Pain ,opiate analgesics and antagonists

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Pain ,opiate analgesics and antagonists

• Dr. Israa

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Mechanism of pain and nociception

• Polymodal nociceptors are the main type of
  peripheral sensory neuron that responds to
  noxious stimuli the majority are non-myelinated
  C fibers whose endings respond to thermal,
  mechanical and chemical stimuli.
• Chemical stimuli causing pain includes
• Bradykinin
• Protons
• ATP
• Vanilloids (e.g. Capsaicin)

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• Stimuli to these receptors (agonist) open cation
  channels and causing membrane depolarization and
  action potential initiation .
• Theses receptors are sensitized by prostaglandins
  which explain the analgesic effect of NSAIDs.
• Nociceptive fibers terminate in the superficial
  fibers of the dorsal horn, forming synaptic
  connection with transmission neurons running to
  the thalamus

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• Transmission in the dorsal horn is subjective to
  various modulatory influence, constituting the
  gate control mechanism
• Descending pathways from the midbrain and brain
  stem exert strong inhibitory effect on dorsal
  horn transmission.
• The descending inhibition is mediated mainly by
  enkephalin, 5-HT from NRM (Neuclus Raphi Magnus)
  and noradrenaline which is released from the
  locus coeruleus .

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• Opioids analgesics causes analgesia partly by
  inhibiting transmission in the dorsal horn,
  partly by activating the descending pathways,
  partly by inhibiting excitation of the sensory
  nerve terminals in the periphery
• C-fiber activity facilitates transmission through
  the dorsal horn through substance P receptors
  and NMDA receptors.

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OPIOID ANALGESICS (NARCOTIC ANALGESICS)

• Analgesia Relief of pain without loss of
  consciousness.
• Opium Natural extract from Poppy plant used for
  social and medicinal purpose for thousands of
  years to produce euphoria, analgesia, sleep and
  to prevent diarrhea
• Opioid drugs natural synthetic morphine-like
  drugs.

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Opioids analgesics and antagonists

• Strong agonists includes
• Alfentanil
• Fentanyl
• Heroin
• Mepridine
• Methadone
• Morphine
• Oxycodone
• Remifentanil
• Sufentanil.

• Moderate agonists includes
• Codeine
• Propoxyphene.

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• Mixed Agonists and Antagonists
• Pentazocine
• Nalbuphine
• Butorphanol
• Buprenorphine

• Opioid Antagonists
• Naloxone
• Naltrexone
• Nalmephine

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Opioid receptors

• The opioid agonists act at specific receptor
  sites to produce their pharmacological effects.
• Opioid Receptors are
• µ (µ1, µ 2)
• ? (?1, ?2, ?3)
• d (d1, d2)

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• They are four endogenous opioid-like substances
  (which also stimulate opioid receptors)
• Metenkephalin Tyr-Gly-Gly-Phe-Met
• Leuenkephalin Tyr-Gly-Gly-Phe-Leu
• Beta Endorphin a 31 amino acid peptide with
  Metenkephalin at N-terminal sequence
• Dynorphin a 17 amino acid peptide with
  Leuenkephalin at N-terminal sequence

