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Opioid analgesics
Opioid analgesics
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  2. 2. <ul><li>  </li></ul>Opioids: Narcotic: imprecise term suggesting &quot;narcosis&quot;: indicated of a somnolent state Opioid analgesic: analgesia (pain absence) without resulting in loss of consciousness/sleep Opioids: Definition all natural/ semisynthetic opium alkaloid derivatives synthetic agents other drugs whose opioid-like effects are blocked by naloxone -nonselective opioid receptor antagonist Source: Opium from the opium poppy Constituents: morphine codeine Thebaine : nonanalgesic Papaverine -- nonanalgesic, vasodilator
  3. 3. Opioids <ul><li>Prototype: morphine </li></ul><ul><ul><li>Morpheus: god of dreams </li></ul></ul><ul><li>Act on endorphin receptors: </li></ul><ul><ul><li>Mu (most important) </li></ul></ul><ul><ul><li>Kappa </li></ul></ul>
  4. 4. History of Opioids <ul><li>Opium is extracted from poppy seeds (Paper somniforum) </li></ul><ul><li>Used for thousands of years to produce: </li></ul><ul><ul><li>Euphoria </li></ul></ul><ul><ul><li>Analgesia </li></ul></ul><ul><ul><li>Sedation </li></ul></ul><ul><ul><li>Relief from diarrhea </li></ul></ul><ul><ul><li>Cough suppression </li></ul></ul>
  5. 5. Natural opioids occur in 2 places: <ul><li>1) In the juice of the opium poppy (morphine and codeine) </li></ul><ul><li>2) As endogenous endorphins </li></ul><ul><li>All other opioids are prepared from either morphine (semisynthetic opioids such as heroin) or they are synthesized from precursor compounds (synthetic opioids such as fentanyl) </li></ul>
  6. 6. Three Opioid Receptors <ul><li>Mu  </li></ul><ul><li>Kappa (k1 & k3) </li></ul><ul><li>Delta </li></ul>
  7. 7. Mu-Receptor: Two Types <ul><li> -1 </li></ul><ul><ul><li>Located outside spinal cord </li></ul></ul><ul><ul><li>Responsible for central interpretation of pain </li></ul></ul><ul><li> -2 </li></ul><ul><ul><li>Located throughout CNS </li></ul></ul><ul><ul><li>Responsible for respiratory depression, spinal analgesia, physical dependence, and euphoria </li></ul></ul>
  8. 8. Kappa Receptor <ul><li>Only modest analgesia </li></ul><ul><li>Little or no respiratory depression </li></ul><ul><li>Little or no dependence </li></ul><ul><li>Dysphoric effects </li></ul>
  9. 9. Delta Receptor <ul><li>It is unclear what delta’s responsible for. </li></ul><ul><li>Delta agonists show poor analgesia and little addictive potential </li></ul><ul><li>May regulate mu receptor activity </li></ul>
  10. 10. No effect Decrease contraction δ Mouse vas deferens No effect Decrease contraction u Guinea pig ileum       Isolated organ bioassays   Inhibit u, δ Dopamine   Inhibit u Acetylcholine       Neurotransmitter release Decrease release Increase release u and/or δ Growth hormone Decrease release Increase release u Prolactin       Hormone regulation   Increase κ Diuresis No effect Increase u, κ Sedation Decrease feeding Increase feeding u, κ, δ Feeding No effect Increase κ Psychotomimesis No effect Decrease transit u, κ Gastrointestinal tract No effect Decrease u Respiratory function No effect Analgesic u, κ, δ Spinal No effect Analgesic u, κ, δ Supraspinal       Analgesia Antagonist Agonist RECEPTOR SUBTYPE      
  11. 11. Mu and Kappa Receptor Activation Physical Dependence Decrease GI motility Dysphoria Euphoria Respiratory Depression Analgesia Kappa Mu-2 Mu-1 Response
  12. 12. Terminology <ul><li>Pure Agonist: has affinity for binding plus efficacy </li></ul><ul><li>Pure Antagonist: has affinity for binding but no efficacy; blocks action of endogenous and exogenous ligands </li></ul><ul><li>Mixed Agonist-Antagonist: produces an agonist effect at one receptor and an antagonist effect at another </li></ul><ul><li>Partial Agonist: has affinity for binding but low efficacy </li></ul>
