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Basic Science
Pharmacology
11 notes available
1 Last Minute Review 2 Neuropharmacology Principles 3 Antiepileptic Drugs 4 Movement Disorder Pharmacology 5 Neuromuscular Pharmacology 6 Headache Pharmacology 7 Pain & Anesthesia Pharmacology 8 Psychopharmacology 9 Stroke & Vascular Pharmacology 10 Immunotherapy & MS Pharmacology 11 Antimicrobials & CNS Infections
Basic Science › Pharmacology

Pain & Anesthesia Pharmacology

Pain & Anesthesia Pharmacology

What You'll Learn

  • Neuropathic pain agents — gabapentin/pregabalin (α2δ Ca channel subunit), SNRIs (duloxetine), TCAs (amitriptyline), carbamazepine (first-line for trigeminal neuralgia)
  • Opioid receptors — mu (analgesia, respiratory depression, constipation), kappa (dysphoria), delta (spinal analgesia); naloxone = competitive antagonist; tramadol lowers seizure threshold and causes serotonin syndrome
  • Local anesthetics — Na channel blockade; esters (pseudocholinesterase) vs amides (hepatic CYP); toxicity = CNS first then cardiac for lidocaine (bupivacaine cardiotoxicity may precede CNS); B fibers (autonomic) blocked first, Aα (motor) last
  • General anesthetics — volatile agents enhance GABA-A and increase ICP; propofol (GABA-A, decreases ICP); ketamine (NMDA antagonist) — classic teaching of ICP elevation; modern TBI/ICU data in sedated/ventilated patients generally do NOT show reliable ICP elevation and may preserve CPP; caution in uncontrolled intracranial hypertension but not absolute prohibition; etomidate = least hemodynamic effect
  • Neuromuscular blockers — succinylcholine (depolarizing) causes hyperkalemia in burns/denervation/SCI and triggers malignant hyperthermia; rocuronium (nondepolarizing) reversed by sugammadex
  • Malignant hyperthermia — RYR1 mutation + volatile anesthetics or succinylcholine; treatment = dantrolene (blocks ryanodine receptor Ca release from SR)
  • Procedural sedation — methohexital activates seizure foci (used in Wada test); thiopental suppresses cortical activity (burst suppression); propofol can activate foci on ECoG
HighYield Pearls
  • Meperidine → normeperidine seizures: AVOID chronic use & in renal failure — toxic metabolite normeperidine accumulates and causes tremor, myoclonus, seizures (not reversed by naloxone); also serotonin syndrome with MAOIs/SSRIs.
  • Methadone — QT prolongation + NMDA antagonism: baseline + follow-up ECG required; long & variable half-life (15–60 h) → delayed respiratory depression; NMDA blockade makes it useful for neuropathic pain and opioid rotation; CYP3A4/2B6 interactions.
  • Tramadol & tapentadol — serotonin syndrome + seizures: mixed μ agonist + 5HT/NE reuptake inhibition; AVOID with SSRIs, SNRIs, MAOIs, TCAs; lowers seizure threshold (especially with renal impairment or bupropion).
  • Opioids in renal failure: AVOID morphine and codeine (active metabolites accumulate — M6G → neuroexcitation/myoclonus). Hydromorphone is safer than morphine but H3G can accumulate (neuroexcitation) — dose reduce + monitor. Prefer fentanyl, methadone, or buprenorphine when CrCl < 30.
  • Buprenorphine = partial μ agonist + κ antagonist: ceiling effect on respiratory depression; can precipitate withdrawal in opioid-dependent patients; high receptor affinity blocks full agonists — preferred for NAS & opioid use disorder in pregnancy.
  • Naloxone vs naltrexone: naloxone = short-acting (IV/IM/IN) for acute overdose — repeat dosing/infusion needed for long-acting opioids (methadone, ER fentanyl); naltrexone = long-acting oral/depot for relapse prevention — must be opioid-free 7–10 days or precipitates severe withdrawal.
  • Bupivacaine cardiotoxicity → INTRALIPID rescue: high lipid solubility → refractory ventricular arrhythmias & arrest that precede CNS toxicity; rescue = 20% lipid emulsion 1.5 mL/kg bolus then 0.25 mL/kg/min infusion; prilocaine/benzocaine → methemoglobinemia → methylene blue.
  • Acetaminophen hepatotoxicity: > 4 g/day (or lower with chronic alcohol/malnutrition) → NAPQI depletes glutathione → centrilobular necrosis; rescue = N-acetylcysteine (most effective < 8 h); preferred analgesic in pregnancy.
  • Duloxetine = only evidence-based agent for CIPN: ASCO guideline — chemotherapy-induced peripheral neuropathy responds to duloxetine; gabapentin/pregabalin/TCAs have not shown benefit in CIPN trials.
  • Ketamine — NMDA antagonist: low-dose infusions for refractory neuropathic pain, opioid-induced hyperalgesia, treatment-resistant depression; AE = dissociation, emergence reactions, hypertension, chronic use → ulcerative cystitis. ICP teaching: classic caution remains, but modern TBI/ICU data in sedated/ventilated patients generally do NOT show reliable ICP elevation and may preserve CPP — caution in uncontrolled IH but not absolute prohibition.
  • Gabapentinoids — renal dosing + abuse potential: bind α2δ subunit of voltage-gated Ca channels → ↓ presynaptic glutamate; pregabalin is Schedule V (euphoria, abuse); both cause sedation, dizziness, weight gain, peripheral edema; renally cleared.