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Endogenous Opioid Peptides (Opiopeptins)
Families Precursors Peptides
Enkephalins Proenkephalins (also known as proenkephalin A) Met-enkephalin Leu-enkephalin
Endorphins Pro-opiomelonocortin (POMC) MSH ACTH ß-Lipoprotein ß-Endorphin
Dynorphins Prodynorphin (also known as proenkephalin B) Dynorphin A Dynorphin B a-Neoendorphin ?-Neoendorphin
Non-opioid peptides
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Opioid Receptors and their Prototypic Ligands
Receptor type Representative Ligands Representative Ligands
Receptor type Endogenous Exogenous
Mu (µ) (µ1, µ2) ?-endorphin Morphine
Delta (d) (d1, d2) Met-enkephalin Etorphine
Kappa (?) (?1, ?2, ?3) Dynorphin A Ethyl-keto-cycla-zocine
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Action and selectivity of some opioids (and opioid antagonists) at various opioid receptors Action and selectivity of some opioids (and opioid antagonists) at various opioid receptors Action and selectivity of some opioids (and opioid antagonists) at various opioid receptors Action and selectivity of some opioids (and opioid antagonists) at various opioid receptors Action and selectivity of some opioids (and opioid antagonists) at various opioid receptors
Drug Receptor type Receptor type Receptor type Receptor type
Drug Mu - µ Mu - µ Kappa - ? Delta - d
Agonists Agonists Agonists Agonists Agonists
Morphine
Codeine
Methadone
Meperidine
Fentanyl
Sufentanyl
Partial and Mixed Agonists Partial and Mixed Agonists Partial and Mixed Agonists Partial and Mixed Agonists Partial and Mixed Agonists
Buprenorphine PA PA Antagonist (-)
Pentazocine PA PA Antagonist (---)
Antagonists Antagonists Antagonists Antagonists Antagonists
Nalaxone and Naltrexone Nalaxone and Naltrexone Antagonist (---) Antagonist (--) Antagonist (-)
Endogenous Peptides Endogenous Peptides Endogenous Peptides Endogenous Peptides Endogenous Peptides
Met-enkephalin
Beta-endorphin
Dynorphin A
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• Three genes have been identified which code for
  opioid peptides
• Beta endorphin and ACTH
• Enkephalins
• Dynorphins
• These neuropeptides are released by stress and
  appear to modulate the release of other
  neurotransmitters.

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Mechanism of Action of opioids

• Morphine binds opioid receptors and thus impairs
  the normal sensory pathways through
• Blockade of calcium channels which leads to
  decreased release of substance P and glutamate
  from the 1st neuron of the sensory pathway (in
  substantia gelatinosa in spinal cord).
• Decreased c-AMP which leads to opening of
  K-channels and hyperpolarization of the 2nd
  neuron of the sensory pathway.

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Mechanism of Action of Opioids
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• B. Effects due to ?-receptor stimulation
• Spinal and peripheral analgesia,
• Dysphoria
• Sedation
• Respiratory depression (less)
• Miosis (less)
• Decrease GIT motility
• Physical dependence

• Effects due to µ-receptor stimulation
• Supraspinal, spinal peripheral analgesia
• Euphoria
• Respiratory depression
• Miosis
• Decreased GIT motility,
• Sedation
• Physical dependence.

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• C. Effects due to d-receptor stimulation
• Spinal analgesia
• Respiratory depression
• Decrease GIT motility .
• They are not true opioid receptors only some
  opioids react with them .

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I. Morphine

• Effective orally, but is much less effective than
  when given parenterally due to first-pass
  metabolism in the liver.
• Metabolism involves glucuronide formation, the
  product of which is excreted in the urine.

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• A. Effects of morphine
• 1. Central Nervous System Effects
• Morphine has mixed depressant and stimulatory
  actions on the CNS.
• - Depressant effects predominate in man.
• - Excitatory effects predominate in cats
  and
• horses.

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• a) Analgesia
• Drowsiness is common
• Continuous dull pain relieved more effectively
  than sharp intermittent pain
• Most patients indicate that they can still feel
  the pain, but that it no longer bothers them
• Morphine is an agonist at µ and ? opioid
  receptors.

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• b) Euphoria and sedation
• It is mainly due to activation of µ-receptor
• c) Emesis
• Morphine directly stimulates the chemoreceptor
  trigger zone, usually transient and disappear
  with repeated administration .
• d) Antianxiety
• e) Miosis (pinpoint pupil).
• It is due to stimulation of the Edenger- Westphal
  nucleus of the oculomotor nerve .

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• f) Cough reflex is inhibited
• This action, surprisingly, does not correlate
  closely with analgesic and respiratory depressant
  effect of opiates, and its mechanism of action at
  receptor level is unclear
• Chemical modification (Codiene and Pholcodiene )
  the antitussive effect can occur at sub-
  analgesic dose.

