Más contenido relacionado



  1. PHL331 Prof. Dr/ Gamal A. Soliman Pharmacy College 1 Lecture-4
  2. ▓ Some definitions 1- Analgesics ▪ Analgesics are drugs used to relieve pain without causing loss of consciousness 2- Opiates ▪ Opiates are natural compounds that are extracted from poppy plant such as morphine and codeine 3- Opioids ▪ Opioids are substance that produce morphine-like effects ▪ Some opioids are widely used medically, some are not. ▪ Ex o Meperidine, Methadone, Fentanyl 4- Opioid peptides ▪ They are peptides that produced by the body and bind to opioid receptors in the brain ▪ Ex o Endorphins. 2
  3. ▓ Opioid analgesics [1] Natural ▪ Naturally occurring opioids can be divided into two classes, phenanthrenes and benzyl isoquinolines ▪ The phenanthrenes are five-ring structures, and the benzyl isoquinolines are three-ring structures. (A) Phenanthrene derivatives ▪ Ex: Morphine, Codeine, Thebaine (X) ❖ Characteristics ▪ Potent CNS effect _ Addictive ▪ Spasmogenic effect ▪ Analgesic (B) Benzyl isoquinoline derivatives ▪ Ex: Papaverine, Noscapine, Narceine ❖ Characteristics ▪ Negligible CNS effect _ Non-addictive ▪ Spasmolytic effect ▪ Non-analgesic 3
  4. [2] Semisynthetic ▪ The semisynthetic opioids are morphine derivatives that obtained by chemical modification of natural opioids ▪ These modifications can produce changes in the pharmacological activity of the opioid. ▪ Ex: Heroin (Acetyl morphine) obtained by acetylation of morphine [3] Synthetic ▪ The synthetic opioids are opioids that are completely synthesized ▪ The synthetic opioids can be classified according to their effect at opioid receptors into : (A) Agonists ▪ Opioid agonists are synthetic drugs that interact with the opioid receptors to produce effects that are similar to morphine ▪ Ex: Meperidine, Methadone, Tramadol (B) Antagonists Or blockers ▪ Opioid antagonists are synthetic drugs that bind to the opioid receptors but produce no functional response. At the same time, they prevent an agonist from binding to these receptors. ▪ Ex: Naloxone, Naltrexone (C) Mixed Agonist-Antagonists ▪ These are drugs that bind to an opioid receptor to produce pain relief and block another receptor that does not produce a physiological effect. ▪ Ex: Nalorphine, Nalbuphine, Butorphanol, Pentazocine, Naltrexone 4
  5. ▓ Opioid receptors ▪ Opioid receptors are widely distributed in the body including brain and spinal cord. ▪ All types of opioid receptors mediate very similar effects. (1) Mu Receptors (μ) ▪ μ receptors are responsible for most of the analgesic effects of opioids, and for some major unwanted effects (e.g. respiratory depression, constipation, euphoria and dependence). (2) Kappa Receptors (κ) ▪ κ receptors contribute to analgesia at the spinal cord level in addition to sedation and hallucinations. (3) Delta Receptor (δ) ▪ δ receptor activation results in analgesia but also can be proconvulsant. 5
  6. ▓ Ascending and Descending pain pathways ❖ Ascending pain pathway ▪ The ascending pathway is how we feel pain. ▪ The process begins when pain sensory neurons, called nociceptors, detect a pain stimulus (signal). ▪ These neurons send the pain signal to the dorsal horn of spinal cord ▪ Once the signal reaches the dorsal horn of the spinal cord, the excitatory neurotransmitters glutamate and substance p are released ▪ Glutamate and substance p transmit pain signals from the spinal cord to the somatosensory cortex in the brain, which recognizes pain. ❖ Descending pain pathway ▪ Once the signal from the ascending pathway reaches the somatosensory cortex, it stimulates the descending pain pathway. ▪ The process begins in a region of the midbrain that transmits signals to the dorsal horn of the spinal cord to release endogenous opioids. ▪ These endogenous opioids further block ascending pain transmission signals. 6
  7. [1] Natural Opioid Analgesics ❑ Morphine ▪ Morphine is a natural alkaloid obtained from Papaver somniferum plant (poppy) ▪ It is one of the a phenanthrene derivative. ❖ Bioavailability : 25% after oral administration (due the first pass metabolism) o Morphine and most morphine-like drugs undergo considerable first-pass metabolism, and are therefore less potent when taken orally than when injected. ❖ Half-life : o The plasma half-life of morphine is 4 – 5 hr. 7
  8. ❖ Metabolism : o Hepatic metabolism occurs in the liver usually by conjugation with glucuronide. o Morphine-6-glucuronide is one of morphine metabolites. It is more active as an analgesic than morphine itself. o Because of low conjugating capacity in neonates, morphine and morphine-like drugs have a much longer duration of action with a possibility of respiratory depression so, these drugs should not be used in young ages. ❖ Excretion : o 90% of the dose are excreted through kidney & 10% through biliary route 8
