Neuropharmacology Principles
Neuropharmacology Principles
What Do You Need to Know?
- Ionotropic vs metabotropic receptors — ionotropic = fast, ligand-gated ion channels (nicotinic, NMDA, AMPA, GABA-A); metabotropic = slow, G-protein coupled (muscarinic, GABA-B, dopamine, 5-HT subtypes)
- CYP450 interactions — carbamazepine, phenytoin, phenobarbital are potent inducers; valproate and fluoxetine are inhibitors; know CYP2D6, 3A4, 2C9, 2C19, 1A2 substrates
- Phenytoin = zero-order kinetics — small dose increases cause disproportionate level rises; highly protein-bound (adjust for low albumin); saturable metabolism
- Blood-brain barrier — lipophilic, small, uncharged molecules cross; P-glycoprotein efflux pump limits CNS penetration of many drugs
- Steady state = 5 half-lives — loading dose bypasses this; Vd determines loading dose; clearance determines maintenance dose
- Valproate + lamotrigine — valproate inhibits lamotrigine glucuronidation → doubles lamotrigine levels → SJS risk; must halve lamotrigine dose
- Enzyme inducers decrease OCP efficacy — carbamazepine, phenytoin, oxcarbazepine, topiramate (>200 mg) induce CYP3A4 → OCP failure
🚩 Don’t Miss — Test-Day Priorities
- BBB crossing rules: lipophilic, small (<500 Da), uncharged molecules cross; P-glycoprotein efflux pump actively pumps drugs OUT of CNS (keeps loperamide non-CNS); L-DOPA uses large neutral amino acid transporter; organic anion transporters handle acidic drugs.
- CYP450 INDUCERS (↓ levels of co-meds): rifampin, CBZ, PHT, PB, primidone, modafinil, St. John’s wort → reduce DOACs (apixaban/rivaroxaban), OCPs, warfarin, transplant immunosuppressants (cyclosporine/tacrolimus), statins, steroids.
- CYP450 INHIBITORS (↑ levels of co-meds): VPA inhibits glucuronidation → doubles LTG (must halve LTG dose, SJS risk); grapefruit juice, macrolides (erythromycin/clarithromycin), azoles (ketoconazole/fluconazole), ritonavir → CYP3A4 inhibitors; fluoxetine/paroxetine → CYP2D6 inhibitors.
- ZERO-ORDER kinetics (constant rate, saturable): phenytoin at therapeutic doses, ethanol, aspirin at toxic levels — small dose ↑ → disproportionate level ↑; half-life NOT constant.
- Steady state = ~5 half-lives regardless of dose; loading dose hits target immediately but does NOT change time to steady state; TDM useful for PHT, VPA, CBZ, PB, lithium, LTG (not LEV/LCM/GBP).
- HLA-B*1502 → screen Asian patients (Han Chinese, Thai, Filipino) before starting CBZ, PHT, or OXC → SJS/TEN risk; HLA-B*5701 for abacavir (non-neuro but classic pharmacogenomics).
- CYP2C19 polymorphism: poor metabolizers → ↑ clobazam/N-desmethyl-clobazam (excess sedation in Dravet/LGS), ↓ clopidogrel activation (FDA boxed warning; use ticagrelor in CYP2C19 LoF after stroke — CHANCE-2).
- CYP2D6 polymorphism (NOT inducible): poor metabolizers → TCA toxicity + no analgesic effect from codeine (cannot convert to morphine); ultra-rapid metabolizers → codeine → toxic morphine, respiratory depression in breastfeeding infants and post-tonsillectomy children (FDA boxed warning).
- APOE ε4 homozygotes → highest ARIA-E/H risk on anti-amyloid mAbs (lecanemab, donanemab); APOE genotyping recommended before therapy.
- Renal dose adjustment required for: LEV, GBP, PGB, topiramate, lacosamide, vigabatrin; hepatic dose adjustment for: VPA, CBZ, PHT, PB, benzodiazepines (avoid in severe liver dz).
- Pregnancy: LTG levels DROP ∼50% by 3rd trimester (↑ glucuronidation & renal clearance) → monitor levels monthly, dose up; LEV also requires dose increase; VPA contraindicated (NTDs, ↓ IQ).
- Geriatric: start low, go slow — ↓ albumin (↑ free PHT), ↓ renal clearance, ↑ sensitivity to BZDs/anticholinergics; pediatric: higher Vd, faster clearance per kg → often need higher mg/kg doses.
