Analgesics: Non-opioids Part 2 PDF

Specific agents Codeine ►Codeine natural with less analgesic, less euphoric and less addiction than morphine. ►Codeine is metabolized in part to morphine, which is believed to account for its analgesic effect ►Codeine is indicated for the treatment of mild to moderate pain and for its antit...

Specific agents Codeine ►Codeine natural with less analgesic, less euphoric and less addiction than morphine. ►Codeine is metabolized in part to morphine, which is believed to account for its analgesic effect ►Codeine is indicated for the treatment of mild to moderate pain and for its antitussive effects. ►It is widely used as an opioid antitussive Why?...... ►It is one of the most commonly used opioids in combination with non-opioids for the relief of pain. ► IV codeine has a greater tendency to release histamine and produce vasodilation and hypotension than does morphine. 1  Semisynthetic narcotic analgesics Hydromorphone, Oxymorphone, Oxycodone, Apomorphine are derivatives of morphine and codeine (i.e.semisynthetic analoges). All are indicated for the relief of mild to severe pain; they are often used in combination with non-opioid analgesics. ►Hydromorphone is 8-10 times as potent as morphine as analgesic and it is indicated for use in severe pain and in high doses for relief of pain in opioid-addicted patients. ► Oxymorphone is 10 times as potent as morphine, with actions similar to those of hydromorphone. It has little antitussive activity, so it is useful analgesic in patients with pulmonary disease who need to retain the ability to cough. ►Oxycodone is nearly 10 times as strong as codeine as analgesic. Co- administered with non-opioid analgesics (e.g. acetaminophen) for moderate-sever pain. ►Apomorphine has very low analgesic action but its main action is on CTZ leading to vomiting and so useful in treating oral poisoning. 2 Prof. Dr. Gehan Hussein Heeba ► Heroin Heroin is diacetylmorphine (derivative of morphine). ♦ It is more potent than morphine but with rapid onset and shorter duration. It passes rapidly into the brain and thus has a rapid onset of action. It is then metabolized to morphine. ♦ It is not available for therapeutic use Why?..... Prof. Dr. Gehan Hussein Heeba 3  Synthetic narcotic analgesics ►Meperidine ♦ it has anticholinergic effects.weak atropine-like actions …. ♦ Synthetic opioid agonist with one tenth (1/10) analgesic action of morphine and with short duration of action. Better absorbed orally and has greater bioavailability than morphine ♦ It does not produce miosis, not produce antitussive effect ….. ♦ It does not prolong labor and not depress fetal RC……. ♦ Meperidine is not used in patients with cardiac dysfunction, since its anticholinergic effects can increase the heart rate. ◊ Meperidine can be used in biliary colic large dose or prolonged treatment…… CNS excitation, convulsions, tremors (toxic metabolite normeperidine) Adverse effects: -It causes RC depression and addiction liability but weaker than morphine. - It causes histamine release and bronchoconstriction - It has weak atropine-like actions → …… 4 Prof. Dr. Gehan Hussein Heeba ►Fentanyl (Alfentanil , Sufentanil) ♦ synthetic derivatives of meperidine. They are the most potent and the shortest duration opioid agonists. ♦ Fentanyl and its related derivatives (alfentanil, Sufentanil) are extremely potent synthetic opioid drugs ♦..... ♦ High lipid solubility, high potency, formulated as long acting transdermal skin patch (12 h) and also, by epidural route (24 h) for sever pain. ♦ They are used as analgesic in chronic pain, adjuncts to general anesthesia and for postsurgical patients in parenteral formulations. ◊ They are safe in patients with renal impairment (Why??)..... ►Methadone ♦ long acting synthetic narcotic analgesic (Has longer duration of action than morphine (t1/2 is 24h).), administered orally (most common) or parentrally. Unlike morphine, it is generally not used epidurally ♦ It has an analgesic profile and potency similar to that of morphine but a longer duration and less liable to produce addiction. ♦ Methadone is a useful analgesic drug for the treatment of moderate to severe pain. ♦ It is useful in the treatment of opioid addiction. Methadone withdrawal symptoms are less severe than other opioids 5 Prof. Dr. Gehan Hussein Heeba  Moderate/ low opioid agonists ►Propoxyphene ♦ Structurally related to methadone but is much less potent as an analgesic. ♦ Weaker analgesic than morphine. ♦ Compared with codeine, propoxyphene is approximately half as potent and is indicated for the treatment of mild pain. ♦ Used in combination with aspirin as analgesic. ►Diphenoxylate (Lomotil = Diphenoxylate + Atropine) ♦ It is a meperidine derivative used as an antidiarrheal. It exhibits no morphine- like effects at low doses, but at higher doses, it produces mild opioid effects, such as sedation, euphoria, and dependence. ►Loperamide (Imodium) ♦ It is a piperidine derivative of diphenoxylate, which acts both at the level of the gut and also in the CNS to reduce GIT motility. Its use as an antidiarrheal and its potency are similar to those of diphenoxylate 6 Prof. Dr. Gehan Hussein Heeba  Mixed Opioid Agonist–Antagonists or Partial Agonists Pentazocine , Butorphanol , Nalbuphine , Nalorphine ► They exhibit agonist activity at Kappa receptors and show antagonist activity on Mu receptors ► They are differ from morphine in that they: 1- produce less respiratory depressant effect (safer in overdose). 