Snapshot A 29-year-old woman is brought into the emergency department by the police due to being found unresponsive in the park. At the scene, an empty syringe was found. Her respirations are 6/min. Physical exam is significant for depressed mental status, bilateral track marks, and miotic pupils. Introduction Opioids act on mu (most important), kappa, and delta transmembrane receptors in the central and peripheral nervous system mu, kappa, and delta receptors are Gi protein coupled inhibition of adenylyl cyclase → decrease cAMP concentration → increased K+ conductance + decreased Ca2+ conductance inhibits presynaptic neurotransmitter release prevents release of acetylcholine, norepinephrine, serotonin, glutamate, and substance P inhibits postsynaptic depolarization Endorphines, enkephalins, and dynorphins are examples of endogenous opioid peptides Pharmacokinetics morphine, hydromorphone, and oxymorphone undergo first pass metabolism morphine gets metabolized to morphine-6-glucoronide, which is highly active (the active analgesic) opioids are generally metabolized by liver into inactive glucuronide conjugates after metabolism they get excreted by the kidneys codeine, oxycodone, and hydrocodone are metabolized by hepatic cytochrome enzymes cytochromes have genetic variability → variable analgesic response meperidine can get metabolized to normeperidine N-demethylation normeperidine can lead to anxiety, tremors, and seizures heroin gets metabolized into 6-monoacetylmorphine, which can be detected on urine screening Clinical Use Drug Classification Subclass Medication Agonists Morphine pain management (acute) Methadone detoxification and maintenance (agonist) treatment of opioid addiction pain management Codeine pain management Mixed agonist-antagonist Buprenorphine maintenance treatment of opioid addiction pain management Antagonists Naltrexone treatment of alcohol dependence opioid overdose Methylnaltrexone opioid-induced constipation Naloxone opioid overdose for reversal of opioid depression Antitussives Dextromethorphan Codeine Others Tramadol pain management Butorphanol pain management Loperamide/dyphenoxylate manages diarrhea Side Effect by System Opiate Pharmacologic Effects by System System Side Effect Central nervous Analgesia Euphoria/dysphoria Miosis tolerance does not develop in miosis Sedation Cough reflex inhibition Cardiovascular Vasodilation Hypotension Pulmonary Respiratory depression Gastrointestinal Constipation tolerance does not develop to constipation Increased tone/pressure in the biliary sphincter Nausea and vomiting Genitourinary Urinary retention May prolong labor Endocrine Increases antidiuretic hormone (ADH) and prolactin secretion Decrease luteinizing hormone (LH) secretion Dermatological Pruritus Flushing Toxicity Acute overdose triad miosis, respiratory depression, and coma respiratory acidosis without metabolic compensation respiratory depression due to ↓ response to ↑ pCO2 Tolerance a decrease in pharmacologic effect after prolonged drug usage secondary to down-regulation of opioid receptors miosis and constipation are not affected by tolerance NMDA receptor antagonists (e.g., ketamine) and delta-receptor antagonists have been reported to prevent opioid tolerance Withdrawal side effects pain originating from the CNS flu-like symptoms lacrimation, sweating, rhinorrhea, and salivation muscle cramps and spasms Drug specific side-effects meperidine (seizures and serotonin syndrome with MAOIs/SSRIs) nalbuphine (hallucinations) Contraindications Head trauma ↑ pCO2 can cause vasodilation and ↑ intracranial pressure Pulmonary dysfunction patient may not be able to compensate for respiratory depression Liver/kidney dysfunction poor excretion mechanisms may result in accumulation Adrenal/thyroid deficiencies opiates may show greater effects Pregnancy fetus may show dependency exception is meperidine