🔍 Buzzwords & Pathognomonic FindingsPK / PD · Interactions / pharmacogenomics · Special populations
PK / PD principles
- “Saturable / Michaelis-Menten kinetics” → zero-order — phenytoin, ethanol, high-dose aspirin
- “Disproportionate level rise with small dose change” → phenytoin zero-order (300 → 400 mg can double level)
- “5 half-lives to steady state” → phenobarbital ~3 weeks, lamotrigine ~5 days
- “Corrected phenytoin = measured / (0.2 × albumin + 0.1)” → hypoalbuminemia underestimates free PHT
- “Low Vd, low protein binding” → dialyzable — lithium, VPA, phenobarbital, salicylates
- “P-glycoprotein efflux” → loperamide stays out of CNS; rifampin/CBZ induce P-gp
Interactions / pharmacogenomics
- “VPA + LTG” → VPA inhibits UGT glucuronidation → doubles LTG → SJS risk — halve LTG dose
- “Rifampin / CBZ / PHT / PB / primidone” → potent CYP inducers → OCP failure, ↓ DOACs, ↓ warfarin chronically
- “Grapefruit juice” → intestinal CYP3A4 inhibitor → ↑ CBZ, midazolam, statins
- “Erythromycin/clarithromycin + CBZ” → diplopia, ataxia (CBZ toxicity)
- “HLA-B*1502 in Asian patient” → screen before CBZ/PHT/OXC — SJS/TEN
- “CYP2C19 LoF + recurrent stroke on clopidogrel” → switch to ticagrelor (CHANCE-2)
- “Breastfeeding mother + codeine + infant respiratory depression” → CYP2D6 ultra-rapid metabolizer (FDA boxed warning)
- “APOE ε4/ε4 homozygote on lecanemab” → highest ARIA-E/ARIA-H risk
- “Smoker quits → clozapine toxicity” → loss of CYP1A2 induction
- “Fluoxetine washout 5 weeks before MAOI” → norfluoxetine long half-life — serotonin syndrome prevention
Special populations / pearls
- “LTG level drops in 3rd trimester” → ↑ glucuronidation + renal clearance → monitor monthly, dose up
- “VPA in pregnancy” → NTDs, ↓ IQ, autism — contraindicated; use LEV or LTG
- “Elderly + low albumin + therapeutic total PHT” → elevated FREE PHT — check free level or correct
- “LEV, GBP, PGB in CKD” → renal dose adjust — risk of myoclonus/sedation
- “Cirrhosis + VPA” → hyperammonemic encephalopathy — check ammonia, consider L-carnitine
- “Pediatric AED dosing” → higher mg/kg (faster clearance, larger Vd per kg)
- “Start low, go slow” → geriatric dosing — especially BZDs, anticholinergics, TCAs
Receptor Pharmacology
Ionotropic vs Metabotropic Receptors
| Feature | Ionotropic | Metabotropic |
|---|---|---|
| Structure | Ligand-gated ion channel | G-protein coupled receptor (GPCR) |
| Speed | Fast (milliseconds) | Slow (seconds to minutes) |
| Mechanism | Direct ion flux | Second messenger cascade |
| Examples | Nicotinic, NMDA, AMPA, GABA-A, 5-HT3, glycine | Muscarinic, GABA-B, dopamine, 5-HT (most subtypes), adrenergic, mGluR |
G-Protein Signaling Families
| G-Protein | Second Messenger | Effect | Receptors |
|---|---|---|---|
| Gs | ↑ cAMP → PKA | Stimulatory | D1, β1, β2, 5-HT4, H2 |
| Gi | ↓ cAMP | Inhibitory | D2, M2, M4, α2, GABA-B, 5-HT1, mu-opioid |
| Gq | ↑ IP3/DAG → PKC + Ca2+ | Excitatory | M1, M3, α1, 5-HT2, H1 |
Key Neurologic Receptors
| Receptor | Type | Mechanism | Agonist | Antagonist |
|---|---|---|---|---|
| Nicotinic (NM) | Ionotropic (Na+/K+) | Fast excitation at NMJ | ACh, succinylcholine | Curare, vecuronium |
| Muscarinic M1/M3 | Gq → IP3/DAG | Excitatory | Bethanechol, pilocarpine | Atropine, benztropine |
| Muscarinic M2 | Gi → ↓ cAMP | Inhibitory (heart, presynaptic) | ACh | Atropine |
| NMDA | Ionotropic (Ca2+, Na+) | Ionotropic; slower than AMPA kinetics; Ca2+ permeable; Mg2+ block at rest; glycine co-agonist | Glutamate + glycine | Memantine, ketamine, PCP |
| AMPA | Ionotropic (Na+) | Fast EPSP | Glutamate | Perampanel |
