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Downing opioids

Pain module

What are the three main endogenous opioids? The 2 not so main endogenous Opioids? Endorphins, Dynorphins, Enkephalins Endomorphins and Nociceptin
Endorphins α, β, γ-endorphins; α, β-neoendorphins; μ receptors
Dynorphins Dynorphin A, dynorphin B; κ receptors
Enkephalins – Methionine enkephalin (met-enkephalin); μ, δ – Leucine enkephalin (leu-enkephalin); δ receptors
Endomorphins Endomorphin 1, endomorphin 2; μ receptors
Nociceptin Not well characterized: Hyperalgesia? Analgesia? ORL1 receptor
Endogenouse opioids are derived from...... For each endogenous opioid class there is one gene that makes all of that type. Eg. Endorphins are all made from one gene, where all of the dyno's are made from another. A large pro-peptide or pre-pro-peptide has these opioids then they are cleaved
μ (mu; MOR; OPRM1)μ (mu; MOR; OPRM1) Mostly presynaptic; can be postsynaptic
δ (delta; DOR; OPRD1)
κ (kappa; KOR; OPRK1)
Nociceptin receptor (NOP) Also known as the ORL1
Opioid receptors are g-protein coupled receptors that can work to affect which channels on the Pre and Post synaptic neurons? Open K channels by inhibiting adenylyl cyclase. Close Ca Channels (presynaptically) to prevent NT realease
Which ORs are generally associated with deactivating the Ca channel on presynaptic neurons? What does this result in? μ receptors, this leads to a decreased amount of NT release.
Which receptor type like to make functional dymers the most? DELTA baby (but they make heterodymers with M and Kappa)
True or False ORs mostly undergo very rapid desensitization True
Which ORs can undergo internalization? internalization is what happens to cause down regulation MORs, DORs can undergo rapid, agonistinduced internalization/downregulation – Endocytic/β-arrestin pathway – Mediated by kinases/phosphatases – Agonist specific; morphine binding to MOR does not cause receptor internalization
Which OR doesn't internalize? KORs do not internalize
Euphoria Meso-limbic dopamine (DA) system is brain’s “reward” pathway – Opioid pathways interact with M-L DA system • μ, κ, δ receptors present in brain areas mediating reward • Dynorphins, enkephalins – Estimated up to 25% become addicted
• Respiratory depression – Inhibit areas of brainstem controlling respiration • Medulla, pons; mediated by μ receptors – Dose-dependent; overdose can kill
Sedation – Drowsiness, mental confusion • Do not induce amnesia – Reticular activating system??? – Used in surgery for sedation, anxiolysis, pain
• Cough suppression – Opioids depress cough reflex – Cough center in medulla; μ receptors
Miosis – Pupil constriction – Mediated by μ, κ receptors
Neuroendocrine – Opioids (OR agonists) inhibit release of some hypothalamic hormones
Nausea and vomiting – Activate chemoreceptor trigger zone in medulla; vestibular system – Most μ agonists produce some nausea, vomiting
Seizures – High doses of opioids (morphine) cause seizures – Inhibit release of GABA; activate pyramidal cells (glutamate) in hippocampus
GI tract – Stomach, intestines, bowel; μ, δ receptors – Constipation; high density of μ receptors in ENS • Decreased secretions; water absorbed more completely – Decreased gastric motility; prolonged gastric emptying; reflux
Kidney – Renal function depressed by opioids • Decreased renal blood flow – μ opioids have antidiuretic effects
Pruritus – Flushing, warming of skin – Intraspinal or systemic injection – Release of histamine
Immune system – Complex effects; direct and indirect – Sympathetic nervous system, HPA axis – μ receptor mediated suppression of immune system
What are the two main types of pain? Nociceptive & Nuropathic
Nociceptive pain – Caused by stimulation of nociceptive (pain) receptors in peripheral nerve fibers – Sensation transmitted over intact neural pathways
Neuropathic pain – Caused by damage to neurons (nociceptive pathways) – Somatosensory system
T/F Opiods are 'front line' for both neuropathic pain and nociceptive pain False Opiods are used for both types but NOT front line for neuropathic pain.