2- produce a low degree of physical dependence and abuse 3- Less constipating effects ► They were developed to reduce the addiction potential of the opioids while retaining the analgesic potency of the drugs. ► They are useful for the treatment of mild to moderate pain, pre-operative and post-operative analgesia. ► Used safely for obstetric analgesia during labor and it is also used as premedication for anesthesia ► All these drugs (except nalbuphine) produce anxiety and excitatory effects related to the sympathetic discharge of norepinephrine …… ► They are potent analgesics in opioid-naive patients but precipitate withdrawal symptoms in patients who are physically dependent on opioids. They are contraindicated in addict patient ???? 7 Prof. Dr. Gehan Hussein Heeba  Miscellanous ►Tramadol and Tapentadol ♦ It is a centrally acting analgesic whose mechanism of action is by: 1-blockade of norepinephrine and serotonin reuptake (inhibit their transporter function). 2- binding to the opioid μ receptor (.....) ♦ Tapentadol was approved in 2008 and has been shown to be as effective as oxycodone in the treatment of moderate to severe pain but with a reduced profile of gastrointestinal complaints such as nausea ♦ Adverse effects: It has relatively fewer side-effects than most opioids (but addiction can occur). It may induce seizures in epileptic patients; the drug is relatively contraindicated in patients with a history of epilepsy Another serious risk is the development of serotonin syndrome, especially if selective serotonin reuptake inhibitor antidepressants are being administered. 8 Prof. Dr. Gehan Hussein Heeba  Opioid Antagonists Naloxone, Naltrexone and Nalmefene are pure opioid antagonists synthesized by relatively minor changes in the morphine structure. They are used in acute opioid toxicity. Pharmacokinetics ►Naloxone is usually given by injection and has a short duration of action (1–2 hours) when given by this route. ► Naltrexone is well absorbed after oral administration but may undergo rapid first-pass metabolism. ► Nalmefene, the newest of these agents, is a derivative of naltrexone but is available only for I.V administration. Like naloxone, nalmefene is used for opioid overdose but has a longer half-life 9 Prof. Dr. Gehan Hussein Heeba Pharmacodynamics ► When given in the absence of an agonist drug, these antagonists are almost inert at doses that produce marked antagonism of agonist opioid effects. ► When given I.V to a morphine-treated subject, the antagonist completely and dramatically reverses the opioid effects within 1–3 minutes. ► In individuals who are acutely depressed by an overdose of an opioid, the antagonist effectively normalizes respiration, level of consciousness, pupil size, bowel activity, and awareness of pain. ► In dependent subjects who appear normal while taking opioids, naloxone or naltrexone almost instantaneously precipitates an acute abstinence syndrome. ► All opioid antagonists will precipitate withdrawal symptoms in opioid-dependent patients. ► Opioid antagonists bind to the opioid receptor with high affinity and have low efficacy. The pure antagonists block the effects of opioids at all opioid receptors. 10 Prof. Dr. Gehan Hussein Heeba Naloxone ► Because of its fast onset (minutes), naloxone administered IV is used most frequently for the reversal of opioid overdose. The half-life of naloxone in plasma is 1 hour. ► It fails to block some side effects of the opioids that are mediated, such as hallucinations. Therapeutic uses of naloxone: ► Acute opioid toxicity: given i.v., the adverse respiratory and CVS effects of opioids are reversed within 1-2 min and lasts for 1-2 hrs. ► Naloxone is approved for use in neonates to reverse respiratory depression induced by maternal opioid use. It is given during labor to mothers who received opioids to prevent neonatal respiratory depression ► Given alone to non-addicts, naloxone produces no pharmacological effects ► Naloxone precipitates withdrawal symptoms in morphine- dependent patients or animals. Pentazocine may also do this. 11 Prof. Dr. Gehan Hussein Heeba  Non-opioid Analgesics Non-steroidal anti-inflammatory drugs (NSAIDs) ►Although the NSAIDs are less effective than the opioids in providing pain relief, they