40. Drug Action on Opioid Receptors Flashcards
Explain the categories of opioid receptors based on potency.
Stong agonists
* Morphine
* Hydromorphone
* Oxymorphone
* Methadone
* Meperidine
* Fentanyl
* Levorphanol
Mild to moderate
* Codeine
* Oxycodone
* Dihyrocodeine
* Hydrocodone
* Propoxyphene
* Diphenoxylate
* Loperamide
Mixed agonists and antagonists
* Nalbuphine
* Buprenorphine
* Butorphanol
* Pentazocine
* Dezocine
Antagonists
* Naloxone
* Naltrexone
* Nalmefene
Describe the basic characteristics of morphine.
Strong agonist of opioid receptors
* found naturally in plants and animals
* a benzylisoquinoline alkaloid with two additional ring closures
* morphine sulfate injection - 50 mg/mL
* morphine sulfate tablet - 60 mg/mL
Explain how morphine acts in the body.
- binds to and activates the u-opioid receptor (STRONG AGONIST) in the CNS and GI –> results in analgesia, sedation, euphoria, physical dependence, and respiratory depression
- binds to and activates the k-opioid receptor to associate with spinal analgesia, miosis (pinpoint pupils), and psychotomimetic effects
- doesn’t directly bind to the d-opioid receptor, but is involved in downstream functions of the d-opioid receptor
What are the effects of morphine?
- analgesia
- euphoria
- respiratory depression
- antitussive
- miosis
- slow GI tract
Describe the association between morphine and analgesia.
Morphine causes analgesia by:
* raising pain threshold at the spinal cord level
* altering the brain’s perception of pain
Patients treated with morphine are aware of the presence of pain, but the sensation is not unpleasant
analgesia - relief of pain without the loss of consciousness
Describe the association between morphine and euphoria.
Euphoria is caused by disinhibition of the dopamine-containing neurons of the ventral tegmental area.
* powerful sense of contentment and well-being.
Describe the association between morphine and respiratory depression.
Morphine causes respiratory depression by reduction of the sensitivity of respiratory center neurons to CO2.
* most common cause of death in acute opioid overdoses
* tolerance to respiratory depression develops quickly with repeated dosing –> allows safe use of morphine for treatment of pain
Describe the association between morphine and cough.
Morphine has antitussive properties
* the receptors involved in the antitussive action are different from those involved in analgesia (inability to feel pain)
Describe the association between morphine and miosis (pinpoint pupils).
Morphine causes miosis because of stimulation of u and k receptors.
* little tolerance to miosis –> all morphine abusers have pinpoint pupils
* Important for diagnosis because many other causes of coma and respiratory depresssion produce dilation of the pupil
Describe the association between morphine and emesis.
Morphine causes emesis (vomiting) because it directly stimulates the chemoreceptor trigger zone in the area postrema.
Describe the association between morphine and diarrhea/constipation.
Morphine relieves diarrhea by decreasing the motility and increasing the tone of the intestinal circular smooth muscle.
* produces constipation with little tolerance developing
* stool softener docusate + stimulant laxative senna = treats opioid-induced constipation.
Describe the association between morphine and diarrhea/constipation.
Morphine relieves diarrhea by decreasing the motility and increasing the tone of the intestinal circular smooth muscle.
* produces constipation with little tolerance developing
* stool softener docusate + stimulant laxative senna = treats opioid-induced constipation.
Describe the association between morphine and the biliary tract.
Morphine can increase biliary tract pressure due to contraction of the gallbladder and constiction of the biliary spincter.
Describe the association between morphine and the cardiovascular system.
At low doses, there are no major effects on blood pressure or heart rate.
At high doses, hypotension and bradycardia may occur.
Describe the association between morphine and histamine.
Morphine releases histamine from mast cells causing urticaria, sweating, and vasodilation.
* should be used with caution in patients with asthma because it can cause bronchoconstriction
What are the medical uses of morphine?
- pain relief
- acute pulmonary edema
- shortness of breath.
- opioid use disorder
Explain tolerance and physical dependence of morphine.
Repeated use of morphine produces tolerance to the respiratory depressant, analgesic, euphoric, and sedative effects of morphine.
* tolerence doesn’t develop for miosis
Physical and psychological dependence can occur with morphine
Withdrawal - produces a series of autonomic, motor, and psychological responses that incapacitate the individual and causes serious symptoms (death is rare)
Describe the characteristics of hydromorphone.
Strong opioid receptor agonist
* orally active and semisynthetic analog of morphine
* approximately 8-10x more potent than morphine
* Preferred over morphine in patients with renal dysfunction due to less accumulation of active metabolites
Describe the characteristics of oxymorphone.
Strong opioid receptor agonist
* semisynthetic opioid analgesic
* oral form is 3x more potent than oral morphine
* oral form available in both intermediate-acting and extended-release
* no clinically relevant drug-drug interactions associated with the P450 enzyme system
Describe the characteristics of fentanyl.
Strong opioid receptor agonist
* synthetic opioid
* has a 100-fold the analgesic potency of morphine
* highly lipophilic
* rapid onset and short duration of action (15-30 mins)
* fentanyl + local anesthetics = epidural analgesia for labor and postop pain
* used in anesthesia for analgesic and sedative effects
* Used in the treatment of cancer patients with breakthrough pain who are tolerant to opioids
Describe the characteristics of methadone.
Strong opioid receptor agonist
* acts by binding to the u-opioid receptor, but also has affinity for the N-methyl-D-aspartate (NMDA) receptor (a glutamate receptor)
* metabolized by CYP3A4, 2B6, and 2D6, and substrate of the ABCB1 efflux transporter in intestines and brain
* Methadone is used for the treatment of opioid dependency (long-term and short periods w/o withdrawal symptoms)
* Also used analgesic in chronic pain –> more effective against neuropathic pain because of activity with NMDA receptor
Describe the characteristics of codeine.
Moderate agonist of opioid receptors
* selective agonist of the u-opioid receptor (less effective than morphine)
* functions as a prodrug of its major active metabolite, morphine, catalyzed by CYP2D6
* CYP2D6 activity varies in patients and ultra-rapid metabolizers may experience higher levels of morphine, leading to possible overdose.
* Genetic polymorphisms of the CYP2D6 gene have implication on codeine associated toxicity
* Drug interactions associated with the CYP2D6 enzyme may alter the efficacy of codeine or lead to toxicity
Explain the medical uses of codeine.
- pain relief
- cough depressant
- diarrhea
Describe the characteristics of oxycodone.
Moderate agonist of opioid receptors
* semisynthetic derivative of thebaine, an opioid alkaloid found in the opium poppy
* metabolized via CYP2D6 and 3A4, excreted via the kidney
* Used for managing moderate to moderately severe acute or chronic pain
* available as controlled-release tablet, first-line treatment for cancer pain with less side effects than morphine
