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Spears CNS 1C
Centrally Acting Analgesics
| Question | Answer |
|---|---|
| Pain is: | Unpleasant sensory & emotional experience with actual or potential tissue damage - good - Usually physiologically relevant/protective |
| Acute pain is: | A sudden noxious sensation; Affects BP, sympathetic activation, induces shock; Management is important to prevent progression to chronic pain |
| Chronic pain is: | persistent noxious sensation; Maladaptive nociception; Sensitization occurring to acute pain; Can result in depression, insomnia, stress-axis activation, compromised immune response; Increased treatment difficulty and addiction risk |
| Pain type: Neuropathic- abnormal CNS or PNS neuronal processing caused by? | Neural tissue damage such as: Inflammation, Diabetic neuropathy, Postherpetic neuralgia (Shingles), Nerve compression, Nerve dissection |
| With Neuropathic pain, Hyperalgesia and/or allodynia are common? | pain sensitizations |
| Neuropathic pain is also considered a dysfunction of? | 1st (nociceptive, peripheral), 2nd order (spinal) neurons, or thalamic neurons |
| Neuropathic pain may be difficult to treat, options are: | Opioids; NSAIDS; Antidepressants; Anticonvulsants |
| In the graph on slide 6, pain sensitization has enhanced pain responses seen with Allodynia (__-_____) vs Hyperalgesia (____) *Allodynia (left-ward shift) | non-noxious (feather, what use to not hurt, now hurts); noxious (painful stimulations such as trauma by a hammer) *we can think of Allodynai as cancer or migraine pain that is (non-noxious like running fingers through your hair but may be painful for pts undergoing cancer tx. |
| Pain Type- Nociceptive--> caused by stimulation of _______ | Nociceptors (Temperature, Mechanical, Chemical); *these are special nerve endings that send pain signals to the CNS) |
| Pain signaling Cascade Steps: | 1. Stimulation 2. Conductance 3. Transmission 4. Relay and perception 5. Modulation *1-4 Ascending pathways *5 Descending pathway |
| In the step 2 (Conduction) of the Pain signaling cascade--> the conduction is mediated by? | 1st order neurons |
| in Step 3 (Transmission) it occurs from the spinal cord to other areas of the: | brain |
| In Step 4 Relay and Perception) it contains 2nd order and 3rd order neurons that are engaged to stimulate the: | thalamus and cortical areas to let the body know that the pain is occurring |
| In Step 5 (modulation), pain can be modulated to ensure that it: | doesn't occur all the time |
| Ascending pathway ensures communication up from the ______ into the brain | periphery |
| Stimualtion (Step 1) Nociceptor activation either by what stimuli? These have a High threshold for activation than tactile neurons | Chemical, temperature, mechanical sensory stimuli |
| Stimulation occurs at the: | -Cell body in dorsal root ganglion (peripheral) |
| Nociceptor Action leads to increased sensitization of nociceptors getting conditions such as: | Hyperalgesia and Allodynia |
| Conduction (Step 2) comes from the periphery to the spinal cord and we get increased Glutamate release in the dorsal horn stimulating fast and slow pain via ______ and __________ fibers | myelinated; unmyelinated *mixture of nerve fibers to propogate an AP |
| Fibers AB(beta)/C--> are a type of nerve injury that is more of what type of pain? | Neuropathic |
| Fibers Ad(delta)/C --> are a type of tissue injury that is more of what type of pain? | Nociceptive |
| Transmission (Step 3) --> Spinal cord to the brain--> increased AP firing along ascending pain pathway (describe)? | in response to AP--> AP opens ip Ca2+ channels (Ca2+ influx) and stimulate vesicle release--> and more release of Glu into the synapse that acts on the postsynaptic Glu receptors including NMDA and AMPA receptors. *postsynaptic Glu signaling will be increased as a result of having more Glu in the synapse |
