Pharmacology of Opiates (Welsh)

Question 1

Describe opiate, opioid, and endogenous opioid peptides.

Answer 1

Opiate: NATURALLY OCCURING opium-derived alkaloid, i.e., morphine or codeine

Opioid: (more inclusive group) - any natural, synthetic, or semi-synthetic compound with morphine-like properties

Endogenous opioid peptides: located primarily in the brain where they function as NTMs or neuromodulators - endorphins, enkephalins, dynorphins

Question 2

Explain the general mechanisms of action of morphine and related opioids in analgesia.

Answer 2

Morphine (inhibitory)

At presynaptic terminal - inhibits formation of cAMP
- inhibits uptake of Ca2+ -> inhibits release of NTMs that convey pain perception - substance P and glutamate

At postsynaptic terminal - opens K+ channel
- hyper polarization of cell -> dampens firing of neuron -> reduces neuron excitability and pain -> no nociception

Question 3

Describe the major uses of morphine and related opioids in the clinic.

Answer 3

Acute:

• analgesia (morphine or heroin)
• respiratory depression
• euphoria
• miosis (pupil constriction)
• cough suppresion (codeine or dextromethorphan)
• intracranial p inc.

Chronic:

• tolerance
• physical dependence

All of the clinically used mu opioid agonists produce these effects

Fentanyl used for cancer patients (stronger than morphine)

Exception:
- meperidine (demerol) -> mydriasis (pupil dilation)

Question 4

Describe the CNS effects of morphine and related opioids, including mood, sedation, respiratory depression, cough suppression, pupil constriction, nausea and vomiting, and skeletal muscle rigidity.

Answer 4

opioids act centrally (in brainstem and dorsal horn) to inhibit transmission and processing of pain signals

euphoric effect (suppress release of GABA and thereby stimulate release of dopamine in neighboring neuron)

respiratory depression

• direct effects on respiratory centers in medulla
• decreased sensitivity to increasing blood levels of CO2 in respiratory center in brainstem
• increased arterial CO2 retention -> cerebral vasodilation -> increased intracranial p
• ** MAJOR TOXICITY OF OPIOIDS and nearly ALWAYS CAUSE OF DEATH FROM OVERDOSE

pupil constriction
miosis = common sign of opioid overdose (reversed by naloxone, atropine, or ganglionic blockers)

nausea and vomiting
direct stimulation of the chemoreceptor trigger zone (CTZ) in area postrema on floor of 4th ventricle - activates vomiting center

Question 5

Define the effects of morphine on the CV system, on histamine release, and on pregnancy and the neonate.

Answer 5

CV:
- bradycardia = caused by stimulation of central vagus nerve

Histamine release:

• morphine, fentanyl, and meperidine -> cause non-immunologic release of histamine, inducing vasodilation and hypotension
• occasionally cause skin redness, urticaria (hives), and pruritus
• NOT an allergy

Pregnancy and neonate:

• used sparingly to relieve labor pain (fentanyl, butorphanol, meperidine)
• all cross placenta (can cause respiratory depression in baby)

Question 6

Compare the pharmacokinetics of morphine, fentanyl, and methadone.

Answer 6

Morphine:

• Fairly rapid absorption
• Wide distribution
• Rapid hepatic clearance from plasma
• 70% first-pass metabolism so usually not taken orally
• Hydrophilic drug so CNS penetration and exit are slow (slow onset and long duration)

Fentanyl

• 80-100x more powerful than morphine
• rapid absorption, wide distribution, short half life (60% first-pass metabolism
• extremely lipophilic, so rapidly crosses BBB and other membrane barriers

Question 7

Describe the relationships between tolerance, withdrawal syndrome, physical dependence, psychological dependence, and addiction with respect to the opioids.

Answer 7

tolerance to analgesia, respiratory depression, euphoria but NO tolerance to miosis and constipation (will see this in addicts)

giving antagonist (naloxone) to physically dependent person causes rapid onset of more severe withdrawal symptoms (sweating, rhinorrhea, vomiting, diarrhea, piloerection, mydriasis, shaking chills)

Question 8

Explain the role of methadone in the treatment of opioid addiction.

Answer 8

long-acting opioid use for DETOXIFICATION to wean addicted individual off morphine, heroin, etc…

doesn’t have same efficacy as heroin but longer half life than opioids

given orally

intensity of withdrawal symptoms is decreased

Question 9

Describe the role of naloxone, naltrexone, partial agonists, and mixed agonist-antagonists in the clinic.

Answer 9

Naloxone

• pure, competitive antagonist at mu, kappa, and gamma receptors (highest affinity for mu)
• rapid-acting: rapidly reverses overdose when injected IV or IM
• gives immediate relief from acute respiratory depression
• multiple or constant dosing - short half life
• not orally active (cannot be swallowed)
• widely used for emergency overdose
• added to many abuse-prone opioid drugs (e.g., oxycodone, buprenorphine)

Naltrexone

• long-acting opioid antagonist used for maintenance therapy and relapse prevention once detoxified
• orally active
• NOT recommended for emergency overdose or detox (use this if this is all you have)

Partial agonists

• act at mu receptor
• buprenorphine (no matter how much is taken, cannot get euphoric state b/c of ceiling effect…)
• oral buprenorphine-naloxone combo used for maintenance therapy

Mixed agonist-antagonists

• act at kappa receptor to produce analgesia and as mu antagonists
• effective analgesics for moderate to severe pain
• relatively limited toxicity
• decreased abuse potential

Question 10

Opioid overdose signs

Answer 10

RESPIRATORY DEPRESSION!

Classic tried:

• miosis
• apnea
• stupor (coma)

Pulmonary edema (later clinical manifestation)