  9. ❖ Pharmacological actions 1- Effect on CNS i- Analgesia ▪ Morphine is a potent analgesic. ▪ It is effective in most kinds of pain, either sensory (due to its effect on pain center) or emotional (due to euphoria) ❖ MOA of morphine as analgesic ▪ 1) At the spinal level, morphine stimulates μ, κ and δ receptors at the dorsal horn of spinal cord, so decreases the release of the excitatory neurotransmitters glutamate and substance p and inhibits the transmission of pain impulses to somatosensory cortex producing analgesia (Spinal analgesia) ▪ 2) At the brain level, morphine stimulates μ, κ and δ receptors of the brain that result in activation of the descending inhibitory pain pathway. ▪ Activation of the descending inhibitory pain pathway results in release of endogenous opioids at the dorsal horn of the spinal cord to further block ascending pain transmission signals (Supra-spinal analgesia) 9
  10. NOTE ▪ Morphine inhibits all types of pain except itching. o It is contra-indicated in case of allergy and itching o This is because morphine use is accompanied by histamine release which irritates the sensory nerve endings ii- Euphoria ▪ Morphine causes a powerful sense of euphoria. ▪ Euphoria is mediated through μ receptors, ▪ Euphoria is not a target for drugs, so no drug is used to induce euphoria iii- Respiratory depression ▪ Only large dose of morphine can induce respiratory depression ▪ Respiratory depression is mediated by μ receptors. iv- Suppression of cough ▪ Morphine can suppress chronic cough (antitussive effect) 10
  11. v. Vagal stimulation ▪ Morphine stimulates the vagal center in the medulla oblongata causing bradycardia vi- Pupillary constriction (Miosis) ▪ Pupillary constriction is caused by μ and κ receptor-mediated stimulation of the oculomotor center. ▪ Pinpoint pupils are an important diagnostic feature in opioid poisoning vii- Nausea and vomiting ▪ Morphine induces nausea and vomiting in up to 40% of patients ▪ The site of action is the chemoreceptor trigger zone in the medulla oblongata 2- Effect on CVS ▪ Hypotension and bradycardia occur with large doses of most opioids, due to : o Vagal stimulation, o Histamine release 11
  12. 3- Effect on smooth muscles (Note that morphine is a spasmogenic drug) i. Constipation due to : o Morphine reduce motility of the gastrointestinal system, resulting in constipation o It increases water absorption so food content become more solid ii. Bronchoconstriction due to: o Vagal stimulation, o Histamine release o Stimulation of μ and δ receptors of bronchi leads to bronchoconstriction iii. Urinary bladder ▪ Morphine increases the contractility of urinary bladder muscle that lead to feeling of urgency ▪ It increases the contractility of the bladder sphincter that lead to difficult micturition o This represents a problem especially in old ages iv. Gall bladder ▪ Morphine increases the pressure in the gall bladder due to contraction of the gall bladder and constriction of the gall bladder sphincter (sphincter of Oddi). o Morphine should be avoided in patients suffering from biliary colic due to gallstones, in whom pain may be increased. 12
  13. ❖ Therapeutic uses 1- For severe pain ▪ Given by IV injection to treat acute pain ▪ Given orally to treat chronic pain 2- As pre-anesthetic medication o in major surgeries NOTES ▪ In case of severe colic: (Note that morphine is a spasmogenic drug) o Morphine should be combined with atropine because atropine inhibits the vagal stimulation that induced by morphine o The spasmolytic effect of atropine can antagonize the spasmogenic effect of morphine ▪ In case of biliary colic o Morphine is contra-indicated in case of biliary colic due to the possibility of gall stones o In this case, morphine can increases the severity of pain 13
  14. ❖ Adverse effects ▪ The most common adverse effects are nausea, vomiting, constipation and respiratory depression ▪ Other adverse effects include bradycardia & hypotension, feeling of urgency, urine retention, difficult micturition ▪ Tolerance and physical dependence occurred with repeated administration 14