| Transmission leads to Glutamate _____ NT and Neuropeptides are involved in the pathway such as? | excitatory; CGRP, substance P, and Neurokinin A |
| Relay and Perception (Step 4)--> Brainstem--> thalamus and cerebral cortex: go to the Reticular formation of the brainstem that dictates: | arousal, emotional *as well as awareness of Pain (let the body know) |
| Relay and Perception--> The Thalamus is important for pain discrimination and will determine based on: | Localization/intensity of pain and have Somatotopic organization as well as some fibers terminate in the PAG* of midbrain |
| Modulation (Step 5)--> Periaqueductal Gray (PAG of brainstem) important for? | descending neurons that become activated in order to release NT that suppress pain |
| PAG of brainstem will release endogenous pain suppresion via the following NT? | Norepi; GABA; Opioids *these will try and decrease the AP firing along the pathway *effect is all simimiar in that they close that presynaptic Ca2+ channel in order to reduce Ca2+ infulx and lower Glu release |
| PAG pain suppressors--> bind to their appropriate receptor on the presynaptic side: | decreasing release of excitatory NT that are stimulating those pain neurons. On the Post0synaptic side: it will cause hyperpolarization of the neuron, either by opening K+ channels or increasing that chloride conductance, so that those post synaptic neruons are less responsive to pain activation. |
| Endogenous opiouds close the presynaptic to reduce Ca2+ meaning less | release of Glu--> less activity on receptor and less AP |
| End result of modulation--> with endogenous release will see decrease of Glu and increase of Cl- conductance on teh post synaptic side as well as hyperpolarizartion leading to: | decreased VG Na+ channels reaching threshold and decrease in AP generation |
| Endogenous opioid system--> Endogenous opioids are cleaved from precursors: | POMC, proenk A, proenk B |
| The 3 types of opioid receptors are? | 1. endorphins 2. Enkephalins (Met- and Leu- 3. Dynorphins |
| Opioid Receptors have preferred affinity 1. Mu - μ – MOR 2. Delta - δ – DOR 3. Kappa - κ – KOR | 1. > endorphin affinity 2. > enkephalin affinity 3. > dynorphin affinity |
| Opioid receptor agonist effects are mostly: | Gi/o coupled *Mediate analgesia, respiratory & GI function, sedation & reward |
| Analgesia | μ, δ, κ |
| Respiratory Function | μ |
| GI tract function | μ, δ |
| Sedation | μ, κ |
| Reward function | μ, δ--> Reinforcement (effect on agonist)/euphoria κ--> Aversion (effect on agonist)/ dysphoria |
| Which of the following is not an example of Neuropathic pain? | Burning hand |
| Agonist activity at which opiod subtype is associated with respiratory depression? | Mu |
| What is the role of mu-opiod receptor agonism in producing antinociception? | Presynaptic Ca2+ channels become inhibited |
| Drugs used in pain management: Non-opioids include? | -NSAIDs/acetaminophen -Glucocorticoids -SNRI (& TCAs) (Increases in NE/5HT) -Pregabalin & Gabapentin (Block presynaptic voltage-gated -Ca2+ channels) -Clonidine (Alpha-2 agonist) |
| 1. With pain, we want to use a: 2. Persistent or increasing pain, we use: 3. More Persistent or increasing pain, we use: | 1. non-opioid analgesic +/- adjuvant 2. Weak opioid +/- non-opioid +/- adjuvant 3. Strong opioid +/- non-opioid +/- adjuvant |
| Definition of Dependence? | Physical with repeated, chronic use |
| Definition of Withdrawal? | -initiated with discontinuation or opioid antagonist -Symptoms: diarrhea, pupil dilation, dysphoria, anxiety |
| Definition of Desensitization? | Acute response to agonist stimulation (minutes to hours) that diminishes opioid receptor signaling (diminshes the signaling to the opioid receptor) -Kinase phosphorylation of opioid receptor |