How do opioids produce analgesia? -by activating GPCRs in regions of brain, spinal cord involved in pain
What are the opioids 2 major GPCR-mediated action on neurons in the ascending pathway? – Inhibit voltage-gated Ca++ channels on presynapticnerve terminals; inhibit NT release • Glutamate, neuropeptides (substance P) – Activate K+ channels on postsynaptic neurons • Hyperpolarization
Where in the spinal cord is the highest concentration of opioid receptors? The dorsal horn and the primary afferents in the DRG (the set of neurons right before it goes to the Dorsal horn in the spinal cord)
ORs inhibit the release of what type of NTs in the Dorsal Root Ganlion (DRG)? The DRG is also called the Primary afferent fiber, this is the 'pain' nerve Excitatory NTs (glutamate ect...)
In the Dorsal horn ORs lead to what? Decreased pain transmission due to an activation of K+ channels leading to hyperpolarization
T/F Canabinoid receptors (CB) are on the post-synaptic neuron in the dorsal horn and have effects similar to ORs F Canabinoid receptors (CB) are on the pre-synaptic neuron (the DRG), it is true they have effects similar to ORs (inhibition of stimulatory NTs release)
The Canabinoids all have **** in their names nabi
The 2 types of Pain Neuropeptides mentioned Substance P Calcitonin gene-related peptide (CGRP)- Binds CALCRL/RAMP1 heterodimer
What do ORs do in the decending pathway? Inhibit the release of GABA onto pain inhibiting neurons
Can esogenous opioids stimulate the release of endogenous opioids? Yes, They can stimulate opioid release. Those that bind MORs mainly, but the others can end up being released also.
Analgesic effects of ORs outside the CNS are..... – Sensory neurons – Pain associated with inflammation sensitive to peripheral opioid actions
T/F Oral Opioids undergo significant FPM TRUE
What are the general PK properties of Opioids? – Highest concentrations in highly perfused tissues – Most readily cross BBB – Some highly plasma protein bound – Can accumulate in some tissues
Generally, are the active metabolites of opioids more or less potent than their precursor? More potent, many Opioids have active metabolites
Codeine is metabolized to morphine by what enzyme? CYP2D6
Morphine is metabolized to what 2 main metabolites and which one is more potent than morphine itself? – Morphine-3-glucuronide (M3G) – Morphine-6-glucuronide (M6G); more potent
Pt's who are poor metabolizers have high or low amounts of which enzyme? WHat does this mean to their response to codien? Low amounts of CYP2D6, they see little effects of the drug
What are the 2 main alkaloid classes in Powdered opium? Phenanthrenes-Morphine, codeine, thebaine (many synthetics) Benzylisoquinolines-apaverine; structurally, pharmacologically different • Noscapine; antitussive
Morphine • Most abundant alkaloid in opium; μ agonist • Most widely used analgesic – Not used for much else; anxiety? SEs – Highly addictive; severe withdrawal syndrome – Can cause histamine release; bronchoconstriction, vasodilation
Codeine • Analgesic, antitussive, antidiarrhetic – Sedative; anxiolytic? • Very low affinity for opioid receptors – Morphine has much higher affinity – Codeine binds nonopioid receptors(NMDA)??