  13. 13. Classification of Opioids: Agonist Partial Agonist/weak antagonist Partial Agonists Pentazocine Antagonist Antagonist Pure Antagonists Naloxone, Naltrexone Agonist Antagonist Agonist-Antagonist Nalbuphine, butorphanol, Buprenorphine Agonist Agonist Pure Agonists Morphine, codeine, meperidine, fentanyl , remifentanil, propoxyphene , hydrocodone , oxycodone KAPPA MU DRUGS
  14. 14. Chemical substitutions: <ul><li>Partial agonist/antagonist characteristics: replacement of methyl moiety on the nitrogen atom with larger substituents </li></ul><ul><li>Allyl substitution: nalorphine and naloxone </li></ul><ul><li>Substitutions at the C3 and C6 morphine hydroxyl groups </li></ul><ul><li>Pharmacokinetic properties altered </li></ul><ul><li>Methyl substitution at C3  reduces first-pass hepatic metabolism by glucuronide conjugation: as a consequence codeine and oxycodone have a higher oral: parenteral potency </li></ul>
  15. 15. Methylated at C3 Codeine Oxycodone Morphine OH OH
  16. 16. Pharmacokinetics: <ul><li>Absorption: </li></ul><ul><li>Opioid analgesics: generally well absorbed from cutaneous / intramuscular/mucosal surfaces </li></ul><ul><li>Fentanyl transdermal: important Route of Administration </li></ul><ul><li>Gastrointestinal absorption: </li></ul><ul><li>some opioids subject to first-pass effects: codeine; oxycodone have high oral: parenteral potency (protected from conjugation by substitution on C3 aromatic hydroxyl) </li></ul><ul><li>Distribution: </li></ul><ul><li>Various extent of plasma protein binding </li></ul><ul><li>Highest concentrations in tissues </li></ul><ul><li>Skeletal muscle: largest reservoir </li></ul><ul><li>For highly lipophilic Opioids (e.g. fentanyl): concentration in adipose tissue </li></ul><ul><li>Blood Brain Barrier: </li></ul><ul><li>Amphoteric agents (possessing both an acidic and basic group, e.g. morphine {phenolic hydroxyl at C3}: greatest difficulty for brain entry) </li></ul><ul><li>other substitutions that C3 improve blood-brain barrier penetration: e.g., </li></ul><ul><li>heroin, codeine </li></ul><ul><li>Neonatal considerations: neonates lack the blood-brain barrier: </li></ul><ul><li>placental opioid transfer (uses in obstetric analgesia) can result in depressed respiration in the newborn. </li></ul>
  17. 17. Pharmacokinetics: <ul><li>Metabolism: </li></ul><ul><li>Opioids with hydroxyl groups: conjugated with glucuronic acid into morphine-6-glucuronide: analgesic potency Examples: morphine , levorphanol; in patients with compromised renal function: accumulation of metabolites cause prolonged analgesia </li></ul><ul><li>Esters: hydrolyzed by tissue esterases: </li></ul><ul><li>Examples: heroin, remifentanil (short duration of action) </li></ul><ul><li>N-demethylation : (minor pathway) accumulation of demethylated meperidine metabolite, normeperidine in patients with decreased renal function or on high dosages cause seizures (more likely in children) </li></ul><ul><li>Oxidative metabolism (hepatic) primary route of phenylpiperidine opioid metabolism: e.g. Fentanyl, alfentanil, sufentanil </li></ul><ul><li>Excretion: </li></ul><ul><li>polar metabolites -- renal; small amounts excreted unchanged </li></ul><ul><li>glucuronide conjugates -- bile (enterohepatic circulation minor) </li></ul>
  18. 18. Mechanism of action <ul><li>Reduce neurotransmitter release; by closing a voltage-gated ca2+ channel on presynaptic neuronal terminals or </li></ul><ul><li>Inhibit postsynaptic neurons (hyperpolarization) by increasing and K+ channel conductance </li></ul>Spinal Cord Sites of Opioid Action K+ Ca++
  19. 19. Mechanism of action:
