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B Blood–Brain Barrier (BBB) Penetration Lipophilic enough to cross BBB, enabling central action. C CYP Enzymes Metabolized mainly by CYP2D6 (to O-desmethyltramadol, active metabolite) and CYP3A4 (to inactive metabolites). D Distribution Widely distributed; volume of distribution ~2.6–2.9 L/kg. Plasma protein binding ~20%. E Excretion 90% renal (mainly as metabolites); 10% fecal. Half-life extended in renal failure. F First-Pass Effect Moderate; hence oral doses are higher than parenteral doses. G Genetic Polymorphism (CYP2D6) “Poor metabolizers” (CYP2D6 deficiency) → less analgesia; “ultra-rapid metabolizers” → toxicity risk. H Histamine Release Minimal compared to morphine → fewer allergic or hypotensive effects. I Intravenous Use 50–100 mg slow IV for acute pain; onset within minutes. J Junction with Monoaminergic System Inhibits serotonin (5-HT) and norepinephrine reuptake → activates descending inhibitory pain pathways. K Kinetics (Pharmacokinetics) Linear up to 400 mg/day. Steady state achieved in 2 days for IR; 4 days for ER. L Lipid Solubility Moderate — helps CNS entry without excessive accumulation. M Mechanism of Action (Dual) ① μ-opioid receptor agonism → ↓ pain transmission. ② Serotonin/Norepinephrine reuptake inhibition → ↑ pain inhibition. N Neurochemistry Enhances monoamine neurotransmission in brainstem and spinal cord; modulates GABAergic neurons indirectly. O Onset of Action IR: 30–60 min; Peak: 2–3 h; Duration: 4–6 h. ER: onset 1–2 h; duration up to 24 h. P Potency ~1/10 the potency of morphine; higher doses needed for similar effect. Q QT Prolongation Risk Rare, but may occur with high doses or combination with QT-prolonging drugs. R Receptors Involved μ-opioid (main), κ-opioid (minor), serotonin transporter (SERT), norepinephrine transporter (NET). S Serotonin Syndrome Risk ↑ when combined with SSRIs, MAOIs, SNRIs, or triptans. Symptoms: agitation, tremor, hyperthermia. T Toxicity (Overdose) Causes CNS depression, miosis, seizures, respiratory depression; treated with naloxone (but less effective due to dual mechanism). U Use Spectrum Postoperative pain, dental pain, neuropathic pain, osteoarthritis, fibromyalgia, cancer-related pain (adjuvant). V Vigilance Monitor for sedation, confusion, and coordination issues (especially elderly). W Withdrawal Mild to moderate compared to morphine: symptoms = anxiety, sweating, chills, nausea. X Xenobiotic Category Classified as a centrally acting synthetic opioid analgesic. Y Year of Discovery Developed in 1977 by Grünenthal GmbH (Germany). 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