Opioid Analgesics

Question 1

General characteristics of opioids

Answer 1

• Opiods are peptides
• Peptide systems appear to be distinct.
• Peptides demonstrate some selectivity for different receptors, but there must also be more regulation at level of gene expression, protein processing, and peptide release.
• Effects of peptides can be antagonized by naloxone.
• Peptides can mediate all of responses seen with exogenous opiate drugs including analgesia, tolerance and dependance.

Question 2

Classes of endogenous opioids + examples

Answer 2

• Enkephalins: act as modulatory NT’s at synapses, found in brain and spinal cord, ex. methionine enkaphalin
• Endorphins: NT and neurohormones, responsible for runners high, found in hypothalamus and pituitary, ß-endorphin is an example
• Dynorphin: role unclear, ex. Dynorphin A
• Endomorphin: μ-receptor selective

Question 3

Opioid mechanisms @ CNS and PNS

Answer 3

• Receptors = μ, δ, and κ
  
  • all are coupled to GTP-binding proteins- Gi and Go .
• Binding decreases neuronal excitability in 3 ways:
• Inhibits release of presynaptic NT’s through inhibition of Ca2+ channels.
• They can also activate K+ channels leading to membrane hyperpolarization.
• Finally, they inhibit cAMP synthesis, which also decreases NT action

Question 4

Sites of opioid action @ CNS and periphery

Answer 4

• analgesia: periaqueductal gray (descending pain), medulla nuclei (side effect-respiratory depression), spinal cord dorsal horn (ascending pain)
• limbic and motor CNS regions: amygdala, hippocampus, striatum (affective response to pain)
• “reinforcement” regions in CNS: ventral tegmentum, nucleus accumbens (addiction-abuse)
• gut: myenteric plexus (side effect-constipation).

Question 5

Opioid Agonists at μ receptors

Answer 5

• Phenanthrines: Morphine, heroin (diacetylmorphine), codeine, oxycodone, ixtcibtub, percodan, percocet, hydrocodone (in vicodin), Tramadol
• Phenylpiperidines: meperidine, loperimide, fentanyl
• Phenylheptamines: methadone

Question 6

Mixed opioid agonists/antagonists and partial agonists

Answer 6

• Benzomorphans: bupernorphine - partial μ agonist and partial morphine antagonist
• Pentazocine: A κ agonist, μ antagonist, spinal analgesia with less respiratory depression. Can also precipitate withdrawal in people dependant on μ agonists.

Question 7

Opioid antagonists

Answer 7

• Naloxone blocks all effects of opiods,
  
  • competitive antagonist, short duration
  • naltrexone, alvimopam

Question 8

Life-threatening side effects of opioid drugs

Answer 8

• **Respiratory depression - primary cause of opiod-induced death (overdose)*** Most important!
  
  • Respiratory function is depressed even at analgesic doses
  • Due to decrease in sensitivity of CO2 in brain stem respiratory centers
  • Increase in blood CO2 → cerebral vasodilation → exacerbate head injury
• Opioids ==> histamine release ==> anaphylaxis

Question 9

Other side effects of opioid drugs

Answer 9

• behavioral effects
• nausea/vomiting
  
  • activated @ low doses
  • depressed @ high doses
• cough suppression
• pupillary constriction
• GI symptoms
  
  • consipation
• urinary retention
• mild CV effects

Question 10

Medical indicaiton for opioid use

Answer 10

• Pain associated with cancer
• Painful diagnostic procedures (in combo with LA and tranquilizers)
• Post-op pain
• Obstetrical anesthesia
• Patient controlled anesthesia
• Cough (lower doses), separate from analgesic actions
• Bile stones (pain treated with opiod), use atropine too to relax SM
• MI: analgesia, alleviates apprehension, decreases cardiac load
• Pulmonary edema associated with heart failure (unknown mechanism, only exception for respiratory conditions)

Question 11

Contraindications for opioid use

Answer 11

• Increased ICP and suspected head injury - can cause cerebral vasodilation
• Depressed respiratory function (asthma, emhpysema, sleep apnea, severe obesity, etc.)
• Hypotension - can cause further decrease in BP
• Shock - opiod agonist might make worse b/c endogenous opiods may be active in shock response

Question 12

Potential drug sources of adverse interaction with opioids

Answer 12

• CNS depressants
• phenothiazines (antipsychotics)
• MAO inhibitors and tricyclic antidepressants

Question 13

Opioid interaction w/CNS depressants

Answer 13

• e.g. barbituates
• Additive or synergistic CNS depression
• Can increase metabolism of some opioids (meperidine)

Question 14

Opioid interaction w/phenothiazines (antipsychotics)

Answer 14

• Used to increase opioid analgesia, but also increases respiratory depression.
• Can also increase hypotensive effects of opioids
• Some can reduce analgesic actions of opioids.

Question 15

Opioid interaction w/MAO inhibitors and Tricyclic Antidepressants

Answer 15

• Increase respiratory depression.
• Can induce CNS excitation, delirium and seizures.
• However, combination therapies using antidepressant 5HT and NE
• Reuptake inhibition and opiate agonist activities may be useful in chronic pain treatment by potentiating the inhibitory descending pain pathway (example: Tramadol)

Question 16

Characteristics of tolerance

Answer 16

• tolerance = a decrease in response to a drug as a result of previous exposure. Need an increased dose to achieve same pharmacological effect.
• Linked to receptor desensitization
• Frequency, dose, and duration of use all contribute
• Significant tolerance not commonly seen over 2-3 weeks at normal therapeutic doses
• Tolerance doesn’t develop for all symptoms:
  
  • no tolerance (GI, pupils)
  • tolerance(analgesia, respiratory depression, euphoria)
• Can generalize to similar drugs such as all µ antagonists
• Tolerance reverses following withdrawal (addict who quits and then relapses may then OD if goes back to old dose)

Question 17

Characteristics of dependence

Answer 17

• Dependence = easily produced by opiods, most common in pain-free individuals abusing them or long term chronic pain treatment
• Physical: the continued use of a drug to maintain a normal physiologic state
• Psychic: the continued desire or craving for a drug (addiction)

Question 18

Characteristics of withdrawal

Answer 18

• Withdrawal: occurs following cessation of opiod administration following prolonged use
• Symptoms include dilated pupils, insomnia, restlessness, yawning, rhinorrhea, sweating, diarrhea, nausea, cramps, chills - a flu like syndrome
• Can be prevented with opiod maintenance therapy
• Can be precipitated in addicts with antagonists or even partial agonists and mixed antagonist/agonists
• Clonidine used to treat withdrawal symptoms caused by sympathetic outflow
• Withdrawal is not life threatening unlike in EtOH and barbituates

Question 19

Opioids vs. Small Molecule NTs

Answer 19

• most neurons: produce conventional NTs and 1+ neuropeptides
  
  • peptides = w/in large dense-core vesicles found in all parts of neuron
  • vs. other NTs = w/in small synapitc vesicles
• Ach- ion channel
• NE - G protein
• GABA - ligand gated ion channel (ionotropic)
• Glutamate - ionotropic and metabotropic
• 5HT - G protein
• Opioids - G protein