do not produce tolerance and physical dependence, as do the opioids. ►These drugs are useful for treatment of pain, fever, and inflammation and for reduction of platelet aggregation. ►The mechanism of action of traditional NSAIDs involves blockade of the production of prostaglandins (PGs) by inhibition of the enzyme cyclooxygenase (COX) at the site of injury in the periphery, thus decreasing the formation of mediators of pain in the peripheral nervous system. ►In 1991 it was discovered that the COX system consisted of two enzymes, COX-1 and COX-2. COX-1 is constitutively active and is the site of action of the NSAIDs, COX-2 is induced by traumatic tissue injury. The discovery of COX-2 led to the hypothesis that the major therapeutic benefit was due to the block of inducible COX-2, while the major problematic side effects of the NSAIDs were due to COX-1 inhibition. ►Aspirin is one of the most important NSAIDs because it decreases pain at predominantly peripheral sites with little cortical interaction and thus has few CNS effects. 12 Prof. Dr. Gehan Hussein Heeba Classification Non-selective COX inhibitors (inhibit COX-1 and COX-2): Salicylic acid derivatives: aspirin, aloxiprine, methyl salicylate, etc. Acetic acid derivatives: indomethacin, sulindac, diclofenac Propionic acid derivatives: iboprufen, ketoprofen, naproxen. Fenamic acid derivatives: mefenamic acid, fulfenamic acid. Pyrazolone derivatives: phenylbutazone Oxicams: piroxicam Selective COX-2 inhibitors: celecoxib, etoricoxib, meloxicam Acetylsalicylic acid (Aspirin) ► Oral absorption is complete; most of absorption occurs from the stomach and upper GIT. Widely distributed to all tissues including CNS. ► Metabolism of salicylates occurs by the hepatic microsomal enzymes. -At low doses, elimination is done by the first-order process. -At high doses, elimination is done by the zero-order process. ► Excretion is increased by alkalinization of urine (pH 8) because in alkaline urine, most of aspirin is ionized and less re-absorbable. Mechanism: Aspirin is non-selective and irreversible COX inhibitor leading to inhibition of both PGs and TXs. This distinguishes it from other NSAIDs, which reversibly inhibit COX enzyme. 13 Prof. Dr. Gehan Hussein Heeba ►Aspirin remains the standard to which most NSAIDs are compared for efficacy. Actions of Aspirin ►Antiplatelet Aggregation: Low dose (75- 150mg) exerts a permanent action on TxA2 synthesis and is the basis for post-MI prophylaxis. Aspirin in high doses(> 6 gm/day) inhibits hepatic prothrombin (factor II) synthesis → prolong bleeding time ►Analgesia: Moderate doses (325 mg) inhibit formation of PGs, which sensitize peripheral pain receptors to algesic mediators such as bradykinin. ►Antipyresis: Moderate doses. Pyrogens increase IL-1, which in the hypothalamus ----► ↑ PGE2 formation ----►↑ temperature "set-point." aspirin lowers it back to normal in hyperthermia. ►Anti-inflammatory: Moderate to high doses. Inhibits COX 2, an enzyme form that is induced in cells that are involved in inflammatory responses. ►Uric Acid Elimination: Low to moderate doses --► ↓ tubular secretion ----► Hyperuricemia (and thus contraindicated in patients with gout). High doses -------►↓ tubular reabsorption -------► uricosuria. ► Prolongation of pregnancy and delay of labor due to inhibition of PGs necessary for uterine contraction during labor. The use of NSAIDs after 20 weeks of pregnancy is not recommended 14 Prof. Dr. Gehan Hussein Heeba Adverse Effects ►GI Irritation ---► Gastritis, ulcers, bleeding. ►Bronchoconstriction - Exacerbation of asthma (due to accumulation of LTs). ►Chronic Use: Associated with renal dysfunction (↓ PGs). Analgesic nephropathy: it is chronic renal failure due to chronic abuse of analgesics, which produce chronic renal ischemia due to ↓ synthesis of renal PGE2 and PGI2 ►Reye’s Syndrome ---► Encephalopathy. Severe hepatic injury: “Reye’s syndrome”: it is a rare and fatal condition occurs if aspirin is used to control fever of some viral infections (e.g. chicken pox, influenza, etc.) in children below 12 years old. There is severe fatty infiltration of the liver, pancreas, and kidney associated with encephalopathy ►Salicylism (Acute aspirin toxicity):Tinnitus,vertigo, hematemesis,dehydration,coma Tachypnea (hyperventilation) and hearing-often first signs of toxicity. Management of Aspirin Overdose: gastric lavage (with activated charcoal) plus ventilatory support. Increased urine volume and its alkalinization facilitate salicylate renal elimination. 15 Prof. Dr. Gehan Hussein Heeba contraindications # GIT disorders:peptic ulcer,gastritis. #Hemorrhagic disorders:hemophilia, thrombocytopenia # Chronic renal diseases: aspirin may aggravate renal failure # Uncontrolled hypertension: risk of fatal bleeding. # Gout: small-to moderate doses may inhibit uric acid excretion. # Bronchial asthma # Children