By: Prof. A. Mazumder

Both the serotonin and norepinephrine systems have their most important cell bodies in a small area of the brainstem that serves as a headquarters or command center for each. Axons project from these headquarters throughout the brain in specific pathways that mediate specific functions.

Pain may cause other effects like sinking sensation, apprehension, sweating, nausea, palpitation, rise in b.p. etc Analgesics relieve pain as symptom without affecting its cause.

OPOID ANALGESICS Opium: The brown resinous material obtained from Papaver somniferum is called opium. It contains two alkaloids: »Phenanthrene derivatives: morphine, codeine »Benzisoquinoline derivatives: Papaverine, noscapine

DETAILED PHARMACOLOGICAL ACTIONS (Contd…) 1.CNS: A.Analgesia: Strong analgesic. Though dull visceral pain is relieved better than sharply defined pain, degree of analgesia increases with dose. Perception of pain & reaction to it are both altered so that pain is not unpleasant. Release of substance P from primary pain afferents in spinal cord & its post synaptic action on dorsal horn neuron is inhibited by morphine. B. Sedation: No anticonvulsant action. Drowsiness occurs without motor incoordination & higher doses cause sleep & coma progressively. c. Respiratory Centre: Depress respiratory centre. D. Cough Centre : It is depressed. E. Vasomotor centre : It is depressed at higher doses & contributes to fall in b.p.

DETAILED PHARMACOLOGICAL ACTIONS (Contd…) 2. CVS: Morphine causes vasodilatation due to release of histamine and depression of vasomotor centre. 3. GIT: Constipation is a prominent feature due to i.Spasm of pyloric and anal sphincter ii.Decrease in propulsive movement iii.Reduction in GI segmentation & lowering of transfer of water & electrolyte from mucosa to lumen.

DETAILED PHARMACOLOGICAL ACTIONS (Contd…) 4. Neuroendocrine system: Influence of morphine on pituitary lowers the secretion of FSH,LH, ACTH while prolactin secretion increases. Morphine release anti-diuretic hormone (ADH) & thereby causes reduction in urine volume. 5. ANS: Morphine causes mild hyperglycemic action due to central sympathetic stimulation & also have a weak anticholinesterase action. 6.Other smooth muscle: Urinary tract: Due to increase in tone of sphincter, urinary urgency increases and there is a difficulty in micturition. Uterus: Action clinically insignificant & may prolong labor. Bronchi: Morphine causes release of histamine resulting in bronchoconstriction. It is not a problem for general but dangerous for asthmatics.

Contd…..

Adverse effects: Acute morphine poisoning: Shock, coma and ultimately death in drug abuser. Treatment by respiratory support and gastric lavage with pot permanganate to remove unabsorbed drug. Naloxone is a specific antagonist in the dose of mg i.v. Tolerance : Morphine causes psychological & physical dependence. Physical manifestations include sweating, anxiety, fear, restlessness, abdominal discomfort, diarrhoea, dehydration, palpitation,rise in b.p and weight loss. Treatment include oral administration of methadone.

Pethidine  Dose is 1/8 th of morphine analgesic can.  Onset of action is rapid but are of short duration.  Does not suppress cough centre.  Constipation and urinary retention is less prominent.  Causes less histamine release.  Local anesthetic action.  Side effects similar to morphine  Overdose of pethidine causes excitatory effect like tremor, mydriasis due to accumulation of norpethidine which has an excitatory effect.  Given mg im/sc and occasionally also given orally or as iv.

OPOID RECEPTORS µ RECEPTOR: µ1 has higher affinity for morphine mediated supraspinal analgesia and is selectively blocked by naloxonazine. µ2 lowers affinity for morphine. Mediate spinal analgesia, respiratory depression, sedation and constipation effect. Κ receptor: Analgesia also caused by kappa receptor stimulation mainly. Mainly k1 & k3 receptors. Respiratory depression, hallucinations, physical dependence and sedation are the common actions seen Δ receptor: Located at dorsal horn of spinal cord. These receptors are also located in lymbic region. Responsible for analgesia, respiratory depression and reduced gastric motility.

NON NARCOTIC ANALGESICS They are weak analgesic and don't depress CNS & don't produce physical dependence. They act on peripheral pain mechanism but also in CNS to raise pain threshold.

CLASSIFICATION OF NONNARCOTIC ANALGESICS A) Nonselective COX inhibitors : –Salicylates: Aspirin –Pyrazolone derivatives: Phenylbutazone –Indole derivatives: Indomethacine, Sulindac –Propionic acid derivative: Ibuprofen, Naproxen, Ketoprofen –Anthranilic acid derivative: Mephenamic acid –Aryl acetic acid derivative: Dicyclofenac –Oxicam derivative: Piroxicam,Tenoxicam –Pyrrolo-pyrrolo derivative: Ketorolac B) Preferential COX-2 Inhibitors: Nimesulide C) Selective COX-2 Inhibitors: Celecoxib D) Analgesic-antipyretic with poor antiinflammatory action: i.Paraaminophenol derivatives: Paracetamol ii.Pyrazolone derivative: Propiophenazone iii.Benzoxazocaine derivatives: Nefopam

Mechanism of action as analgesic, antipyretic and anti-inflammatory agent  Aspirin inhibit COX irreversibly by acetylating one of its serine residues and this results in inhibition of PG synthesis resulting in its action as analgesic, anti-inflammatory, antipyretic agent. NSAIDs block pain sensation mechanism induced by bradykinin, interleukin and other allergic substances. They are more active against inflammation associated with pain. ANALGESIC  NSAIDs reduce body temp but don't cause hypothermic action in normo-thermic individuals. NSAID block pyrogen induced pyrexia. ANTIPYRETIC  PG are one of the several mediators of inflammation. Inhibition of COX don't depress production of other mediators like cytokines, leukotrienes and platelet activation factors. ANTIINFLMMATORY.

OTHER ADVERSE EFFECTS OF NSAIDs Salicylate Poisoning: dehydration, vomiting, restlessness, hallucination, convulsion followed by coma leading ultimately to final death. Treatment: Ext cooling and i.v treatment with sodium, potassium, and glucose. Gastric lavage to remove unused drug. Blood transfusion & Vit K is to be supplemented if there is a bleeding. Gastrointestinal: gastric irritation, peptic ulceration. Renal: sodium & water retention, chronic renal failure CNS: Headache, mental confusion, seizure precipitation. Hematological: Bleeding, hemolytic anemia. Other: Asthma, skin rashes.

NIMESULIDE  Selective COX-2 inhibitor.  Analgesic, anti-inflammatory and antipyretic action comparable to other NSAIDs  Used primarily to treat painful inflammation like sports injury, ear nose throat disorders, dental surgery, low backache, fever.  Adverse effect include: nausea, rash, loose motion, hepatic failure.  Dose: 100mg b.d

Choice of NSAIDS: Mild to moderate pain with little inflammation: Paracetamol, ibuprofen (low dose) Acute musculoskeletal or injury associated with inflammation: Dicyclofenac Short lasting pain with min inflammation: Nefopam Rheumatoid arthritis, gout, rheumatoid fever: Aspirin (high dose), indomethacine, naproxen, piroxicam. Patients with history of asthma: Nimesulide Combination therapy should be restricted for a limited period.