  20. 20. Mechanism of action: <ul><li>Enhance activity in descending aminergic bulbospinal pathways (antinociceptive pathway) that exert inhibitory effects on the processing of nociceptive information in the spinal cord. </li></ul>
  21. 21. Pharmacological actions: <ul><li>CNS effects: (  and  receptor-mediated) </li></ul><ul><li>Analgesia, sedation, euphoria, respiratory depression. </li></ul><ul><li>Analgesia: Pain Components </li></ul><ul><li>Affective (emotional): Opioids have greater effect on this element </li></ul><ul><li>Sensory </li></ul><ul><li>Analgesia results from complex interactions involving: sites in the brain, spinal cord, peripheral tissue (selective action on neuronal modulators and transmitters of pain ;other sensory modality/motor functions: remain intact) </li></ul>
  22. 22. Pharmacological actions: <ul><ul><li>Euphoria: </li></ul></ul><ul><ul><ul><li>Anxiolytic; pleasant; &quot;floating sensation&quot;; </li></ul></ul></ul><ul><ul><ul><li>Individuals not in pain may experience dysphoria </li></ul></ul></ul><ul><ul><li>Sedation: </li></ul></ul><ul><ul><ul><li>Common consequence of opioid administration </li></ul></ul></ul><ul><ul><ul><li>Limited amnesia </li></ul></ul></ul><ul><ul><ul><li>Given as monotherapy, Opioids produce sleep from which individual can be easily awakened </li></ul></ul></ul><ul><ul><ul><li>  Opioids in combination with sedative-hypnotics induce very deep sleep </li></ul></ul></ul><ul><ul><ul><li>Significant Sedation: more likely with phenanthrene derivatives (e.g., morphine, oxycodone etc. less likely with synthetic agents e.g. fentanyl, meperidine) </li></ul></ul></ul>
  23. 23. Pharmacological actions: <ul><ul><li>Respiratory Depression: </li></ul></ul><ul><ul><ul><li>Significant respiratory depression (inhibiting brain stem respiratory centers) </li></ul></ul></ul><ul><ul><ul><li>Respiratory depression is dose-related influenced by extent to sensory input </li></ul></ul></ul><ul><ul><ul><li>opioid induced --slight respiratory depression: tolerated in patients with no prior respiratory difficulty </li></ul></ul></ul><ul><ul><ul><li>  opioid induced -- slight respiratory depression: poorly or not tolerated in patients with: </li></ul></ul></ul><ul><ul><ul><ul><ul><li>Asthma </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Chronic obstructive pulmonary disease (COPD) </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Cor pulmonale </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Increased intracranial pressure </li></ul></ul></ul></ul></ul>
  24. 24. <ul><li>Cough Suppression </li></ul><ul><li>Opioids suppress the “cough center” in the brain </li></ul><ul><li>Especially effective: codeine </li></ul><ul><ul><ul><li>management of pathologic cough </li></ul></ul></ul><ul><ul><ul><li>management of patients with endotracheal tubes </li></ul></ul></ul><ul><ul><ul><li>Associated with: secretion accumulation-- leading to atelectasis, airway obstruction </li></ul></ul></ul><ul><li>  Miosis </li></ul><ul><ul><li>Pupillary constriction: commonly seen with opioid agonists </li></ul></ul><ul><ul><li>Blocked by opioid antagonists </li></ul></ul><ul><ul><li>No development of tolerance </li></ul></ul><ul><ul><li>Mechanism: </li></ul></ul><ul><ul><ul><li>Edinger-Westphal nucleus of the oculomotor nerve </li></ul></ul></ul><ul><ul><ul><li>Parasympathetic system -- may be blocked by atropine </li></ul></ul></ul>Pharmacological actions:
  25. 25. Pharmacological actions: <ul><li>Truncal Rigidity: </li></ul><ul><ul><li>Increased large trunk muscle tone: Supraspinal action </li></ul></ul><ul><ul><li>Most often seen with highly lipophilic Opioids, upon rapid IV administration e.g. Fentanyl, sufentanil, alfentanil </li></ul></ul><ul><ul><li>Reversal of Truncal rigidity done by opioid antagonists </li></ul></ul><ul><ul><li>Maintenance of analgesia with reduced Truncal rigidity needs concurrent neuromuscular blocking drug use. </li></ul></ul><ul><li>Nausea and Vomiting: </li></ul><ul><ul><li>Opioid analgesics: stimulate brain stem chemoreceptor trigger zone (CTZ) </li></ul></ul><ul><ul><li>Vestibular component may also be present </li></ul></ul>
