L9: Opioid receptor antagonist

Objectives

1. Discuss the mechanism behind opioid addiction

2. Discuss partial and mixed agonist, and antagonist

3. Discuss nonsteroidal anti-Inflammatory drugs and nonopioid analgesics

Tramadol

1. MOA

2. What does it use COMBO with?

3. Therapeutic Action

1. Weak, atypical mu-opioid receptor agonist

   1. Inhibit reuptake of serotonin and NE

2. In combination with acetaminophen improves its analgesic efficacy

3. Less adverse effects, no GI bleeding

Levorphanol

1. MOA

2. Uses to treat

Binds to opioid receptors, NMDA antagonist, SNRI

Used to treat moderate to severe pain

Partial and mixed agonist Drugs

Nalbuphine

Nalbuphine

1. MOA

2. Action

3. Ceiling effect

1. Kappa-agonists, weak antagonist at µ and δ receptors

2. Used to relieve moderate pain

   1. Given with general anesthesia before surgery

   2. Reverse the pruritus induced by neuraxial opioid administration

3. A ceiling effect for respiratory depression

Buprenorphine

1. MOA

2. Therapeutic Action

3. Withdrawal?

1. Partial agonist at the µ receptor → more potent than morphine

2. Opioid addiction treatment, and opioid detoxification

3. Withdrawal symptoms - less severe and shorter duration

What is used for opioid detoxicfication?

Buprenorphine alone

Drugs for opioid dependence

• Formulation and

• DUR

• Effect?

Sabutex: Buprenorphine alone

Saboxone: Buprenorphine and naloxone (naloxone was added to prevent the abuse of buprenorphine via IV administration)

• Sublingual, parenteral, transderma

• Llong duration of action

• Reduced Euphoria, respiratory depression

Opioid Addiction- Mechanism

GABA – inhibits brain reward pathway

Opioids inhibits GABA action – Activate reward Pathway

Naloxone

• What kind of receptor?

• MOA

• Overdose

• Opioid receptor Antagonist

• Rapidly reverse the effect of µ -receptor agonist

• Reverse the coma, and respiratory depression of opioid overdose

Nasal Spray- Narcan → How does it work?

• Reverse the effects of high levels of opioids

• Reverse deadly overdoses

Naltrexone

1. Class?

2. Dosage

3. Duration of action?

4. ADE

1. Opioid receptor antagonist (reduce acute dopamine release at nucleus accumbens)

2. A single oral dose of naltrexone blocks the effect of injected heroin for up to 48hrs

3. Longer duration of action → XR formulation

4. Lead to hepatotoxiciy

Opioid Crisis-treatment options → name 3

1. Methadone maintenance therapy

2. Buprenorphine maintenance therapy

3. Naltrexone therapy - extended-release naltrexone (Vivitrol®)

Lofexidine

• USE

• MOA

• Long-term treatment plan for managing opioid use disorder

• α2 -adrenergic receptor agonist

• Reduces the release of NE and suppresses sympathetic nervous system

Ketamine

1. Class

2. MOA

3. USE

4. Risk

1. NMDA receptor antagonist

2. Inhibits NMDA receptor

   1. induction and maintenance of central sensitization

3. Used for acute severe pain

4. Minimize the risk of respiratory depression

Name 2 types of Analgesics

1. Orphenadrine citrate: orphenadrine citrate, aspirin, and caffeine

2. Dextromethorphan

   1. antitussive (cough suppressant) drug

   2. reduce chronic pain symptoms and postoperative pain

   3. high dose required for analgesia

Antiepileptic drugs : gabapentin, pregabalin, lamotrigine and carbamazepine

Adrenergic agonist: Clonidine- agonist to alpha 2- receptors

Analgesics- Antidepressants

1. Tricyclic antidepressants- blocking sodium channels

   1. Amitriptyline, Nortryptyline Imipramine

2. SNRIs- used in the treatment of Neuropathic pain and fibromyalgia

   1. venlafaxine

   2. duloxetine

   3. Milnacipran

3. SSRIs least effective

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

• MOA

• PK

1. Inhibition of cyclooxygenases enzyme activity (COX-1 and COX-2)

   1. Inhibition of prostaglandin biosynthesis

2. NSAIDs decrease the recruitment of leukocytes AND cross BBB (inhibit prostaglandin generation)

4 major classes of NSAIDS

1. Indole acetic acid derivatives (indomethacin)

2. Pyrrole acetic acid derivatives (diclofenac and ketorolac)

3. Propionic acid derivatives (ibuprofen) benzothiazines (piroxicam)

4. COX-2 selective inhibitors (Celecoxib, rofecoxib and valdecoxib)

Non-NSAID - acetaminophen

Indole acetic acid derivatives

1. Drugs

2. Therapeutic Action

3. Use

1. Indomethacin, Sulindac, Etodolac

2. To treat mild to moderate pain

3. Indomethacin- arthritis, gout, ankylosing spondylitis

4. Sulindac- Osteoarthritis, rheumatoid arthritis, ankylosing spondylitis:

5. Etodolac- rheumatoid arthritis, osteoarthritis

Pyrrole acetic acid derivatives

1. Drugs

2. Use

3. ADE

1. Diclofenac, Ketorolac

2. Diclofenac – arthritis, postoperative pain - more potent than indomethacin and naproxen

3. Ketorolac - oral or parenteral- for short term pain control - used in post surgical patients

4. Stevens-Johnson syndrome, GI bleeding

Acetaminophen

1. MOA

2. Therapuetic Action

3. MOA

4. ADE

5. Antidote

1. Inhibition of prostaglandin synthesis weak inhibitor of COX-1 and COX-2 - inhibit COX-3 (cyclooxygenase enzyme expressed selectively in the brain)

2. Analgesic, antipyretics, no anti-inflammatory properties

3. p-aminophenol → Narachidonoylphenolamine (AM404)

   1. Interacting with endocannabinoid and TRPV1 receptor

4. Hepatotoxic

5. Acetylcysteine replenishes glutathione supply to liver → Toxic NAPQI: Normal breakdown of high-dose acetaminophen creates a dangerous waste product called NAPQI. → NAPQI is inactivated by conjugation with glutathione

WHO-3 Step Analgesic pain ladder