Test 4: Opioids Basic Overview & Pharmacokinetics Flashcards
What are the 2 main groups of Opioids?
-Benzylisoquinoline Alkaloids
-Phenanthrenes
What are the Benzylisoquinoline Alkaloids?
-Muscle relaxants. No analgesic properties
-Structure is based on benzene ring - 6 carbons
-Ex: Papaverine. Non-Analgesic, antispasmodic
What is the chemical structure of the Phenanthrenes?
-3 fused benzene rings (called a Phenanthrene Ring)
-C6H6: 6 carbons in a ring each with 1 hydrogen
What is the example drug of the Phenanthrenes?
Morphine: Naturally occurring
-Principle active compound from Opium
-Comparison for all other agents
-Strong agonist useful in treating severe pain.
-Hydromorphone and oxymorphone are also in this class
How does Codeine differ in chemical structure from Morphine?
Substitution of an ether for one of the alcohols of the phenanthrene nucleus
What is the Phenylpiperidine Class?
Synthetic drugs created by breaking the chemical bonds of morphine and restructuring them.
-Only have 2 of the original 5 rings of the basic morphine molecule.
-Fentanyl, Alfentanil, Remifentanil, Sufentanil, and Meperidine.
-Meperidine was the 1st synthetic opioid.
What are the example drugs of the Semi-Synthetic opioid agonist class?
-Hydromorphone (Dilaudid)
-Heroine
-Oxymorphone
-Oxycodone
What is Nalbuphine (Nubain)?
A synthetic agonist-antagonist.
-Agonizes Kappa receptors (helpful in pain response without causing respiratory depression. Has a ceiling effect)
-Antagonizes Mu receptors
-Useful in OB (maintains respirations)
-DO not use if hx of recovering narcotic addiction
In general, what are the basic pharmacokinetic principles of opioids?
-Highly lipid soluble
-Weak bases
-Highly protein bound
-Largely ionized at physiologic pH (pKa is > 7.4)
What are the endogenous opioid agonists?
-Enkephalins, endorphins, and dynorphins.
-All share a common amino acid terminal sequence with a small variation\
-Terminus part is what varies, and that is what makes it an opioid receptor agonist.
-Newer discoveries: Nociceptin, Endomorphin 1 & 2
What is the “opioid motif” or “opioid message”?
Try-Gly-Gly-Phe – Met or Leu
-necessary for interaction at the receptor site
Describe the cellular MOA of opioids.
1) Opioid agonist binds to the GPCR.
2) The GPCR becomes active (has 3 subunits: Alpha, beta, and gamma)
3) Inhibitory effects are produced
-Alpha: Inhibits adenylyl cyclase = dec cAMP
-Beta & Gamma: Inhibits VG Ca channel = dec Ca influx
-Also K+ efflux is increased = hyperpolarization
4) All of these inhibitory effects result in membrane hyperpolarization and reduction of neuronal excitability.
What is different between the 3 opioid receptor subtypes?
They are all GPCRs: have 7 transmembrane loops (both intra and extracellular)
-The 3 opioid receptor subtypes share 55%-58% sequence homology (same structure)
-Diversity is greatest in the extracellular loops/external portions of the protein
-External loops are thought to be important in the discriminating between ligands
Describe the inhibitory effects that result from opioid stimulation of the Alpha subunit on the GPCR?
-Inhibition of Adenylyl Cyclase = Decreased cAMP
-Causes decreased conductance of Ca++ channels & opened K+ channels
-Results in decreased neuronal excitation and inhibition of neurotransmitter/neuropeptide release
-Harder for postsynaptic side to respond to an AP. Interrupting pain signaling.
Abrupt withdrawal of opioids can cause a rebound disinhibition of cAMP, causing what side effects?
Increased irritability
Restlessness
Tremors
Chills
Muscle cramps
Sweating
Mydriasis
Abdominal Pain
Diarrhea
Increased HR
Where are opioid receptors located in the Brain?
-Periaqueductal Gray
-Area Postrema
-Limbic System
-Cerebral Cortex
-Thalamus
Where are opioid receptors located in the Spine?
Substantia Gelatinosa of the Dorsal Horn.
-Spinal analgesia occurs by activation of presynaptic opioid receptors, which leads to decreased calcium influx and decreased release of neurotransmitters involved in nociception.
Where are opioid receptors located in the Peripheral Nervous System (PNS)?
-GI tract (constipation)
-Vasculature
-Lungs
-Heart
-Immune system
How does Supraspinal Analgesia occur?
Brainstem modulates nociceptive transmission via inhibitory pathways of the spinal cord.
-Occurs through activation of the opioid receptors in the brain that cause inhibition of the nerves involved in pain pathways
-Descending signals to block pain sensors or modulate response in some way.
Supraspinal analgesia occurs through activation of opioid receptors in the medulla, midbrain, and other areas, which causes inhibition of neurons involved in pain pathways.
How does Spinal Analgesia occur?
-Occurs via activation of presynaptic opioid receptors in the spine decreasing release of the neurotransmitters of nociception
-Involved in sending pain signals up to the thalamus to be interpreted. Can block the transfer of pain signals upwards
-Pain signals travel to the thalamus via the dorsal horn and the spinothalamic tract.
-Inhibits the release of Substance P.
T/F: Supraspinal + spinal = synergistic pain relief
True
What are the effects caused by Mu Receptor stimulation?
-Supraspinal & Spinal analgesia
-Bradycardia
-Respiratory Depression
-Euphoria, Sedation, Prolactin release, mild hypothermia, catalepsy, indifference to environmental stimulus
-Miosis
-Inhibition of GI peristalsis; N/V
-Urinary retention
-Pruritus
-Physical dependence
What are the effects caused by Kappa Receptor stimulation?
-Supraspinal & Spinal analgesia
-Possible respiratory depression (would need a significant dose to achieve)
-Sedation, dysphoria, psychomimetic reactions (hallucinations, delirium)
-Miosis
-Diuresis (inhibition of vasopressin release)
-Low abuse potential
-Anti-shivering
What is Dysphoria?
A distorted sense of impending doom.