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• g) Respiration depression
• Due to a direct effect on the brain stem
  respiratory center.
• Death from narcotic overdose is nearly always due
  to respiratory arrest.
• It occur at therapeutic doses but not accompanied
  with cardiac center depression in contrast to
  other CNS depressant like general anesthetic
  agents.

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• h) Other effects
• Morphine is a basic drug causes the release of
  histamine causes the body to feel warm and the
  face, nose to itch, bronchoconstriction and
  hypotension .
• It also abolishes hunger
• It dilate the cerebral vessels and increase
  intracranial pressure

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• 2. Cardiovascular Effects
• Postural orthostatic hypotension due primarily to
  decreased V.M.C. activity leading to peripheral
  vasodilation, which may be also due in part to
  histamine release.
• In congestive heart failure, morphine decreases
  the left ventricular workload and myocardial
  oxygen demand.

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• 3. Endocrine Effects
• Increases prolactin secretion
• Increases vasopressin (ADH) secretion (oliguria).
• Decreases pituitary gonadotropin (LH FSH)
  secretion.
• Decreases stress induced ACTH secretion.

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• 4. Gastrointestinal Effects
• It decrease the motility and increase the tone of
  the intestinal circular muscle and the tone of
  the anal sphincter , it also causes contraction
  of the gallbladder and constriction of the
  biliary sphincter.
• Constipation (tolerance does not develop to this
  effect).
• Diphenoxylate and Loperamide can be used in the
  treatment of diarrhea.
• They decrease GIT motility and peristalsis

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• 5. Genitourinary Effects
• Morphine prolong the second stage of labor by
  decreasing the strength, duration and frequency
  of uterine contraction
• Inhibit urinary bladder voiding reflex (sometimes
  catheterization may be required in some cases )

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• B. Adverse Reactions
• Generally direct extensions of their
  pharmacological actions.
• Respiratory depression, apnea
• Nausea and vomiting
• Dizziness, orthostatic hypotension, edema
• Mental clouding, drowsiness
• Constipation, ileus
• Biliary spasm (colic)
• Dry mouth
• Urine retention, urinary hesitancy
• Hypersensitivity reactions (contact dermatitis,
  urticaria)
• Immunosuppression (recurrent infections)

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• C. Precautions
• Respiratory depression, particularly in the
  newborn and patients with COPD
• Orthostatic hypotension
• Histamine release (asthma)
• Drug interactions (with other CNS depressants)
• Tolerance and cross tolerance to other opioids
• Benign prostatic hyperplasia(may precipitate
  urine retention
• Dependence (psychological physical)
• Liver disease (accumulation of the drug)
• Increase intracranial pressure and head injury
  (it enhances cerebral ischemia)

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• D. Therapeutic uses
• - Analgesia myocardial infarction, terminal
  cancer, surgery, obstetrical procedures
• - Dyspnea due to pulmonary edema
• - Severe diarrhea.

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II. Other Opioid (Narcotic) Analgesics

• A. Heroin (diacetyl morphine)
• µ- agonist
• Heroin is more lipid soluble than morphine and
  about 2½ times more potent
• It enters the CNS more readily
• It is a schedule I drug and is not used
  clinically, but it is a drug of abuse.

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• B. Codeine
• From opium or synthesized by methylation of
  morphine
• Has a much better oral /parenteral absorption
  ratio than morphine.
• Effective for mild to moderate pain, cough,
  diarrhea.
• Metabolized in part to morphine by
  O-demethylation.
• µ- receptor agonist.
• Has a more potent histamine-releasing action than
  morphine.
• Dependence liability of codeine is less than
  that of morphine, .
• It is 1/12 as potent as morphine

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• C. Dextromethorphan
• Excellent oral antitussive
• No analgesic effect
• No GI effects
• No respiratory depression

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• D. Meperidine (Pethidine)
• Produces analgesia, sedation, euphoria and
  respiratory depression.
• Less potent than morphine, 80-100 mg meperidine
  equals 10 mg morphine.
• Shorter duration of action than morphine (2-4
  hrs).
• Meperidine has greater excitatory activity than
  does morphine and toxicity may lead to
  convulsions.
• Meperidine appears to have weak atropine-like
  activity.
• It does not constrict the pupils to the same
  extent as morphine.

