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Transcript
Lec.16,17 Opioids analgesics Pain: is 'an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage'. This implies that the degree of pain experienced by the patient may be unrelated to the extent or presence of underlying tissue damage and that emotional or spiritual distress can add to the patient's experience of pain. Nociception: physiological process by which pain is perceived. Hyperalgesia: an increased amount of pain associated with a mild noxious stimulus. Allodynia : pain evoked by a non-noxious stimulus or spontaneous pain without any precipitating stimulus. Analgesia : reduction in pain sensation. An analgesic: defined as a drug that relieves pain. Analgesics classified as: 1- opioids 2- non-opioids, e.g. nonsteroidal anti-inflammatory drugs (NSAIDs). 3- Co-analgesics or adjuvants : are drugs that have a primary indication other than pain but are analgesic in some conditions. For example, antidepressants and anticonvulsants also act to reduce nociceptive processing in neuropathic pain. OPIOID ANALGESICS Opioid is a generic term for natural or synthetic substances that bind to specific opioid receptors in the CNS, producing an agonist action. Mechanism of action Opioids act to reduce the intensity and unpleasantness of pain. They produce their effects by activating specific G protein-coupled receptors in the brain, spinal cord and peripheral nervous system. There are three major classes of opioid receptor: δ-opioid, κ-opioid and μopioid, which correspond respectively to their endogenous ligands, dynorphin, enkephalin and β-endorphin. Agonist activity at opioid receptors acts to open potassium channels and prevent the opening of voltage-gated calcium channels. This reduces neuronal excitability and inhibits the release of pain neurotransmitters. 1 Lec.16,17 Opioids analgesics 2 Lec.16,17 Opioids analgesics Morphine is the major analgesic drug contained in crude opium and is the prototype strong μ receptor agonist. Codeine is present in crude opium in lower concentrations and is inherently less potent, making codeine the prototype of the weak opioid agonists. Morphine Actions: a. Analgesia b. Euphoria: Morphine produces a powerful sense of contentment and well-being. c. Respiration: Morphine causes respiratory depression by reduction of the sensitivity of respiratory center neurons to carbon dioxide. d. Depression of cough reflex: Both morphine and codeine have antitussive properties. e. Miosis: The pinpoint pupil characteristic of morphine use results from stimulation of μ and κ receptors. f. Emesis: Morphine directly stimulates the chemoreceptor trigger zone in the area postrema that causes vomiting. g. GI tract: Morphine relieves diarrhea by decreasing the motility and increasing the tone of the intestinal circular smooth muscle. Morphine also increases the tone of the anal sphincter. Overall, morphine and other opioids produce constipation. h. Cardiovascular: Morphine has no major effects on the blood pressure or heart rate at lower dosages. With large doses, hypotension and bradycardia may occur. i. Histamine release: Morphine releases histamine from mast cells causing urticaria, sweating, and vasodilation. Therapeutic use: 1-Analgesia: Morphine is the prototype opioid agonist. Opioids used for pain in trauma, cancer, and other types of severe pain. 2-Treatment of diarrhea :Agents commonly used include diphenoxylate and loperamide 3-Relief of cough: Morphine does suppress the cough reflex, but codeine and dextromethorphan are more commonly used. 4-Anesthesia: Opioids are used as pre anesthetic medications, for systemic and spinal anesthesia, and for postoperative analgesia. 3 Lec.16,17 Opioids analgesics Adverse effects: 1- With most μ agonists, severe respiratory depression can occur and may result in death from acute opioid overdose. 2- Elevation of intracranial pressure, particularly in head injury, can be serious. Morphine should be used with caution in patients with asthma, liver disease, or renal dysfunction. 3-Physical and psychological dependence can occur with morphine and with some of the other agonists. Withdrawal produces a series of autonomic, motor, and psychological responses that incapacitate the individual and cause serious symptoms, although it is rare that the effects cause death. Codeine is a naturally occurring opioid that is a weak analgesic compared to morphine. It should be used only for mild to moderate pain. Codeine is commonly used in combination with acetaminophen (paracetamol) for management of pain. Codeine exhibits good antitussive activity at doses that do not cause analgesia. Oxycodone is a semisynthetic derivative of morphine. It is orally active and is sometimes formulated with aspirin or acetaminophen. Its oral analgesic effect is approximately twice that of morphine. Fentanyl a synthetic opioid chemically related to meperidine, has 100-fold the analgesic potency of morphine and is used for anesthesia. The drug is highly lipophilic and has a rapid onset and short duration of action (15 to 30 minutes). It is usually administered IV, epidurally, or intrathecally. Fentanyl is combined with local anesthetics to provide epidural analgesia for labor and postoperative pain. 4 Lec.16,17 Opioids analgesics Partial Agonists and Mixed Agonist–Antagonists Buprenorphine is classified as a partial agonist, acting at the μ receptor. Buprenorphine tablets are indicated for the treatment of opioid dependence and are also available in a combination product containing buprenorphine and naloxone. Naloxone was added to prevent the abuse of buprenorphine via IV administration. Pentazocine acts as an agonist on κ receptors and is a weak antagonist at μ and δ receptors. Pentazocine promotes analgesia by activating receptors in the spinal cord, and it is used to relieve moderate pain. Other analgesics Tramadol is a centrally acting analgesic that binds to the μ opioid receptor. The drug undergoes extensive metabolism via CYP450 2D6, leading to an active metabolite with a much higher affinity for the μ receptor than the parent compound. In addition, it weakly inhibits reuptake of norepinephrine and serotonin. It is used to manage moderate to moderately severe pain. Its respiratory depressant activity is less than that of morphine. Opioids antagonists Naloxone is a competitive antagonist at μ, κ, and δ receptors, with a 10-fold higher affinity for μ than for κ receptors. Naloxone is used to reverse the coma and respiratory depression of opioid overdose. It rapidly displaces all receptor-bound opioid molecules and, therefore, is able to reverse the effect of a morphine overdose. Within 30 seconds of IV injection of naloxone. Naltrexone has actions similar to those of naloxone. It has a longer duration of action than naloxone, and a single oral dose of naltrexone blocks the effect of injected heroin for up to 24 hours. 5