Highly potent agonists – Phenanthrenes; morphine, hydromorphone, oxymorphone, heroin – Phenylheptylamines; methadone – Phenylpiperidines; fentanyl, remifentanil, sufentanil,
Phenanthrenes morphine, hydromorphone, oxymorphone, heroin
Phenylheptylamines methadone
Phenylpiperidines fentanyl, remifentanil, sufentanil,
Moderately potent agonists – Phenanthrenes; codeine, hydrocodone, oxycodone – Phenylheptylamines; propoxyphene – Phenylpiperidines; diphenoxylate, difenoxin, loperamide
Phenanthrenes codeine, hydrocodone, oxycodone
Phenylheptylamines propoxyphene
Phenylpiperidines diphenoxylate, difenoxin, loperamide
Hydromorphone Dilaudid – Morphine derivative • Highly potent analgesic; μ agonist – Mostly used in hospital (IV)
Oxymorphone Opana – Thebaine derivative – Highly potent analgesic; μ agonist • Anxiolytic, antidepressant – Produces less euphoria, sedation than morphine, other opioids
Oxycodone OxyContin • Synthesized from thebaine • Moderate potency – κ receptor agonist/partial agonist/μ receptor agonist • Relatively high oral bioavailability • Effective for mild to moderate pain • Can be compounded with other therapeutic agents; NSAIDs
Hydrocodone from codeine • Moderately potent analgesic – Often compounded with acetaminophen (Vicodin) – High affinity for μ receptor; lower affinity for δ receptors • Good oral bioavailability • Hepatic metabolism – Active metabolite: hydromorphone
Methadone • Highly potent μ receptor agonist; analgesic – NMDA antagonist – Inhibits catecholamine reuptake transporters • Good oral bioavailability • SLOW metabolism; long duration of action • Used to treat opioid dependence
Propoxyphene Dextropropoxyphene (Darvon) • Structurally related to methadone • Moderate potency μ receptor agonist – Others? • Analgesic and antitussive; mild-to-moderate pain • Has been used to treat opioid dependence • Withdrawn in US; overdoses
Fentanyl • Highly potent μ receptor agonist – Analgesic; 100 times more potent than morphine – OD deaths • Rapid onset, short duration of action • Commonly used during surgery (IV) – Induce anesthesia, produce analgesia • Administered in many forms
Remifentanil Ultiva – Fentanyl derivative; μ receptor agonist – Ultra short acting; half-life under 20 minutes – Primarily used to induce sedation, analgesia during surgery
Sufentanil Sufenta – μ receptor agonist; almost 500 times more potent than morphine – Sedation, analgesia; primarily used in surgery – Extreme respiratory depression
Meperidine/Pethidine Demerol • First synthetic opioid • Fast-acting analgesic; less potent than morphine – μ, κ receptor agonist – Inhibits DAT, NET • For long time was opioid analgesic of choice – Local anesthetic effects • Severe drug interactions with MAO inhibitors
Levorphanol Levo-Dromoran – Eight times more potent than morphine; analgesia – Varying affinity for μ (highest), δ, κ, σ receptors • NMDA antagonist – Less nausea and vomiting than other opioids
Tapentadol Nucynta – Analgesic for moderate/severe pain – μ agonist; σ2 agonist – Norepinephrine reuptake inhibitor
Nalbuphine Nubain: Mixed Action Opioid – κ receptor agonist – μ receptor antagonist – Primarily used as analgesic (injectable)
Buprenorphine Mixed Action Opioid – κ, δ receptor antagonist – μ, ORL receptor partial agonist – Analgesic; antidepressant? – FDA approved for opioid addiction
Butorphanol Stadol:Mixed Action Opioid – κ receptor agonist; analgesia – μ receptor antagonist – Used primarily for acute pain
Pentazocine Mixed Action Opioid – Analgesic for moderate/severe pain – κ receptor agonist; analgesia – Weak μ receptor antagonist/partial agonist – Often in combination with other drugs • Acetaminophen
Tramadol Ultram • Analgesic treat moderate/severe pain – Weak μ agonist; metabolite strong μ agonist – Inhibits serotonin, NE reuptake – Antagonist at serotonin 5HT2C receptors, muscarinic receptors • Less respiratory dep., constipation than other opioids
Anti-Diarrhea Agents Diphenoxylate Difenoxin Loperamide (Imodium)-– Crosses BBB, P-glycoprotein pumps back out • Not addictive
Antitussives • Codeine, hydrocodone • Noscapine – Naturally occurring alkaloid in opium – σ receptor agonist
Dextromethorphan – Potent σ 1 agonist; lower affinity for μ – Metabolite NMDA receptor antagonist at PCP site • Dissociative hallucinogen – SERT, NET inhibitor – Will bind some nicotinic receptor subunits Not effective in children? – Induces histamine release
Naloxone – Inverse agonist at μ receptors: κ, δ receptors too? – Primarily used to treat opioid overdose – High first-pass metabolism; administered IV
Naltrexone – Competitive antagonist at μ, κ receptors – Longer duration of action than naloxone – Blocks euphoric effects of opioids; opioid dependence – One of only therapeutic drugs to treat alcohol dependence
What effects of the drug have little tolerance buildup Moderate and HIgh? Little: Miosis, constipation Moderate: Analgesia, sedation High: Euphoria
T/F If you build up a tolerance to one opioid you are more tolerant to the others T
Mixed action opioids (4) Butorphanol Pentazocine Nalbuphine Buprenorphine
Created by: Roeout



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