotter (>370c). hypothalamus senses the change and body cooling mechanism is activated, i.e. AN3 activation producing vasodilatation and sweating. As a result more hot blood from the interior of the body reaches the skin and heat is discipitated through the cooler external environment. Sweat is evaporated from the skin away with the latent heat of evaporation thus making the body cool. If the set point becomes 390c from 370c then vasodilatation will occur at 390c never at 370c.

At molecular level the resetting of set point occurs by chemical mediators—cytokines, IL1, TNF, Interferon—that are secreted by the neutrophils and other WBC when there is neutrophilic leukocytosis during inflammation.

These TNF and Cytokines stimulate cyclo-oxygenase pathway, as a result PGE2 is formed in the hypothalamus and hypothalamic temperature set point is reset at a higher temperature. Aspirin prevents PGE2 formation and prevents pyrexia / fever.


v     Anti-platelet activity—Thromboxane A2 combines with the TBA2 receptors present in the platelet and helps plaque formation.

*** we give low dose of Aspirin for anti-platelet activity as the cyclo-oxygenase pathway within the platelet is more sensitive to low dose (75-100mg) of Aspirin. Aspirin at low dose inhibits the cyclo-oxygenase pathway within the platelet permanently and as platelet is a non-nucleated cell it cannot regenerate the enzyme. Cyclo-oxygenase pathway of endothelium is not so sensitive to low doses and they can regenerate the enzyme as they are nucleated.

Also at low dose Prostacycline and other PG formation is not inhibited, Prostacycline has vasodilatation activity thus prevents thrombus formation.


*** in high doses both TBA2 and PGI2 (Prostacycline) is blocked. 8 days before surgery Aspirin should be stopped. Platelet has a life span of 8 days.


GIT effects—PG has following effects on GIT—

↑ Mucus production

↑ Blood supply

↑ HCO3 secretion

↓ HCl secretion                                                        


Aspirin inhibits PG thus reversing all the effects causes irritation of the mucosa. It also causes epigastric disorders, nausea, vomiting.

Gastric irritation → gastric bleeding → gastric ulceration → gastric perforation.


Uricosuric effect—dose dependant—

§    Large dose—↑ excretion of uric acid

§    Small dose—↓ excretion of uric acid, so salicylate like Aspirin is not used in gout. Other NSAIDs is used.


CNS effects—at higher doses—slaicylism—tinnitus, ↓ hearing, vertigo, transient deafness.


Respiratory effects—

At low doses—

↑ peripheral O2 consumption due uncoupling of oxidative phosphorylation → ↑ CO2 production → stimulates the respiratory center → hyperventilation → respiratory alkalosis (wash out of O2)

Body compensates it—

Respiratory alkalosis → ↑ pH of blood → ↑ renal loss of HCO3 with Na, K and H2O → hyperkalemia, dehydration → compensated respiratory acidosis (more HCO3- loss and accumulation of H+)


At high doses—

Crosses the BBB → directly inhibits the respiratory center → ↓ respiratory rate → accumulation of CO2 → uncompensated respiratory acidosis.



Aspirin and other NSAID are rapidly and completely absorbed from the GIT (stomach and upper part of the small intestine). Aspirin is converted into salicylate and acetate. ½ life is 3-5 hours. It also binds with the plasma proteins. Extensively metabolized mainly by the glycine conjugation {glycine conjugation 75%, glucoronic conjugation 15%, free salicylate 9%, oxidation-gentistic acid 1%}. Rapidly excreted through kidney. pH of urine modifies urinary excretion, alkalinazation promotes excretion.


Therapeutic use—


A.    As analgesics—frequently used in mild to moderate pain, relieves musculo-cutaneous pain of somatic origin.

§    Arthralgia

§    Headache

§    Myalgia

§    Toothache

§    Rheumatoid arthritis

§    Dysmenorrhea





***drug of choice for Rheumatoid Arthritis.

B.     As anti-inflammatory—drug of choice for mild inflammation.

§    Rheumatic fever

§    Reiters syndrome {arthritis + urethritis + conjunctivitis}

§    Rheumatoid arthritis

§    Psoriatic arthritis

§    Osteoarthritis

§    Synovitis

§    Mild SLE

§    Tendonitis

§    Ankylosing spondylitis

§    Myositis


C.    As anti-pyretic—

§    Symptomatic relief of fever.

