mixed agonist-antagonist

**Definition:** Drugs that have different intrinsic activities at different receptor subtypes. In board pharmacology the term refers to opioid analgesics that stimulate kappa (κ) receptors and block or only partially stimulate mu (μ) receptors.

**Key drugs** - **Nalbuphine:** κ agonist and μ antagonist. Used for moderate to severe pain and for opioid-induced pruritus. - **Butorphanol:** κ agonist and partial μ agonist/antagonist. Used for migraine (nasal spray) and labor analgesia. - **Pentazocine:** κ agonist and weak μ antagonist or partial agonist. It can cause psychotomimetic effects (dysphoria, hallucinations). - **Contrast with buprenorphine:** This is a **partial μ agonist**, not a classic mixed agonist-antagonist. It has high affinity, dissociates slowly, and has a ceiling effect on respiratory depression. It is used for opioid use disorder and chronic pain.

**Receptor effects** - μ: supraspinal analgesia, respiratory depression, euphoria, miosis, constipation, physical dependence. - κ: spinal analgesia, dysphoria, sedation, miosis, and less respiratory depression. - δ: analgesia, with a possible role in mood.

**Pharmacologic features** - **Ceiling effect:** Higher doses don't give proportionally more analgesia or respiratory depression, so they are safer in overdose than full agonists. - **Lower abuse and dependence potential:** κ activation causes dysphoria rather than euphoria. - **Can precipitate acute withdrawal** in patients physically dependent on full μ agonists (morphine, heroin, fentanyl, oxycodone), because they displace the full agonist from the μ receptor and replace it with weaker activity. - **Reversal:** Naloxone only partially or inconsistently reverses their effects, and larger doses may be needed. - **Adverse effects:** Sedation, nausea, sweating, dysphoria or psychotomimetic effects (especially pentazocine), and less constipation than full agonists. - **Cardiovascular:** Pentazocine and butorphanol may increase cardiac workload (raise pulmonary arterial pressure and cardiac work), so they are avoided in MI.

**Clinical pearls for boards** - Don't give a mixed agonist-antagonist or partial agonist to a patient on chronic full-agonist opioids. It can precipitate withdrawal (agitation, diarrhea, mydriasis, piloerection, yawning, rhinorrhea). - Because of their ceiling effect, they have limited use in severe or chronic pain. - Obstetric analgesia: nalbuphine and butorphanol are used in labor, with less neonatal respiratory depression than full agonists, though neonatal monitoring is still needed. - Antagonist-only drugs: naloxone (IV, short-acting, for overdose) and naltrexone (long-acting, for opioid and alcohol use disorder).

**Mnemonic:** "NBP" (Nalbuphine, Butorphanol, Pentazocine) for the mixed agonist-antagonists; "Buprenorphine = partial μ agonist."

**General pharmacology note:** Outside opioids, "mixed agonist-antagonist" can describe any drug that activates some receptors and blocks others. An example is tamoxifen, a selective estrogen receptor modulator (SERM) that is an antagonist in breast tissue and an agonist in bone and endometrium.