Medical Pharmacology Chapter 44:  Opioids

Opioids

•  Nomenclature

  • "Narcotic" -- imprecise term suggesting "narcosis": indicated of a somnolent state

  • "Opioid analgesic" -- more appropriate: suggesting 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 (Narcan) -nonselective opioid receptor antagonist

•   Source

  • Opium -- from the opium poppy

    • Constituents:

      • Morphine

      • Dodeine

      • Thebaine-- nonanalgesic

      • Papaverine-- nonanalgesic, vasodilator

• Classification/Chemistry

  • Opioid Classification:

    • Full agonists (high efficacy, strong agonists)

    • Partial agonists

      1. May cause agonist effects; may displace full agonists thereby reducing their effects.

      2. A partial agonist may act either as an agonist or antagonist

    • Antagonists: multiple opioid receptor subtypes allow agonists/antagonist combination effects -- e.g.:

      • Opioid -- agonist at one opioid receptor subtype; partial agonist or antagonist at another subtype -- "agonist-antagonists" or "mixed agonist-antagonists"

    • Examples:

      • Naloxone (Narcan): pure antagonist: no effects normally associated with agonist binding

      • Morphine: full agonist at mu receptor

      • Codeine: partial or "weak" agonist -- < maximal effect with complete receptor saturation

      • Nalbuphine (Nubain)  : agonist that one opioid receptor; antagonist at another

• 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 (see below)

    • 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.

    •  

      Morphine

       

    • Codeine and Oxycodone (methylated at C₃)

• Acetylation of both morphine hydroxyls results in heroin which has more rapid access across the blood-brain barrier compared morphine; in the brain heroin:

  • Is rapidly hydrolyzed to monoacetylmorphine and morphine

• Endogenous Opioid Peptides

  • Morphine (and related agents) cause analgesia by acting the brain regions containing peptides which have opioid-like properties

  • Endogenous substances = endogenous opioid peptides

  • Previous used term "endorphin" now refers to ß-endorphins and related peptides derived from the precursor: prepro-opiomelanocortin

  • Most widely distributed opioid analgesic peptides:

    • Pentapeptides

      1. Methionine-enkephalin (met-enkephalin)

      2. Leucine-enkephalin (leu-enkephalin)

  • Three major precursor proteins:

    • Prepro-opiomelanocortin (POMC) {contains}:

      • Met-enkephalin sequence

      • ß-endorphin sequence

      • Some nonopioid peptides:

        1. ACTH

        2. ß-lipotropin

        3. Melanocyte-stimulating hormone

    • Preproenkephalin (proenkephalin A ) {contains}:

      • Six copies of met-enkephalin

      • One copy of leu-enkephalin

    • Preprodynorphin (proenkephalin B) {contains-- active peptides containing the leu-enkephalin sequence}:

      • Dynorphin A

      • Dynorphin B

      • α and →β neoendorphin

  • Endogenous opioid precursors: localized at pain modulation brain regions

    • May be released during: stress (pain; pain anticipation)

    • Precursor molecules also found:

      • Adrenal medulla

      • Neural plexuses of the gut

Pharmacokinetics

• Absorption

  • Opioid analgesics: generally well absorbed destined cutaneous/intramuscular/mucosal surfaces

  • Fentanyl transdermal: important Route of Administration

  • Gastrointestinal absorption:

    • Some opioids-- subject to first-pass effects:

    • Codeine; oxycodone -- high oral: parenteral potency (protected from conjugation by substitution on C₃ aromatic hydroxyl)

• Distribution

  • Various extent of plasma protein binding

  • Highest concentrations in tissues: function of perfusion

  • 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:

      1. Placental opioid transfer (uses in obstetric analgesia) can result in depressed respiration in the newborn.

• Metabolism

  • Conversion to polar metabolites; renal excretion

  • Opioids with hydroxyl groups: likely conjugated with glucuronic acid

    • Examples: morphine , levorphanol (Levo-dromoran) 

    • Morphine-6-glucuronide: analgesic potency (perhaps > parent compound morphine)

    • In patients with compromised renal function:accumulation metabolites -- prolonged analgesia

  • Esters: hydrolyzed by tissue esterases:

    • Examples: heroin, remifentanil (short duration of action)

  • N-demethylation: minor pathway

    • Accumulation of demethylated meperidine (Demerol)  metabolite, normeperidine:

      • Patients with decreased renal function or on high dosages: CNS excitatory effects:

        •  Seizures (more likely in children)

  • Oxidative metabolism (hepatic) primary route of phenylpiperidine opioid metabolism:

    • Fentanyl (Sublimaze)

    • Alfentanil (Alfenta)

    • Sufentanil (Sufenta)

• Excretion

  • Polar metabolites are associated with renal excretion with small amounts excreted unchanged

  • Glucuronide conjugates entering the bile may be subject toenterohepatic circulation to a minor extent.

