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Opioids

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