| Desensitization cuases uncoupling of receptor-G-protein complex from ____ _______ | 2nd messengers *(more so with Mu and delta receptors) |
| Desensitization induces receptor _________ | internalization (on the MOR and DOR, but not the KOR) *leads to recruitment of B-arrestin mediated |
| Tolerance is known as? | -Long-term desensitization (days to weeks due to exposure to agonist and changes in neuron environment) -Plasticity (change in neuronal growth and communication/excitability also change once tolerance has developed) -Requirement for higher therapeutic doses needed to acheive response |
| Tolerance can also lead to _____-_______ b/w drugs | cross-tolerance *only only higher doses for analgesics, but also other CNS depressants as well as higher amounts of alcohol |
| High tolerance will develop in what effects of the opioids? | **Analgesia, euphora, dysphoria, mental clouding, sedation, respiratory depression, antidiureses, N/V, Cough suppresion |
| Tolerance will NOT develop for what effects of opioids? *tolerance won't effect these effects* | **Miosis (pupil constriction); Constipation; Convulsions |
| Opioids used in pain management: High Agonist Affinity opioids are? | Morphine, Hydromorphone, Oxymorphone, Methadone,, Meperidine, Fentanyl, Sufentanil, Alfentanil, Remifentanil |
| Opioids used in pain management: Moderate agonist affinty opioids are? | Codeine, Oxycodone, Dihydrocodeine, Hydrocodone, Diphenoxylate, Difenoxin, Loperamide, Dextromethorphan |
| Opioids used in pain management: BIASED agonist affinty opioid is? (Newest) | Oliceridine |
| Opioids used in pain management: Mixed action opioids are? | Nalbuphine, Buprenorphine, Butorphanol, Pentazocine, Tramadol, Tapentadol |
| Opioids used in pain management: Antagonists opioids are? | Naloxone, Naltrexone, Nalmfene |
| Which drugs are more potent than Morphine? | Hydromorphone; Oxymorphone; Levorphanol; Oxycodone; Fenanyl; Sufentanil |
| The High affinity agonists are used for? | -Pain management -Antitussive properties (lower doses) -Opioid detoxification (methadone) |
| AE of the following High affinity opiod agonists: Morphine, Hydromorphone*, Oxymorphone*, Levorphanol*, Oxycodone* consists of? | euphoria, drowsiness, respiratory depression, miosis, N/V, hyperthermia, hormone imbalance Note: CYP2D6 metabolizes oxycodone oxymorphone Limited use for levorphanol |
| Methadone and Meperidine MOA? | High affinity agonist Antimuscarinic (meperidine) NMDA antagonist/Blocks NET& SERT (methadone) |
| Methadone and Meperidine Uses? | Pain management Antitussive properties (lower doses) Opioid detoxification (methadone) |
| AE of Methadone and Meperidine? | Normeperidine metabolite can cause seizures *Note: Opioid abuse treatment (methadone) Less tolerance/depend. w/ methadone |
| Fentanyl*, Sufentanil*, Alfentanil, Remifentanil MOA? | High affinity agonist * More potent than morphine |
| Fentanyl*, Sufentanil*, Alfentanil, Remifentanil Uses? | Pain management Antitussive properties (lower doses) Opioid detoxification (methadone) |
| AE of Fentanyl*, Sufentanil*, Alfentanil, Remifentanil? | increased OD *Note: Carfentanil veterinary med, ~100x more potent than fentanyl |
| Moderate Opioid Agonists consists of? | Codeine, Dihydrocodeine, Hydrocodone, Dextromethorphan, Diphenoxylate, Difenoxin, Loperamide |
| Codeine, Dihydrocodeine, and Hydrocodone--> MOA? | moderate affinty agonist |
| Codeine, Dihydrocodeine, and Hydrocodone--> Uses? | Pain management Antitussive properties (lower doses) |
| Codeine, Dihydrocodeine, and Hydrocodone--> Notes? | Less potent than morphine Codeine morphine Hydrocodone hydromorphone Oxycodone oxymorphone |
| Dextromethorphan MOA? | Weak affinty agonist |
| Dextromethorphan Uses? | Cough suppressant, anti-tussive agent (Little analgesia at normal dose) |