Pharmacodynamics

• Mechanism of Action

  • Analgesia: specific receptor binding -- localization:

    • Spinal cord

    • Brain

• Receptor Types

  • Mu (μ)

  • Delta (γ)

  • Kappa (κ)

  • General Opioid Receptor Characteristics:

    • G protein coupled receptor family

    • Significant amino acid sequence homology

    • Each-receptor: subtypes

      • μ₁, μ₂

      • γ₁, γ₂

      • κ₁, κ₂

  • Receptor types and physiological effects:

    • Mu (μ) :Analgesia, euphoria, respiratory depression, physiological dependence

    • Most opioid analgesics: act at the mu receptor

    • Delta (γ) and Kappa (κ): Spinal analgesia

  • Drugs/endogenous opioids: Receptor- type affinity

    • morphine -- (μ)

    • pentazocine -- (κ) some (μ)

    • endogenous opioid peptides:

      • leu-enkephalin --(γ)

      • dynorphin --(κ)

  • Opioid Receptor Subtype

    Drug	Mu (m)	Delta (d)	Kappa (k)
    Opioid Peptides
    Enkephalins	Antagonist	Agonist
    beta-endorphin	Agonist	Agonist
    Dynorphin	Weak Agonist		Agonist
    Agonists
    Codeine	Weak Agonist	Weak Agonist
    etorphine	Agonist	Agonist	Agonist
    fentanyl (Sublimaze)	Agonist
    meperidine (Demerol)	Agonist
    methadone (Dolophine)	Agonist
    Morphine	Agonist	Weak Agonist
    Agonist-antagonists
    Buprenorphine	Partial Agonist
    dezocine (Dalgan)	Partial Agonist	Agonist
    nalbuphine (Nubain)	Antagonist		Agonist
    pentazocine (Talwain)	Antagonist or Partial Agonist		Agonist
    Antagonist: naloxone (Narcan)	Antagonist	Antagonist	Antagonist

• Cellular Action

  • Opioids:  G protein linked  affecting:

    • Ion channel state

    • Intracellular Ca²⁺ levels

    • Protein phosphorylations states

  • Two well-defined opioid actions:

    1. Reduction in neurotransmitter release by closing a voltage-gated Ca²⁺ channel on presynaptic neuronal terminals.

    2. Inhibition of postsynaptic neurons through membrane-potential hyperpolarization by increasing K⁺ channel conductance.

     

• Spinal cord presynaptic sites

  • Spinal Cord Sites of Opioid Action

  • Reduction in neurotransmitter release affects acetylcholine, norepinephrine, glutamate, serotonin, and substance P systems.

  •  

    Pain Neurochemistry

    Serotonin, bradykinin, histamine, prostaglandins, substance P (sP) , and various ions (ie, H+ or K+)--the biochemical mediators released as a result of tissue injury--have been implicated in nociceptive activation and sensitization (hyperalgesia).  Hyperalgesia results in enhancement of spontaneous pain via a reduction in pain threshold and a lengthening in duration of nociceptor response to stimuli.  PGE1, PGE2, and PGF2a, are the most potent prostaglandins to produce these sensitization effects.  Substance P, synthesized by cells of the spinal ganglia, has been identified at the peripheral terminal of unmyelinated primary afferent fibers.  This putative neurotransmitter may play a role in the propagation of visceral nociceptive pain from the gastrointestinal (GI) tract, ureters, and urinary bladder.  In addition, to sP, other potential nociceptive transmitters include glutamate, aspartate, somatostatin, cholecystokinin, and vasoactive intestinal polypeptide. courtesy of Roxane Pain Institute used with permission

• Opioid Receptor Distribution

  • Spinal cord: dorsal horn

  • Primary afferents to pain transmission neurons

    • Opioid agonists:

      • Inhibit excitatory transmitters release from these primary afferents

      • Inhibit dorsal horn pain transmission neurons

      • Clinical application: directed demonstration of opioid agonists allow regional analgesia which minimizes CNS side effects

• Systemic Opioid Administration

  • Action in both supraspinal and spinal sites

  • Important opioid binding sites in descending pathways

    • Rostral ventral medulla

    • Locus ceruleus

    • Midbrain periaqueductal gray

  • Administration of exogenous opioids promotes release of endogenous opioids

• Tolerance/Physical Dependence

  • Repeated opioid administration:

    • Gradual loss of effect, e.g. tolerance

  • Physical Dependence = physiological withdrawal symptoms (abstinence syndrome) if an antagonist is administered or the agonist is stopped.

  • Tolerance is not developed equally to all opioid effects.

•  

  Opioid Effects: Degree of Tolerance Developed

  High	Intermediate	Limited/None
  Analgesia	Bradycardia	Miosis
  Euphoria, dysphoria		Constipation
  Mental clouding		Convulsions
  Sedation		Antagonist actions
  Respiratory depression
  Antidiuresis
  Nausea/vomiting
  Cough suppression

  adapted from Figure 31-4: Way, W.L., Fields, H.L. and Way, E. L. Opioid Analgesics and Antagonists, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p. 505.

 

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