Pcl 401 Narcotic And Non-Narcotic Analgesics PDF

PCL 401: NARCOTIC AND NON-NARCOTIC ANALGESIC BY Dr. O.M. AIYELERO  INTRODUCTION Pain : The International Association for the Study of Pain (IASP) defined pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage...

PCL 401: NARCOTIC AND NON-NARCOTIC ANALGESIC BY Dr. O.M. AIYELERO  INTRODUCTION Pain : The International Association for the Study of Pain (IASP) defined pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage”. - Harold Merskey (1964) - IASP 1979  INTRODUCTION Narcotics (Opioids) includes natural opiates and semi-synthetic alkaloids derived from opium poppy, pharmacologically similar synthetic drugs that interacts with opioid receptors.  OPIOD RECEPTORS (O.R.) AND EFFECTS  Mu receptors: Supraspinal analgesia, respiratory depression, euphoria and physical dependence.  Kappa receptors : spinal analgesia, miosis and sedation.  Delta receptors: analgesia, respiratory depression, affective behaviour, reduction in GI motility. ORL 1 receptors (recently identified by cloning techniques) Endogenous opioid peptides These serve as neuromodulators which are produced and secreted by nerve cells (i.e., neurons) and act in the brain and spinal cord to modulate (regulate) the actions of other neurotransmitters. They include  Enkephalins  Endorphins  Dynorphins  OPIOIDS Agonists  Strong eg Morphine Methadone Mepridine  Moderate eg Codiene, oxycodone  Weak eg Propoxyphene  OPIOIDS CLASSIFICATION Cont’d Mixed agonist-antagonist eg  Buprenorphine  Nalbuphine Antagonists eg  Naloxone  Naltrexone  MECHANISM OF ACTION OF OPIOIDS CELLULAR ACTIONS: O.R. are G coupled receptors and their stimulation inhibits adenylcylase and decreases intracellular cAMP content. They also act through ion channels, promote K + channel openning, causing hyperpolarization; and inhibit voltage- gated calcium channel leading to inhibition of transmitter release.  ACUTE EFFECTS OF OPIOID ANALGESICS Analgesia- perception of pain and reaction to it. Sedation – drowsiness, higher doses produce sleep and coma. Mood and subjective effects – produces a calming effect, feeling of detachment and inability to concentrate and euphoria. Respiratory depression- dose-dependent depression of respiratory center. Antitussive actions – supression of cough reflex by unknown mechanism is the basis for the clinical use of opiods as antitussives.  ACUTE EFFECTS OF OPIOID ANALGESICS On the smooth muscle- opioids (with the exception of meperidine) cause contraction of biliary smooth muscle, reduction of uterine tone which may prolong labour. GI effects- constipation occurs through decreased intestinal peristalsis. Miosis – pupillary constriction is a characteristic effect of all opioids except meperidine, which has a muscarinic blocking action. Miosis is blocked by naloxone and atropine.  CHRONIC EFFECTS OF OPIOID ANALGESICS TOLERANCE Marked tolerance can develop to the just-mentioned acute pharmacologic effects with the exception of constipation and miosis. Addicts may consume 50 times the dose without adverse effect.  CHRONIC EFFECTS OF OPIOID ANALGESICS cnt’d DEPENDENCE – defined as compulsive craving resulting from repeated drug administration. There is physical dependence due to psychological response to chronic therapy with these drugs particularly the strong agonists. Physical dependence is revealed on abrupt discontinuance as an abstinence syndrome eg rhinorrhea, lacrimation,  CLINICAL USES OF OPIOD ANALGESICS Analgesia: relieving traumatic, visceral, ischemic (MI), postoperative, burn and cancer pain. Cough supression Treatment of diarrhea eg diphenoxylate, loperamide given orally. Management of acute pulmonary edema: morphine used parenterally. Anesthesia  TOXICITY Most of the adverse effects of the opioids analgesics (eg nausea, constipation, and respiratory depression ) are predictable extension of pharmacological effects. In addition, overdose and drug interactions are very important.  TOXICITY cnt’d A. OVERDOSE A triad of pupillary constriction, comatose state, and respiratory depression is characteristic, the latter is responsible for most fatalities. Treatment of overdose involves the use of antagonists eg naloxone and other therapeutic measures, especially, ventilatory support.  TOXICITY cnt’d B. DRUG INTERACTIONS  The most important drug interactions involving opioid analgesics are additive CNS depression with ethanol,sedative- hypnotics, antipsychotics, TCADs, and anti- histamines.  Concomittant use of some opioids (eg meperidine) with MAO inhibitors increases the incidence of hyperpyrexic coma.  Meperidine also causes serotonin syndrome with SSRI.  OPIOID ANTAGONISTS Eg Naloxone ,nalmefene, and naltrexone. Are pure opioid receptor antagonists that have few other effects. Produce marked antagonism of agonist effects and have greater affinity for mu receptors than for other receptors. Major clinical use of these drugs is in the management of acute opioid OPIOID ANTAGONISTS ctn’d Naloxone and nalmefene are given intravenously. Multiple doses of naloxone is needed due to short duration of action (1-2 h). Naltrexone blocks the action of strong agonist eg heroin for at least 24 h after oral use. Naltrexone decreases the craving for ethanol and is approved for adjunctive use in alcohol dependency programmes.  