🔍 Quick ReferenceMechanism · Adverse effects · Use / pearls
Mechanism
  • Gabapentin / pregabalin → bind α2δ subunit of voltage-gated Ca2+ channel → ↓ presynaptic glutamate release
  • Methadone → μ agonist + NMDA antagonist + SNRI activity (and hERG blockade → QT)
  • Tramadol / tapentadol → μ agonist + 5HT/NE reuptake inhibition (mixed mechanism)
  • Buprenorphine → partial μ agonist + κ antagonist (high affinity, ceiling effect)
  • Ketamine → non-competitive NMDA receptor antagonist
  • Capsaicin → TRPV1 agonist → substance P depletion & C-fiber desensitization
  • Local anesthetics → voltage-gated Na channel blockade (use-dependent; ester vs amide)
  • NSAIDs / celecoxib → COX1/COX2 inhibition → ↓ prostaglandins (celecoxib COX2-selective)
  • Acetaminophen → central COX inhibition; metabolized to NAPQI by CYP2E1
Adverse effects / toxicity
  • Normeperidine seizures + serotonin syndrome → meperidine (especially renal failure or with MAOI/SSRI)
  • QT prolongation + torsades → methadone (dose-dependent; ECG monitoring required)
  • Serotonin syndrome + lowered seizure threshold → tramadol / tapentadol
  • Myoclonus + neuroexcitation in renal failure → morphine (M6G); hydromorphone safer than morphine but H3G can still accumulate — dose reduce + monitor
  • Refractory cardiac arrest rescued by intralipid → bupivacaine toxicity
  • Methemoglobinemia → methylene blue → benzocaine / prilocaine
  • NAPQI hepatic centrilobular necrosis → N-acetylcysteine → acetaminophen overdose
  • Anticholinergic toxicity + orthostatic hypotension + QT → amitriptyline (TCA) — avoid in elderly
  • GI bleeding + AKI + cardiovascular risk → NSAIDs (diclofenac, rofecoxib withdrawn)
  • Dissociation + emergence reactions + ulcerative cystitis → ketamine
  • Peripheral edema + weight gain + sedation → gabapentinoids
  • Precipitated withdrawal in opioid-dependent patient → buprenorphine or naltrexone initiation
Use / pearls
  • Chemotherapy-induced peripheral neuropathy (CIPN) → duloxetine — only evidence-based agent (ASCO)
  • Diabetic neuropathy first-line (ADA / AAN) → duloxetine, pregabalin, gabapentin, amitriptyline
  • Postherpetic neuralgia — focal → lidocaine 5% patch or capsaicin 8% patch
  • Opioid use disorder in pregnancy → buprenorphine (less severe NAS than methadone in some trials) or methadone
  • Acute opioid overdose → naloxone IV/IM/IN — repeat dosing/infusion for long-acting opioids (methadone, ER fentanyl)
  • Refractory neuropathic pain or opioid-induced hyperalgesia → IV ketamine infusion cycles; rotate to methadone (NMDA antagonism)
  • Bupivacaine LAST (local anesthetic systemic toxicity) → 20% intralipid 1.5 mL/kg bolus then 0.25 mL/kg/min
  • Acetaminophen overdose → N-acetylcysteine (most effective within 8 h); pregnancy preferred analgesic
  • Renal failure (CrCl <30) — preferred opioids → fentanyl, methadone, buprenorphine; AVOID morphine, codeine, meperidine; hydromorphone safer than morphine but H3G can accumulate (neuroexcitation) — dose reduce + monitor
  • Treatment-resistant depression + chronic pain → ketamine / esketamine infusions
  • Trigeminal neuralgia first-line → carbamazepine (oxcarbazepine alternative)
  • Long-term opioid relapse prevention → naltrexone (oral or depot Vivitrol) — require 7–10 days opioid-free
Neuropathic Pain Agents
Drug / Class Mechanism Indications Key Side Effects / Notes
Gabapentin / Pregabalin Bind α2δ subunit of voltage-gated Ca2+ channels → ↓ presynaptic glutamate release Diabetic neuropathy, postherpetic neuralgia, fibromyalgia (pregabalin) Sedation, dizziness, edema; renally cleared; pregabalin has linear pharmacokinetics
Duloxetine / Venlafaxine (SNRIs) Serotonin + NE reuptake inhibition → descending pain inhibition Diabetic neuropathy (duloxetine FDA-approved), fibromyalgia Nausea, HTN (venlafaxine at high doses); serotonin syndrome risk
TCAs (amitriptyline, nortriptyline) Na channel blockade + serotonin/NE reuptake inhibition Neuropathic pain, migraine prophylaxis Anticholinergic effects; QT prolongation; nortriptyline better tolerated than amitriptyline
Carbamazepine Na channel blockade (use-dependent) First-line for trigeminal neuralgia; glossopharyngeal neuralgia SIADH; agranulocytosis; SJS/TEN (screen HLA-B*1502); CYP3A4 autoinduction
Topical lidocaine (5% patch) Local Na channel blockade Postherpetic neuralgia, localized neuropathic pain Minimal systemic absorption; well tolerated
Capsaicin (topical) TRPV1 agonist → C-fiber desensitization; depletes substance P Postherpetic neuralgia (8% patch), diabetic neuropathy Initial burning; high-concentration patch applied in clinic
Board Pearl

Carbamazepine is first-line for trigeminal neuralgia. Lancinating facial pain in V2/V3 triggered by chewing or touch = carbamazepine. Oxcarbazepine is an alternative with fewer drug interactions. Screen HLA-B*1502 in patients of Southeast Asian descent before starting.

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