§    No effect on underlying cause.

§    Not given to children (Reye’s Syndrome)


D.    As antiplatelet—{low dose→75-100mg}, can be used for prophylaxis—

§    Thrombo-embolism


§    Myocardial infarction

§    Unstable angina

§    TIA (transient ischaemic attack)

§    Stroke


E.     As keratolytic effect—in Hyper-Keratotic disorder

F.      Fungal infection—used in Epidermophytosis

G.    Used to remove corn—(10-20)% ointment


H.    Patent Ductus Arteriosus—Indomethacin is given (aspirin cant be given to children)

{PG is responsible for patent ductus arteriosus, Indomethacin inhibits PG}


I.       Gynaecological disorder—Dysmenorrhoea (Mefenamic Acid)


J.       Obstetrical disorder—threatened abortion, premature labour, pre-eclamptic toxemia

{Aspirin is not given at the end of term as we need PG then}


K.    Ophthalmic disorder—diabetic nephropathy, cataract, macular oedema.


Adverse effects—

o  GIT—(commonest)— Chemical irritation→ gastric erosion→ ulceration→ bleeding→ perforation.


o  Hypersensitivity—in 15% patients—probably mediated by leukotriens, May involve inhibition of bronchodilators



Allergic rhinitis

Bronchial asthma

Angioneurotic oedema

Anaphylaxis (rare)


o  CNS—mild form is slaicylism and severe form is salicylate intoxication—






Skin eruption


Acid-base disturbance


Respiratory failure




o  Respiratory system—respiratory depression, uncompensatory respiratory and metabolic acidosis

o  Metabolic effects—hyperthermia and metabolic acidosis

o  Hypo-prothrombinemia

o  Reye’s syndrome—aspirin is not given in children with viral diseases, there may be fulminating hepatitis with cerebral oedema.



1. Children under 8 years of age

2. Peptic ulcer

3. Bleeding disorder

4. Late pregnancy



Adult dose—325-975mg

Antiplatelet dose—70-100mg


Acute salicylate/Aspirin poisoning—when toxicity is more convulsion and coma may develop and there is frank electrolyte disturbance and dehydration.


Sign symptoms of acute aspirin poisoning—{Fatal dose varies from man to

  man, in adult it is 15-30gm.}

§    Nausea

§    Vomiting

§    Evidence of acidosis

§    Dehydration

§    Hyperthermia

§    Mental confusion

§    Convulsion

§    Coma






Treatment of Aspirin Poisoning—

   i.     Hyperthermia and dehydration must be corrected immediately by—

a. Ice-packing

b. Cold rectal saline

c.  I-V infusion

ii.     Correct Na-K bicarbonate imbalance

iii.     Use diuretics with alkaline solution

iv.     Control seizure by IV Diazepam

 v.     Correct Prothrombin time by IV vit-K

vi.     Aspirin remains for prolong time in the stomach. So, emetics and gastric lavage must be done. Where facilities available estimate plasma.

vii.     Haemodialysis should be made when the drug concentration in the plasma is greater than 100μgm/ml.

viii.     When haemorrhagic features occur, blood transmission should be done

ix.     Treatment of acid-base imbalance

 x.     Ventilatory assistance




NIMESULIDE (new compound)

Mechanism of Action of Nimesol differs from the conventional NSAID. Most of the NSAID inhibit the CO pathway thus production of PG, Thromboxane etc. Nimesulide although a weak inhibitor of the PG synthesis, act chiefly by inhibiting the functioning of WBC.

During inflammation WBC are activated and produces cytokines. Cytokines in turn helps in synthesis of PG. Nimesulide inhibits the release of cytokines from WBC. So Nimesulide has strong anti-inflammatory effect and also an analgesic.



Both are propionic acid derivatives. Ketoprofen has dual effect on the PG and Leukotriens, its a new drug and long acting.



It is available as tablet, injection, eye-drop and gel forms. It has anti-inflammatory, analgesic and anti-pyretic effects.

Recommended for chronic inflammatory conditions like rheumatoid arthritis, osteoarthritis, acute musculoskeletal pain and also in post operative ophthalmic inflammations like in cataract.



Slightly more toxic than Aspirin.