  15. ❑ Codeine ▪ Codeine is a natural alkaloid obtained from Papaver somniferum plant (poppy) ▪ It is one of the a phenanthrene derivative. ▪ Chemically, codeine is a methyl morphine o In the liver, a small amount of codeine is converted to morphine. ▪ Codeine is more absorbed by mouth than morphine with bioavailability of 60%, o This is due to the presence of methyl group that renders codeine more lipid soluble ▪ Codeine has only 10% of the analgesic potency of morphine. o So, the analgesic dose of codeine that produce the same analgesic potency of morphine should be 10-time that of morphine, but this large dose may induces respiratory depression o so codeine used now as analgesic in combination with another analgesic (paracetamol) for more effective pain relief. o Codeine is contra-indicated for children less than 12 years because it causes mortalities in children due to respiratory depression _ in this case, dextromethorphan is the substitute ▪ Unlike morphine, it causes little euphoria and is rarely addictive. ▪ Codeine has marked antitussive activity. ❖ Therapeutic uses ▪ Used mainly for suppression of dry cough due to its strong antitussive effect ▪ Used as analgesic for mild types of pain (in combination with paracetamol). 15
  16. [2] Semisynthetic opioids ❖ Heroin (Acetyl morphine) ▪ Produced by acetylation of morphine ▪ It was used as analgesic and antitussive ▪ Now, it is not used clinically because it is highly addictive 16
  17. [3] Synthetic opioids (A) Agonists ❑ Meperidine (Pethidine) ▪ Meperidine is very similar to morphine in most of its pharmacological effects ▪ It has an antimuscarinic action (Atropine-like effect) ▪ The antimuscarinic action of meperidine may cause dry mouth and blurring of vision as side effects. ▪ Bioavailability : 50% _ because it is more lipid soluble ▪ Meperidine has only 10% of the analgesic potency of morphine. ▪ The duration of action of meperidine is slightly shorter than that of morphine ▪ Meperidine is partly N-demethylated in the liver to norpethidine, which has hallucinogenic and convulsant effects. 17
  18. ❑ Fentanyl & Alfentanil ▪ Both are meperidine derivatives ▪ Fentanyl and alfentanil are highly potent meperidine derivatives. ▪ They are more potent than morphine as analgesics, but with a more rapid onset and shorter duration of action (15 – 30 min) ▪ To prolong their duration of action, thy are used in the form of skin batches to be used directly on the painful area ▪ Ex: Fentanyl skin batch _ with duration of action of 12 hr ▪ Does not prepared for oral administration due to extensive first pass metabolism 18
  19. ❑ Methadone ▪ It is one of the synthetic opioids ▪ Available for oral administration only ▪ Although the chemical structure of methadone is completely different from the chemical structure of morphine, it has an analgesic effect equivalent to that of morphine. ▪ The main difference being that its duration of action is considerably longer (>24 h). ▪ It is less addictive ▪ Used only in the hospitals for treatment of opioid addiction ❑ Tramadol ▪ It is a weak agonist at μ receptors ▪ Tramadol has only 10% of the analgesic potency of morphine. ❖ Therapeutic uses: ▪ Not used clinically except as analgesic ▪ Used as post operative analgesic in major surgeries especially in orthopedic surgery 19
  20. ❑ Loperamide & Diphenoxylate ▪ They are synthetic opioids that bind to opioid receptors in the intestinal wall to slow gut movement. o They act on peripheral opioid receptors only, not central o They can not pass through the BBB so produce less CNS side effects ❖ Therapeutic uses ▪ Loperamide and diphenoxylate are two antidiarrheal medications that are used to treat acute and chronic diarrhea 20
  21. (B) Mixed agonist-antagonist ▪ These are drugs that bind to an opioid receptor to produce pain relief and block another receptor that does not produce a physiological effect. Ex: ▪ Nalorphine, Nalbuphine, Butorphanol, Pentazocine, Naltrexone ❖ MOA ▪ They act by stimulating kappa receptors, so they are kappa agonists o This result in spinal analgesia ▪ They act by blocking of mu receptors, so they are mu antagonists ▪ Their analgesic efficacy is less than that of morphine ❖ Therapeutic uses ▪ Used for chronic pain NOTES ▪ They block mu receptors so no way to induce respiratory depression and addiction ▪ They are contra-indicated for treatment of chronic morphine toxicity (addict patients) ▪ Using of these drugs to addict patients lead to acute withdrawal syndrome 21
  22. (C) Opioid Antagonists (Opioid blockers) ▪ Opioid Antagonists act by blocking the opioid receptors (μ, κ and δ). Ex: ▪ Naloxon _ injection (short duration, for 1 hr) ▪ Naltrexone _ oral (long duration, 10 hr) ▪ They block the actions of endogenous opioid peptides (Endorphins) as well as those of morphine-like drugs ▪ They produce very little effect in normal persons but produces a rapid reversal of the effects of morphine and other opioids. ❖ Therapeutic uses ▪ The main clinical uses of opioid antagonists are to treat respiratory depression caused by opioid overdose, and to reverse the effect of opioid analgesics ▪ Opioid Antagonists have no important adverse effects but precipitates withdrawal symptoms in addicts. ▪ Opioid antagonists are contraindicated in case of chronic addicts with respiratory depression symptoms 22
  23. 23 The lecture end Thank you