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• Does not cause as much constipation as morphine
• Purely synthetic µ- agonist
• Not an effective antitussive agent.
• less effect in uterine contraction commonly
  employed in obstetrics also causes less urine
  retention
• Adverse reactions to Meperidine
• Respiratory depression
• Tremors
• Delirium and possible convulsions
• Dry mouth
• Severe reaction if given with MAOI, consists of
  excitement, hyperthermia and convulsions it is
  due to accumulation of pethidine (norpethidine)
  metabolite but the details are still unclear.

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• E. Fentanyl
• µ- agonist, related chemically to meperidine.
• Approximately 80 times more potent than morphine,
  main use in anesthesia .
• Duration of action very short (t1/2 20 min).
• Can be given IM, IV, transdemally or via patient
  controlled infusion system and may be given
  intrathecally.
• Often used during cardiac surgery because of its
  negligible effect on the myocardial
  contractility.

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• F. Sufentanil
• A synthetic opioid related to fentanyl.
• About 7 times more potent than fentanyl.
• Has a slightly more rapid onset of action than
  fentanyl.

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• G. Methadone
• Pharmacology and analgesic potency similar to
  morphine µ- receptor agonist.
• Very effective following oral administration.
• Longer duration of action than morphine due to
  plasma protein binding (t1/2 approximately 25
  hrs).
• Used in methadone maintenance programs for
  treatment of opioid addicts and for opiate
  withdrawal syndrome (it reduces the physical
  abstinence syndrome) make it possible to wean the
  addict from opioids.

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• H. Propoxyphene
• A methadone analog.
• Used orally to relieve mild to moderate pain, it
  is weak analgesic often combined with
  Paracetamol.
• Has a low addiction potential
• The most common adverse effects are dizziness,
  drowsiness, and nausea and vomiting.
• CNS depression is additive with other CNS
  depressants (alcohol and sedatives).
• Can cause cardio- toxicity and pulmonary edema
  which can not reversed by naloxone

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III. Mixed Narcotic Agonists/Antagonists

• These drugs produce analgesia, but have a lower
  potential for abuse and do not produce as much
  respiratory depression.

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• A. Pentazocine
• µ agonist (analgesia) and - ?- antagonist (less
  respiratory depression).
• Orally, it has about the same analgesic potency
  as codeine.
• Adverse reactions Nausea, vomiting, dizziness,
  dysphoria, nightmares visual hallucinations.
• Rarely used nowadays

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• B. Nalbuphine
• Resembles pentazocine pharmacologically.
• Like morphine, nalbuphine reduces myocardial
  oxygen demand. May be of value following acute
  myocardial infarction due to both its analgesic
  properties and reduced myocardial oxygen demand.
• Most frequent side effect is sedation.
• Less propensity to produce psychotomimetic side
  effects

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• C. Butorphanol
• Resembles pentazocine pharmacologically.
• 3.5 to 7 times more potent than morphine.
• Not available for oral administration
• They exhibit ceiling of respiratory depression
  effect

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• D. Buprenorphine
• A partial agonist at µ-receptor.
• 200 times more potent than morphine.
• Low potential abuse, but can precipitate
  withdrawal in addicts
• In naive persons it acts like morphine
• Major use is office-based detoxification of
  opioids
• Causes less sedation, respiratory depression and
  hypotension even in high doses.

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IV. Opiate Antagonists

• Opiate antagonists have no agonist properties.
  They are utilized to reverse opiate induced
  respiratory depression and to prevent drug abuse.
• A. Naloxone (Narcan)
• Pure opiate antagonist at all opioid receptors
• Given parenterally -Short duration of action
  (1-4 h)
• Can precipitate withdrawal in addicts.

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• B. Naltrexone
• Oral pure opioid antagonist
• Long duration of action
• Contraindicated in liver disease
• Used in late stages of opioid addiction treatment
  ( also in treatment of alcoholism).
• C. Nalmephine
• Long-acting parenteral opioid antagonist.