NON-NARCOTIC ANALGESICS Or Aspirin-like analgesics or Analgesic- antipyretic and anti-inflammatory agents. CLASSES: a. NSAIDs Aspirin Other non selective NSAIDs Cox-2 inhibitors b.DMARDs  Classification : Analgesic and Anti Inflammatory Drugs NON-SELECTIVE COX INHIBITORS 1. Salicylates – Aspirin, Salicylamide, Benorylate, Diflunisal. 2. Pyrazolone derivatives – Phenyl b utazone, O xyphenyl-butazone. 3. Propionic acid derivatives – Ibuprofen, Naproxen, Ketoprofen, Fenoprofen, Flurbiprofen, Oxaprozin. 4. Indole derivatives – Indomethacin, Sulindac.  CLASSIFICATION 5. Anthranilic acid derivative – Mephanimic acid, Flufenamic acid. 6. Aryl acetic acid derivative – Diclofenac, Tolmetin. 7. Oxicam derivative – Piroxicam, Tenoxicam. 8. Pyrrolo pyrrole derivatives – Ketorolac. Preferential COX-2 inhibitors Nimesulide Meloxicam Nabumetone. Selective COX-2 inhibitors Valdecoxib Celecoxib Rofecoxib  Analgesics with poor Anti- inflammatory action 1. Paraminophenol derivative - Paracetamol (Acetaminophen) 2. Pyrazolone derivative - Metamizol, Propiphenazone 3. Benzoxazocine derivative - Nefopam  Cox (Cyclooxygenase) Cyclooxygenase (COX), officially known as prostaglandin_x0002_endoperoxide synthase (PTGS), is an enzyme (specifically, a family of isozymes, EC 1.14.99.1) that is responsible for formation of prostanoids, including thromboxane and prostaglandins such as prostacyclin, from arachidonic acid.  The names "prostaglandin synthase (PHS)", "prostaglandin synthetase (PHS)", and "prostaglandin- endoperoxide synthetase (PES)" are older terms still sometimes used to refer to COX.  Cox 1 vs Cox 2 In the 1990s it was discovered that there are two forms of the cyclooxygenase enzyme: COX-1 and COX- 2. The latter is the one responsible for inflammation. COX- 1 is known to be present in most of the tissues in our bodies. In the gastrointestinal tract, COX-1 maintains the normal lining of the stomach and intestines, protecting the stomach from the digestive juices. The enzyme is also involved in kidney and platelet function.  COX-2, on the other hand, is primarily found at sites of inflammation. Both COX-1 and COX-2 produce the prostaglandins that contribute to pain, fever, and inflammation, but since COX- 1's primary role is to protect the stomach and intestines and contribute to blood clotting, using drugs that inhibit it can lead to unwanted side effects.  Mechanism of actions of NSAIDs  cox 1 and cox 2 pathway  Lipo-oxygenase pathway  Interference with G-protein-mediated signal transduction by NSAIDs may form the basis of an analgesic mechanism unrelated to inhibition of prostaglandin synthesis.  Central action may be mediated by endogenous opioid peptides or blockade of the release of serotonin (5- hydroxytryptamine; 5-HT).  Mechanism involving inhibition of excitatory amino acids of N-methyl-D_x0002_aspartate receptor activation has also been proposed  Pharmacological actions CNS – Depressant and stimulant action CVS – Causes vasodilation GIT – Constipation Smooth muscles – Increased ureter contraction, Bronchoconstriction ANS – Mild hyperglycemia  Adverse effects Analgesics doses are usually well tolerated but anti_x0002_inflammatory doses are usually associated with adverse effects when used for a long period. A. G.I tract:- Epigastric distress, nausea, vomiting, erosive gastritis, peptic ulcer, increase occult blood loss in stools are common B. Allergic reactions are not common and may be manifested as rashes, photo sensitivity etc. c. Hemolysis ADVERSE EFFECTS (CONTD) D. Nephrotoxicity E. Reye’s syndrome F. Salicylism G. Acute salicylate intoxication.  Functions of NSAIDs They reduce high temperature and fever They reduce inflammation They reduce pain NSAIDs have anti-clotting properties. In the case of aspirin, this property helps prevent the blocked arteries that can cause heart attacks or stroke.  USES OF NSAIDs Acute or chronic conditions where pain and inflammation are present. Rheumatoid arthritis Osteoarthritis Inflammatory arthropathies (e.g. ankylosing spondylitis, ) Acute gout Dysmenorrhoea  USES (CNTD) Metastatic bone pain Headache and migraine Postoperative pain Mild-to-moderate pain due to inflammation and tissue injury Pyrexia Renal colic They are also given to just born infants whose ductus arteriosus is not closed within 24 hours of birth  CONTRAINDICATIONS Ulcer Asthma Patient with nasal polyp Diabetes Gout Influenza (Reye’s syndrome) Hypo coagulation state  CONTRAINDICATIONS Chronic allergic disorders Chronic liver disease Renal failure Salicylate allergy Breast feeding mothers Pregnancy  MOA: PARACETAMOL It is surprising that after more than 100 years, the exact mechanism of action of paracetamol remains to be determined. There is evidence for a number of central mechanisms, including effects on prostaglandin production, and on serotonergic, opioid, nitric oxide (NO), and cannabinoid pathways, and it is likely that a combination of interrelated pathways are in fact involved.  Drug interactions Anticoagulants - the effect of warfarin and other coumarins may be enhanced by prolonged regular use of paracetamol with increased risk of bleeding. Occasional doses have no significant effect. Metoclopramide – may increase speed of absorption of paracetamol. Domperidone – may increase speed of absorption of paracetamol. Colestyramine – may reduce absorption if given within one hour of paracetamol. Imatinib - restriction or avoidance of concomitant regular