OPIOIDS Pharmacology

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OPIOIDSPharmacology

• James R. Boyce, M.D., FRCP(C)
• Division Director, Anesthesia Services
• UAB Department of Anesthesiology

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History

• Opium, poppy seed pods
• Papaver somniferum
• Ancient documents (Greek, Egypt, Roman)
• 1803 Sertürner, Isolated morphine
• Morpheus, Greek God of Dreams

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Basic Pharmacology

• Morphine 10 of 20-alkaloid volume
• Structure
• (Morphine, pg 513)
• Substitute at N-Ch3 Naloxone
• Acetylation of C3 C6 Heroin

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Endogenous Opioid Peptides

• MET - Encephalins
• Opioid Precursor Proteins LEU - Encephalins
• Found at brain sites for Endomorphin
• pain modulation
• Found in adrenal medulla
• Found in gut neural plexus
• More Delta than MU

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Pharmacokinetics

• Good absorption through most membranes, i.e.,
  fentanyl patch
• Oral Route limited efficacy 2 to
  glucuronidation (first pass)
• Methyl group at C3 protects from glucuronidation
  codeine

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Drug Distribution

• Vessel rich group
• Muscle mass reservoir
• Heroin (C3 C6) crosses BBB (blood brain
  barrier)
• Crosses placenta

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Metabolism

• Conjugation w/ glucuronide polar?excreted in
  kidney
• Morphine 6 glucuronide active NB renal
  failure
• Hydrolysis esters (Heroin, remifentanil)
• To Morphine
• N-Demethylation (oxycodone, merperidine, seizures
  if metabolites accumulate renal failure)
• Cytochrome P-450 oxidation fentanyl

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Pharmacodynamics

• Receptors in brain spinal cord
• Types
• MU morphine (sub 1,2)
• Analgesia, euphoria, respiratory depression,
  physical dependency
• Delta Kappa (female gt male)
• Some analgesia
• Strong binding with enkephalins

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Cellular Actions

• Receptors linked to G proteins
• Ion gating
• Intracellular Ca disposition
• Phosphorylation

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Cellular Actions

• Opioids close voltage gated Ca channels
• Reduce presynaptic transmitter release from pain
  nerves
• ACH, serotonin, glutamate, nor-epi, substance P
• All 3 receptors function this way

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Cellular Actions

• Opioids open postsynaptic K channels ?
  hyperpolarize ? cells resist depolarization and
  pain impulse transmission, mainly MU

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Receptor Distribution

• Autoradiographic localization
• MU, Delta, Kappa in dorsal horn
• M-d-k primary afferent pain nerves
• Rationale for spinal opioids
• Pain modulating descending pathways
• Rostral ventral medulla
• Locus ceruleus
• Midbrain periaqueductal gray

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Receptor Distribution

• Opioids inhibit inhibitory intermediate neurons
  which allows descending inhibitory modulating
  neurons to be activated !!!

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Receptor Distribution

• Central MU receptoractivation releases endogenous
  opioids
• Peripheral MU receptors in inflamed tissue
  clinical arthroscopy

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Tolerance Physical Dependence

• Tolerance increasing dose for constant effect
• Physical dependence always present with
  tolerance withdrawal or abstinence syndrome when
  drug withheld
• MU receptor manifestation
• Associated with increased c AMP and enhanced GABA
  release

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Chronic Pain

• Peripheral sensitization increase excitability
  of sensory nerves (peripheral receptors)
• Central sensitization dorsal horn becomes more
  responsive

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New Analgesics

• Decrease synaptic transmission in nociception
• Ligand gated ion channel receptors
• Examples
• Blockers for VR1 receptors (heat, acidity)
• Blockers for P2X receptors (purines are ligands)
• Mexiletine blocks PN3/SN5 sodium channel in
  dorsal horn