  26. 26. Pharmacological actions: <ul><li>Cardiovascular Effects: Usually minimal effects (some bradycardia) </li></ul><ul><li>BP : in the absence of stress, well maintained; With stress cause hypotension due to Peripheral arterial dilation, venous dilation & may be due to central vasomotor effects and histamine release </li></ul><ul><li>Effects on the myocardium are not significant in normal individuals. However in patients with coronary artery disease & AMI, 8 to 15 mg of morphine administered intravenously produces a decrease in oxygen consumption, left ventricular end-diastolic pressure, and cardiac work at the same time relieves emotional apprehension. </li></ul><ul><li>Reduced blood volume: increased susceptibility to opioid hypotensive effects can aggravate hypovolumic shock. </li></ul><ul><li>With respiratory depression (secondary to opioid administration), PCO2 increases and causes: </li></ul><ul><ul><ul><li>Cerebral vasodilation </li></ul></ul></ul><ul><ul><ul><li>An increase in cerebral blood flow </li></ul></ul></ul><ul><ul><ul><li>An increase in intracranial pressure </li></ul></ul></ul>
  27. 27. Pharmacological actions: <ul><li>Gastrointestinal Opioid Effects: </li></ul><ul><ul><li>Constipation: Local enteric & CNS mechanisms involved </li></ul></ul><ul><ul><li>Stomach: motility decreases, tone increases & gastric acid decreases </li></ul></ul><ul><ul><li>Small Intestinal Effects: tone: increases; with spasm </li></ul></ul><ul><ul><li>Large Intestinal Effects : propulsive peristaltic waves diminished,tone </li></ul></ul><ul><ul><li>increased, These effects delay fecal passage (constipating), promote water </li></ul></ul><ul><ul><li>reabsorption (constipating) Opioid pharmacological actions in the large </li></ul></ul><ul><ul><li>intestine are the basis for opioid use in management of diarrhea </li></ul></ul><ul><ul><li>Biliary tract: </li></ul></ul><ul><ul><li>Opioids: promote biliary smooth muscle constriction: biliary colic </li></ul></ul><ul><ul><ul><li>Sphincter of Oddi may constrict: </li></ul></ul></ul><ul><ul><ul><li>biliary and pancreatic secretion reflux </li></ul></ul></ul><ul><ul><ul><li>elevated plasma lipase/amylase </li></ul></ul></ul>
  28. 28. <ul><li>Effects on the Hypothalamic thermoregulatory centers : Opioids alter the equilibrium point of the hypothalamic heat-regulatory mechanisms, such that body temperature usually falls slightly. However, chronic high dosage may increase body temperature </li></ul><ul><li>Neuroendocrine: </li></ul><ul><ul><li>Opioid analgesics promote release of: </li></ul></ul><ul><ul><ul><li>Antidiuretic hormone* </li></ul></ul></ul><ul><ul><ul><li>Prolactin </li></ul></ul></ul><ul><ul><ul><li>Somatotropin </li></ul></ul></ul><ul><ul><li>Opioid analgesics inhibit released of: (GnRH) and (CRF), from hypothalamus thus decrease circulating concentrations of (LH) & (FSH), ACTH, and  - endorphin decreased . As a result of the decreased concentrations of pituitary trophic hormones , the concentrations of testosterone and cortisol also decreased </li></ul></ul>Pharmacological actions:
  29. 29. Pharmacological actions: <ul><li>Genitourinary tract: </li></ul><ul><ul><li>Renal Function: depressed </li></ul></ul><ul><ul><li>decreased renal plasma flow </li></ul></ul><ul><ul><li>Bladder and ureteral tone: increased </li></ul></ul><ul><ul><ul><li>urinary retention (particularly in postoperative patients) </li></ul></ul></ul><ul><ul><ul><li>increased opioid-induced ureteral tone may worsen ureteral colic due to renal calculus </li></ul></ul></ul><ul><ul><li>Uterus: </li></ul></ul><ul><ul><ul><li>Prolong labor </li></ul></ul></ul><ul><li>Other Effects: </li></ul><ul><ul><li>Flushing, sweating, itching: central effects & histamine early </li></ul></ul><ul><ul><li>Opioid affecting the immune system by influencing: </li></ul></ul><ul><ul><ul><li>chemotaxis </li></ul></ul></ul><ul><ul><ul><li>antibody production </li></ul></ul></ul><ul><ul><ul><li>the disciple effort of responses </li></ul></ul></ul>
  30. 30. Adverse effects: <ul><li>Dysphoria : behavioral restlessness; hyperactivity </li></ul><ul><li>Respiratory depression: slight respiratory depression not tolerated in patients with: </li></ul><ul><ul><ul><li>Asthma </li></ul></ul></ul><ul><ul><ul><li>Chronic obstructive pulmonary disease (COPD) </li></ul></ul></ul><ul><ul><ul><li>Cor pulmonale </li></ul></ul></ul><ul><ul><ul><li>increased intracranial pressure </li></ul></ul></ul><ul><li>Nausea and vomiting </li></ul><ul><li>Increased intracranial pressure </li></ul><ul><li>Hypotension: worsened by preexisting hypovolumia or by other medications given concurrently (e.g. nitroglycerin in acute management of myocardial infarction) </li></ul><ul><li>Constipation </li></ul><ul><li>Urinary retention </li></ul><ul><li>Urticaria , itching </li></ul><ul><li>Tolerance and physical dependence: clinical appearance on two-three weeks of frequent administration of therapeutic doses </li></ul><ul><li>Cross-tolerance: individuals tolerant to morphine effects are also tolerant to other opioid agonists </li></ul><ul><li>Antagonist-precipitated withdrawal: rapidly developing, powerful abstinence syndrome cause by administration of naloxone or another antagonist </li></ul><ul><li>  Psychological Dependence </li></ul>
  31. 31. Opioid Effects: Degree of Tolerance Developed       Convulsions   Mental clouding Constipation   Euphoria, dysphoria Miosis Bradycardia Analgesia Limited/None Intermediate High   Cough suppression   Nausea / vomiting   Antidiuresis   Respiratory depression Antagonist actions   Sedation
  32. 32. Some Symptoms of Opioid Withdrawal Hyper ventilation Yawning Piloerection Hostility Diarrhea Anxiety Vomiting Muscular aches Hyper ventilation Chills Lacrimation Rhinorrhea
  33. 33. <ul><li>Acute opioid toxicity: </li></ul><ul><li>May result from clinical overdosage, accidental overdosage in addicts, or attempts at suicide. </li></ul><ul><li>Occasionally, a delayed type of toxicity may occur from the injection of an opioid into chilled skin areas or in patients with low blood pressure and shock. </li></ul><ul><li>Symptoms and Diagnosis: The triad of coma , pinpoint pupils , and depressed respiration strongly suggests opioid poisoning. </li></ul>Adverse effects:
  34. 34. Treatment: <ul><li>The first step is to establish a patent airway and ventilate the patient. </li></ul><ul><li>Opioid antagonists can produce dramatic reversal of the severe respiratory </li></ul><ul><li>depression and the antagonist naloxone is the treatment of choice. </li></ul><ul><li>However, care should be taken to avoid precipitating withdrawal in dependent patients, who may be extremely sensitive to antagonists. </li></ul><ul><li>The safest approach is to dilute the standard naloxone dose (0.4 mg) and slowly administer it intravenously, monitoring arousal and respiratory function. </li></ul><ul><li>Patients should be observed for rebound increases in sympathetic nervous system activity , which may result in cardiac arrhythmias and pulmonary edema </li></ul><ul><li>For reversing opioid poisoning in children , the initial dose of naloxone is 0.01 mg/kg. If no effect is seen after a total dose of 10 mg, one can reasonably question the accuracy of the diagnosis. </li></ul><ul><li>Pulmonary edema sometimes associated with opioid overdosage may be countered by positive-pressure respiration. </li></ul><ul><li>Tonic-clonic seizures, occasionally seen as part of the toxic syndrome with meperidine and propoxyphene, are ameliorated by treatment with naloxone. </li></ul>
