Leffler 1a

Question 1

Opioids:ADME

Answer 1

• Absorption
  
  • subject to first pass effect
    
    • much higher oral dose is needed than parenteral dose
    • codeine and oxycodone has reduced first-pass effect
  • Buccal (Lozenges)
  • Transdermal patches (fentanyl patch)
  • nasal spray
  • IV
• Distribution
  
  • leave blood rapidly
  • concentrate in highly perfused tissues
• Metabolism
  
  • Most are glucuroniated (Phase II metabolism)
    
    • to M3G(neuroexcitatory) and M6G (analgesia)
• Excretion:
  
  • Renal

Question 2

Opioid Drug Classification:

Answer 2

• Pure Opioid Agonists
• Agonist-Antagonist Opioids (mixed)
• Pure Opioid Antagonists

Question 3

Morphine

Answer 3

• Pure opioid agonist prototype
• General MOA:
  
  • ​agonist at MU receptors
  • less at KAPPA
• Therapeutic use: Mainly analgesic

Question 4

Morpine: ADME

Answer 4

• Absorption:
  
  • PCA Pump
  • IV
  • IM
  • Oral
  • subcutaneous
  • epidural
  • intrathecal
• Metabolism:
  
  • 1st pass metabolis m
  • Glucuronidatd to M6G(analgesia) and M3G(neuroexcitatory)
• Excretion:
  
  • Renal (mostly)

Question 5

Morphine: Tolerance and Dependence

Answer 5

• Tolerance:
  
  • prolonged Tx=tolerance to analgesia, Euphoria, sedation, respiratory depression
  • little tolerance to miosis and constipation
  • cross tolerance to other opioid agonists
• Physical Dependence
  
  • minimize withdrawal by tapering dose overe 3 days
    
    • or 7-10 days in addict

Question 6

Morphine: Specific Clinical Uses

Answer 6

• Analgesia
  
  • pre and post operative analgesia (regional analgesia via epidural or intrathecal)
  • Pain of terminal illness
  • Visceral pain of trauma (Burns, cancer, acute MI, renal/biliary colic)
  • Continued dull pain is relieved more effectivley than sharp intermittent pain (but can be achieved with higher doses)
  • Controlled pain in patient
• Acute pulmonary edema
  
  • relieves dyspnea
• Pre-anesthetic
  
  • supplement to anesthesia

Question 7

Morphine: Specific Adverse Effects

Answer 7

• Respiratory Depression:
  
  • direct inhibition of respiratory center in brainstem
  • decreased respiratory rate
• Constipation
  
  • decreased GI motility
• Sedation
• Emesis-Nausea and Vomiting
  
  • direct stimulation of the CTZ in the medulla
• Elevation of ICP
• Urinary Retention
• Orthostatic hypotension
• Miosis (pin poin pupil)
• Pruritus
• Loss of recent memory
• decreased abilty to concentrate

Question 8

Morphine: Contraindications

Answer 8

• Pregnant
  
  • physical dependence of infant
• Labor and Delivery
  
  • can suppress uterine contractions and prolong labor
  • respiratory depression in neonate
• Emphysema and COPD
  
  • Decreased respiratory reserve, can reduce resipration in patient with impaired pulmonary function
• Head injury
  
  • can increase respiratory depression and increase ICP
• IBD
  
  • Toxic Megacolon
• Drug Interactions:
  
  • Other CNS depressants:
    
    • antipsychotic
    • antidepressents
    • antiepileptics
  • MAOIs (monoaminno oxidase inhibitors)
    
    • hyperthermia
    • seizures
    • coma

Question 9

Other Pure opioid agonists?

Answer 9

• Hydromorphone
• Oxymorphone
• Levorphanol
• Meperidine
  
  • short term use only
  • toxic metablite that could accumulate and cause CNS excitation
  • serotonin syndrome when given with MAOIs
• Fentanyl
• Methadone
• Codeine
  
  • prodrug
• Oxycodone, Hydrocodone
• Diphenoxylate/Atropine,Difenoxin,Loperamide
  
  • treat diarrhea
  • minimal dependency liability

Question 10

Codeine

Answer 10

• Pure Opioid agonist
• Prodrug
  
  • metabolized by CYP2D6–>Morphine (active component)

Question 11

Mixed Action Opioids

Answer 11

AKA Agonist-Antagonist Opioids

• Partial Antagonist/Agonist at Mu receptor and Agonist at Kappa receptor
• Drugs:
  
  • Pentazocine
  • Butorphanol
  • Nalbuphine

Question 12

Mixed Action opioids used for:

Answer 12

• Moderate pain
• Not much:
  
  • respiratory depression
  • euphoria
  • potential for abuse
• Less dependence than morphine
• Given alone=Analgesia
  
  • less analgesia than morphine
• If given to a patient already taking a pure opioid, it will inhibit the analgesia
• Increase workload of the heart
  
  • avoid in MI patients
• Can precipitate withdrawal in patients who are physically dependent on pure opioid agonists

Question 13

Buprenophrine

Answer 13

• Mixed action opioid
• Buprenorphine + Nalozone=Suboxone
• MOA:
  
  • partial Mu agonist
  • Full antagonist at Kappa
• Used to maintain abstinence from addiction (heroin)

Question 14

Methadone HCl

Answer 14

• More effective orally than morphine
• Abstinence:
  
  • slower in onset
  • longer in duration
  • less intense
• Detoxification and maintenance of heroin addicts
• used as an analgesic in chronic pain

Question 15

Opioid Antagonists:

Answer 15

• MOA:
  
  • antagonist at MU and Kappa receptor
• used to treat opioid OD, but also post operative opiod depressoin
• Drugs:
  
  • Naloxone (narcan)
    
    • prototype
    • block or reverse the effects of morphine
      
      • respiratory depression
      • coma
      • analgesia
    • Nasal spray
  • Naltrexone
    
    • similar to naloxone but oral
  • Nalmefene
    
    • Long-acting analog of naltrexone

Question 16

Opioid antagonist usd to treat opioid-induced constipation with advanced illness or pain:

Answer 16

• Methylnaltrexone
  
  • injectable
  • long term use
• Alvimopam
  
  • short term
  • post operative

Question 17

Spinal Cord Transection: Immediate vs Long Term results

Answer 17

• Immediate Results:
  
  • Areflexia-loss of all reflexes
  • Flaccid paralysis
  • loss of autonomic function
  • lasts 3-4 weeks in humans
• Long Term:
  
  • Slow return of reflex actions
  • Hyperreflexia-Reflexes strengthen:
  • Spastic paralysis
  • Pathological reflex:
    
    • babinski sign
    • Clonus
    • Clasp-Knife response

Question 18

Myotatic (Stretch Reflex)

Answer 18

• Role=posture
• Myotatic-extended muscle
• Graded resistance to change in muscle length
• Muscle spindle=sensory receptor
• Length detector:
  
  • muscle spindle attached parallel to extrafusal fibers