| Dextromethorphan AE? | Dizziness, drowsiness, restlessness, GI distress, N/V *Note: Structurally like Codeine |
| Diphenoxylate, Difenoxin, Loperamide MOA? | Weak agonist |
| Diphenoxylate, Difenoxin, Loperamide Uses? | Antidiarrheals Little CNS effects |
| Diphenoxylate, Difenoxin, Loperamide Notes? | Poor analgesic affect |
| Oliceridine MOA? | *High affinity-MOR biased agonist *G-protein specific (μ-GPS) pathway activator |
| Oliceridine Uses? | Analgesia (comparable to morphine) *Less opioid-related adverse effects |
| Oliceridine AE? | Abuse/addiction Respiratory depression Constipation Risk combined with BZDs other CNS depressants |
| Oliceridine Notes? | Selectively activates the G-protein pathway Reduced/minimal activation of the β-arrestin pathway |
| The idea behind the Biased opioid agonist such as Oliceridine--> it tends to have the ligand facvoring the action of 1 pathway rather than both the G-protein and Arrestin signaling with the opioid receptor. What occurs is that in favoring the G-protein: | is that the G protein is responsible for the analgesic affect where as the beta-arrestin is ignored, preventing the recruitment of bad SE of opioids (Respiratory depression, constipation, etc) *preference means less opioid-related effects |
| Figure on slide 29 demonstrates a conventional opioid on comparison to Oliceridine--> | the conventional opioid activates both G-protein and B-arrestin wher with the activation of the G-protein (Analgesia, RD, N/V/ Liking/ Dependence) and B-arrestin (RD/N/V) |
| Hypothesis behind Oliceridine is that it gives: | -similar analgesia, less RD, less N/V, and similar liking/dependence |
| What are our Mixed-opioid Agonist drugs? | Buprenorphine; Nalbuphine; Butorphanol; Pentazocine; Tramadol; Tapentadol |
| Buprenorphine MOA? | MOR partial agonist KOR antagonist (binding evidence for agonist activity) |
| Buprenorphine uses? AE? | 1. Analgesia, Opioid detoxification, Heroin addiction therapy 2. Fatigue, headache, sleep disturbance, sedation, constipation, N/V Note: *Slow receptor dissociation (MOR > KOR/DOR)* Avoid w/ full agonist/currently using addicts |
| Nalbuphine and Butorphanol MOA? Uses? AE? | 1. MOR partial antagonist (Nal.); Partial agonist (But.); KOR agonist 2. Analgesia 3. Sedation Notes: Greater sedation with butorphanol Avoid w/ full agonist/currently using addicts |
| Pentazocine MOA? Uses? AE? | 1. MOR partial agonist; KOR agonist 2. Analgesia 3. Injection irritation |
| Tramadol and Tapentadol MOA? Uses? AE? | 1. Mild-moderate MOR agonist; SERT & NET blocker 2. Analgesia 3. Dizziness, drowsiness, nausea/vomiting, increased seizure risk Notes: Tramadol > @ SERT Active metabolite has higher MOR affinity; Tapentadol > @ NET (alpha2 agonist) |
| The following drugs are your opioid antagonists? Shared Indication? | Naloxone, Naltrexone, Nalmefene, Naldemidine, Naloxegol, Linaclotide, Lubiprostone *Management opioid-induced adverse effects |
| Naloxone, Naltrexone, Nalmefene MOA? Uses? AE? | 1. Competitive, neutral antagonist; Nonselective 2. Opioid addiction/overdose treatments; Reversal (naloxone); Maintenance (naltrexone, nalmefene) 3. Opioid withdrawal-like effects Note: Naloxone – short t1/2; Naltrexone – long t1/2; Analgesic effects (Very low naltrexone dose) |
| Naldemedine and Naloxegol MOA? Uses? AE? | 1. **Peripheral MOR antagonist (NOT CENTRAL ACTING) 2. Gastrointestinal agents, OIC 3. Abdominal pain, N/V/D |
| Linaclotide and Lubiprostone MOA? Uses? AE? | 1. Peripheral Cl- channel activator 2. Gastrointestinal agents, OIC 3. Abdominal pain, N/V/D, flatulence, HA |
| Chronic morphine use may result in the development of tolerance to all of the following, EXCEPT? | Constipation |
| Which of these are more potent than morphine? | Fenanyl; Levorphanol |
Created by:
Xander635
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