  35. 35. Contraindications/Therapeutic Cautions: <ul><li>For patients receiving the opioid agonists: </li></ul><ul><ul><li>Do not administer a mixed agonist-antagonist (e.g. Pentazocine): withdrawal may be precipitated. </li></ul></ul><ul><ul><li>Diminishment of analgesia may occur in patients with head injuries: opioids may induce a further increase in intracranial pressure </li></ul></ul><ul><li>Pregnancy: chronic use </li></ul><ul><ul><li>Fetus may become physiological independent in utero </li></ul></ul><ul><ul><ul><li>withdrawal symptoms may appear in the early postpartum time frame </li></ul></ul></ul><ul><ul><ul><li>management of fetal withdrawal symptoms: </li></ul></ul></ul><ul><ul><ul><ul><li>mild: management with diazepam </li></ul></ul></ul></ul><ul><ul><ul><ul><li>more severe: oral methadone; tincture of opium (paregoric) </li></ul></ul></ul></ul><ul><li>Patients with impaired lung function: </li></ul><ul><ul><li>Acute respiratory failure may be precipitated by opioid-mediated respiratory depression </li></ul></ul><ul><li>Patients with impaired hepatic or renal function: </li></ul><ul><ul><li>Half-life may be prolonged in patients with impaired renal function; e.g. morphine and its active metabolite morphine-6-glucuronide may accumulate (reduction in dosage) </li></ul></ul><ul><ul><li>Since the liver is the primary metabolic site for morphine and related compounds, very use in patients with pre-hepatic coma may be inappropriate </li></ul></ul><ul><li>Patients with endocrine disorders: </li></ul><ul><ul><li>Adrenal-insufficiency (Addison's disease) or hypothyroidism (myxedema): prolonged, exaggerated opioid responses </li></ul></ul>
  36. 36. Therapeutic uses: <ul><li>Analgesia: </li></ul><ul><ul><li>Opioids most effective in severe, constant pain & less effective in sharp, intermittent pain </li></ul></ul><ul><ul><li>Management of cancer pain; pain associate with other terminal illnesses </li></ul></ul><ul><ul><li>Obstetrical labor: cause fetal/neonatal opioid depression reversible by naloxone </li></ul></ul><ul><ul><li>Renal / Biliary Colic: </li></ul></ul><ul><li>Acute Pulmonary Edema: </li></ul><ul><ul><li>IV morphine: relieves dyspnea secondary to pulmonary edema </li></ul></ul><ul><ul><li>Possible mechanism of action: </li></ul></ul><ul><ul><ul><ul><ul><li>Reduced awareness of shortness of breath </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Reduced patient anxiety </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Reduced preload (decreased vascular venous tone) </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Reduced afterload (decreased peripheral resistance) </li></ul></ul></ul></ul></ul><ul><li>Cough: </li></ul><ul><ul><li>Cough suppression: occurs at lower doses than for opioid analgesia </li></ul></ul><ul><ul><li>Reduced usage of opioids for cough suppression: due to newer non-analgesic, nonaddictive synthetic agents </li></ul></ul>
  37. 37. Therapeutic uses: <ul><li>Diarrhea: </li></ul><ul><ul><li>All diarrhea controllable with opioids </li></ul></ul><ul><ul><li>Diarrhea secondary to infection, treat the infection with appropriate chemotherapy </li></ul></ul><ul><ul><li>Current antidiarrheals utilize agents selected for the gastrointestinal tract with limited CNS actions </li></ul></ul><ul><li>  Opioids and Anesthesia: </li></ul><ul><ul><li>Anesthetic Premedication advantageous because of Sedative-Anxiolytic-Analgesic properties </li></ul></ul><ul><li>Intraoperative Use: ( general ) </li></ul><ul><ul><li>Adjuncts to other anesthetics </li></ul></ul><ul><ul><li>At high doses: primary anesthetic component </li></ul></ul><ul><ul><ul><li>Cardiovascular surgery &Other high-risk surgery (desire to minimize cardiovascular depression) </li></ul></ul></ul><ul><li>( regional ) </li></ul><ul><ul><li>Epidural </li></ul></ul><ul><ul><li>Subarachnoid spaces </li></ul></ul><ul><ul><li>Rectal suppositories & Transdermal patch </li></ul></ul><ul><ul><li>Patient controlled analgesia (PCA): common use </li></ul></ul>