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New Analgesic

• W-conotoxin (marine snail toxin) blocks some
  N-type Ca channels
• Ketamine NMDA aspartate blocker minimizes
  central sensitization (preemptive analgesia)
• GABA pentin, epibatidine (nicotinic agonist)
  modify central release of nociception transmitters

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Opioids Organ System Effects

• CNS
• Analgesia sensory affective
• Euphoria (when given for pain)
• Dysphoria when no pain
• Sedation (with phenanthrenes) horses excitement
• Respiratory depression
• Vent
• CO2

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Opioids Organ System Effects

• CNS
• Cough suppression codeine
• Miosis all opioids
• No tolerance (diagnosis)
• Blocked by antimuscarines
• Truncal rigidity
• Supraspinal
• Pancuronium
• Nausea / vomiting
• Chemoreceptor trigger zone
• Vestibular

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Opioid Organ System Effects

• CVS
• Inotropic ?
• Dromotropic ?
• Chronotropic
• Fentanyl brady
• Meperidine tachy
• BP down if hypovolemic venous pooling
• Respiratory depression ??PCO2 ??CBF ??ICP

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Opioid Organ System Effects

• GI
• Constipation decreased peristalsis
• Decreased gastric acidity
• Spasms colicy pain
• Biliary
• Construction of sphincter of Oddi
• GU
• ?U/O ?RPF ?GFR ?ADH ?Na reabsorption
• Ureteral colic
• Urinary retention

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Opioid Organ System Effects

• Uterus Prolonged Labor
• Neuroendocrine
• ?ADH
• ?Prolactin
• ?Somatotropin
• ?Luteinizing hormone
• Immune
• ?Natural killer cell cytolytic activity

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Clinical Pharmacology

• Analgesia
• Most common error under dosing
• Fixed-interval better than prn dosing
• Alpha-2 agonists potentiate analgesia
• Placental transfer neonatal narcosis
• Bowel spasms (opiate induced) can aggravate
  abdominal pain

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Clinical Pharmacology

• Acute Pulmonary Edema CHF
• Morphine
• ?Preload
• ?Negative intrathoracic pressure
• ?After load

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Clinical Pharmacology

• Cough
• Codeine
• Diarrhea
• Phenylpiperidines are good
• Codeine

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Clinical Pharmacology

• Anesthesia
• Premedicants (IM or IV sedation)
• Induction (IV)
• Pre-emptive analgesia
• Maintenance (IV bolus or Infusion)
• Use sympathetic signs
• Pupil size
• Sweating
• Heart rate
• BP

Pre op Use Alters Dosing
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Anesthesia

• Epidural or intrathecal
• Great analgesia
• Itching (R? low dose naloxone)
• APS (Acute Pain Service)
• Thoracic epidural
• Bupivicaine with opioid
• PCA
• Patient controlled analgesia
• ? Patient comfort
• ? Opioid used

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Clinical Pharmacology

• Tolerance
• After 2-3 weeks use
• More with large dosages
• Respiratory depression
• Nontolerant 60 mg M/S respiratory arrest
• Tolerant 2000 mg M/S respiratory arrest
• Miosis no tolerance

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Clinical Pharmacology

• Physical Dependence
• MU related
• Always with tolerance
• Definition withdrawal or abstinence syndrome
  6-10 hours after last dose or immediately after
  naloxone

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Clinical Pharmacology

• Physical Dependence (continued)
• Sign / Symptoms Rhinorrhea, lacrimation,
  yawning, chills, gooseflesh, hyperventilation,
  hyperthermia, mydriasis, muscle aches, vomiting,
  diarrhea, anxiety, hostility, exacerbation of
  pain, pulmonary edema (naloxone).
• Manifestations
• Peak 48 hours
• Dissipate 5 days

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Important Clinical Principle

• GIVE OPIATE ABUSERS WHAT
• THEY NEED WHEN ANALGESIA
• IS REQUIRED

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Clinical Pharmacology

• Antagonist
• Naloxone
• 0.4 mg per vial
• .04 mg bolus
• Duration 2 hours (remorphinized)