Usually used in special situations—

§    Patent ductus arteriosus (PDA)

§    Acute gouty arthritis

§    Ankylosing spondylitis

§    Pericarditis, pleuritis (extra-articular inflammatory condition)





§    Popular, safer alternate to Aspirin (as anti-pyretic and analgesic)

§    Domestic analgesic

§    Used in both adults and children

§    Over the counter drug (OTC)

§    Very less adverse effect in there therapeutic dose

§    It has central action but no peripheral action

§    It is also called Acetaminophane (in America)


Chemistry—para-amino phenol derivatives, active metabolite of phenocetin.



§    It is rapidly and almost completely absorbed

§    ½ life is 2 hours, 50% bound to protein

§    mostly metabolized by conjugation (Sulphate and Glucoronide conjugation)

§    excreted by kidney

§    a small amount of Paracetamol produces highly active metabolite—N-Acetyl Benzoquinone, produces hepatotoxicity when there is overdose. But fortunately they react with SH group of glutathione to form a harmless substance. But when there is excess Paracetamol—all the SH group of glutathione are used up and accumulating in the blood the toxic substance can cause hepatic necrosis.


Mechanism of Action—same as NSAID.


Pharmacological effects—

o  Analgesic and anti-pyretic effect like Aspirin

o  No (or very little) anti-inflammatory and anti-platelet effects because it mainly acts centrally but these are peripheral actions

o  No effect on uric acid level

o  Little or no effect on GIT, Respiratory system, CVS and acid base regulation.



1. Useful in mild to moderate pain like headache, pyrexia, myalgia, post partum pain etc.

2. In case of patients allergic to Aspirin (rash, bronchospasm etc)

3. Patient with hemophilia.

4. Patient with PUD (peptic ulcer disease)

5. Children with viral diseases.

6. Patients who are taking other uricosuric drugs (salicylate competes with the uric acid in tubular secretion)


Adverse effects—usually well tolerated.

At therapeutic dose—mild ↑ in hepatic enzymes (SGPT) without jaundice.

At larger dose— Severe hepatotoxicity with central lobular necrosis after the active metabolite uses up all the glutathione. Analgesic nephropathy, Dizziness, Excitement.


Toxicity—with usual dose is rare, but occasionally there is skin rash. Very rarely hematological disturbance.

Ex—Thrombocytopenia and chronic use of Paracetamol can cause hepatotoxicity.


Acute Paracetamol poisoning—after taking a over dose of drug (10gm / 20 tablets of 500mg). in the initial 1st and 2nd day  there may be nausea, vomiting , abdominal pain and nothing more because sign symptoms of liver necrosis takes time to manifest.

After 2-4 days sign symptoms of liver damage begins to appear showing ↑ SGOT, ↑ SGPT, ↑ Bilirubin concentration in blood, ↑ Prothrombin time.

Treatment—prompt diagnosis is the key to success, where facilities present Paracetamol blood concentration should be done for the diagnosis and prognosis of the treatment.

*** Paracetamol has antidote but aspirin has none.


Actual treatment—

§    Supportive treatment

§    Gastric lavage (no active charcoal)

§    Specific treatment contains N-acetyle cystein (NAC), should be given obviously before the liver cells die (within 10 hours of poisoning).

§    NAC solution can be given orally

§    Where available IV preparation of Acetyle Cystein should be used

§    When AC is not available or significant liver damage is not likely to develop Methionine 250mg 6 hourly (maximum 10gm) by mouth should be given.

§    Haemodialysis


Mechanism—AC and Methionine are the precursors of Glutathione in the body. Activated charcoal can bind with them, that is why charcoal is not used.


Differences between Paracetamol and Aspirin—





Acetyl salicylic acid

N-Acetyl Para-amino Phenol

Mode of action

Acts peripherally

Acts centrally




Half life

3-5 hours

2 hours


By Glycine conjugation

By H2SO4 and

glucoronic acid conjugation


Alkalinity of the urine promotes excretion

Not so

Hepatic toxicity

Do not cause

May cause

Peptic ulcer bleeding


Do not cause

Anti-inflammatory and anti-platelet effects




No antidote is present

N-Acetyl Cystein

On uric acid excretion

Influences uric acid excretion

No action


Present (PUD, Bleeding disorder, children under 8, late pregnancy and bronchial asthma)