  38. 38. Methadone (Phenylheptylamines) <ul><li>Pharmacodynamics : </li></ul><ul><ul><li>Similar to morphine, longer acting </li></ul></ul><ul><ul><li>Reliable following oral administration </li></ul></ul><ul><ul><li>Compared to morphine, methadone tolerance and physical dependence develops more slowly </li></ul></ul><ul><ul><li>Following abrupt methadone discontinuation withdrawal symptoms less severe than with morphine </li></ul></ul><ul><ul><ul><li>Useful drug for detoxification in maintenance of chronic, heroin addict </li></ul></ul></ul><ul><ul><ul><li>Cross-tolerance with heroin (methadone prevents addiction-reinforcing heroin actions) </li></ul></ul></ul>
  39. 39. Phenylpiperidines (e.g. Meperidine, fentanyl, Diphenoxylate, Loperamide) <ul><li>Meperidine: </li></ul><ul><ul><li>Significant anticholinergic (antimuscarinic) effects </li></ul></ul><ul><ul><li>Contraindicated in the presence of underlying tachycardia </li></ul></ul><ul><ul><li>May have a negative ionotropic cardiac effect </li></ul></ul><ul><ul><li>Risk of seizures: due to accumulation of CNS active metabolite, normeperidine </li></ul></ul><ul><li>Fentanyl group: (fentanyl, sufentanil, alfentanil, remifentanil) differences in biodisposition & potency </li></ul><ul><ul><li>Sufentanil : 5-7 times more potent than fentanyl </li></ul></ul><ul><ul><li>Alfentanil less potent than fentanyl ,more rapid acting & shorter duration of action </li></ul></ul><ul><ul><li>Remifentanil: Rapidly metabolized: tissue cholinesterases resulting in: Extremely short half-life </li></ul></ul><ul><li>  Diphenoxylate: metabolite (difenoxin) </li></ul><ul><ul><li>In management of diarrhea used in combination with atropine </li></ul></ul><ul><ul><li>limited abuse potential </li></ul></ul><ul><li>Loperamide: </li></ul><ul><ul><li>management of diarrhea </li></ul></ul><ul><ul><li>limited abuse potential </li></ul></ul>
  40. 40. Opioid agonist-antagonists: <ul><li>Pentazocine: </li></ul><ul><ul><li>Common: sedation + analgesia in therapeutic doses </li></ul></ul><ul><ul><li>Sweating, Dizziness, Nausea: common at higher doses </li></ul></ul><ul><ul><li>Respiratory Depression: significant respiratory depression less likely than with pure opioid agonists; reversible by naloxone; agonist antagonists (nalorphine) less likely to be effective in reversing respiratory depression </li></ul></ul><ul><ul><li>Psychotomimetic effects: agonist-antagonists </li></ul></ul><ul><ul><ul><li>Nightmares, Anxiety, Hallucinations </li></ul></ul></ul><ul><li>Nalbuphine: </li></ul><ul><ul><li>Kappa (k) agonist;  antagonist </li></ul></ul><ul><ul><li>Parenteral administration </li></ul></ul><ul><ul><li>Possibly less respiratory depression than with morphine </li></ul></ul><ul><ul><li>When respiratory depression occurs: may be more difficult to reverse with naloxone </li></ul></ul><ul><li>Buprenorphine: </li></ul><ul><ul><li>Long acting, potent, Partial  agonist </li></ul></ul><ul><ul><li>Slowed dissociation form receptor hence relative naloxone-reversal resistant </li></ul></ul><ul><li>Butorphanol: </li></ul><ul><ul><li>Analgesic equivalent to Buprenorphine and Nalbuphine, more sedation </li></ul></ul><ul><ul><li>Kappa (k) agonist </li></ul></ul>
  41. 41. THANK YOU

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