| GABA-A | Ionotropic (Cl−) | Fast IPSP | Muscimol; modulators: BZDs, barbiturates | Bicuculline (competitive GABA antagonist), picrotoxin (Cl− channel blocker); flumazenil = BZD-site antagonist only (does NOT block GABA binding or Cl− channel) |
| GABA-B | Gi → ↑ K+, ↓ Ca2+ | Slow IPSP | Baclofen | Saclofen (experimental) |
| D1 | Gs → ↑ cAMP | Activates direct pathway | Fenoldopam | — |
| D2 | Gi → ↓ cAMP | Inhibits indirect pathway | Pramipexole, ropinirole, bromocriptine (D2/D3 preferring: D3 > D2 for pramipexole; D2/D3 for ropinirole) | Haloperidol, chlorpromazine |
| 5-HT1B/1D | Gi | Cranial vasoconstriction | Triptans | — |
| 5-HT2A | Gq | Cortical excitation | LSD, psilocybin | Atypical antipsychotics: risperidone (canonical), clozapine; quetiapine (weak 5-HT2A) |
| 5-HT3 | Ionotropic (cation) | Emesis trigger | — | Ondansetron |
| α1 adrenergic | Gq → IP3/DAG | Vasoconstriction | Phenylephrine | Prazosin (PTSD nightmares) |
| α2 adrenergic | Gi → ↓ cAMP | ↓ Sympathetic outflow | Clonidine, guanfacine | Yohimbine |
| β1 adrenergic | Gs → ↑ cAMP | ↑ HR, ↑ contractility | Dobutamine | Propranolol (tremor), metoprolol |
Board Pearl
BZDs increase FREQUENCY; barbiturates increase DURATION of GABA-A Cl− channel opening. Barbiturates can open the channel without GABA (no ceiling effect → fatal overdose). Flumazenil reverses BZDs only, not barbiturates.
Mnemonic: G-Protein Receptor Families
- Gs ("stimulatory"): D1, β1, β2, H2, V2 — think "D1 BAH" (D1, Beta, Adrenergic, Histamine)
- Gi ("inhibitory"): D2, M2, α2, GABA-B — "all the 2s are inhibitory" (D2, M2, α2) plus opioid receptors
- Gq ("excitatory/Ca2+"): M1, M3, α1, 5-HT2, H1 — "the odd-numbered muscarinics + alpha-1"
Drug Metabolism — CYP450 System
Key CYP Enzymes in Neurology
| CYP Enzyme | Neurologic Substrates | Inducers | Inhibitors |
|---|---|---|---|
| CYP3A4 | Carbamazepine, midazolam, diazepam, cyclosporine, statins, OCPs, apixaban | Rifampin, carbamazepine, phenytoin, phenobarbital, St. John's wort | Grapefruit, ketoconazole, erythromycin/clarithromycin, verapamil, diltiazem, fluconazole, ritonavir/protease inhibitors |
| CYP2D6 | TCAs, codeine → morphine, tramadol, tamoxifen → endoxifen, metoprolol, risperidone, dextromethorphan (NB: fluoxetine/paroxetine are inhibitors, not substrates) | Not significantly inducible | Fluoxetine, paroxetine, bupropion, quinidine |
| CYP2C9 | Phenytoin, warfarin, siponimod (requires CYP2C9 genotype-based dosing), valproate (minor) | Carbamazepine, phenobarbital, rifampin | Fluconazole, amiodarone, valproate |
| CYP2C19 | Phenytoin, phenobarbital, clobazam, diazepam, clopidogrel | Carbamazepine, rifampin | Fluoxetine, omeprazole, topiramate |
| CYP1A2 | Theophylline, olanzapine, clozapine, ropinirole, tizanidine | Smoking, charbroiled meats, rifampin | Fluvoxamine, ciprofloxacin |
Board Pearl
Smoking induces CYP1A2 — patients on clozapine or olanzapine who quit smoking can develop toxicity from rising drug levels. Conversely, starting smoking can drop levels and cause breakthrough symptoms.
Board Pearl
Clopidogrel is a prodrug activated by CYP2C19; LOF carriers (poor metabolizers) have reduced antiplatelet effect (FDA boxed warning); test in setting of stroke recurrence on therapy or use ticagrelor (CHANCE-2).
Zero-Order vs First-Order Kinetics
| Feature | First-Order | Zero-Order |
|---|---|---|
| Rate | Proportional to drug concentration | Constant (independent of concentration) |
| Half-life | Constant | Not constant; increases with dose |
| Clinical implication | Predictable dose-response; most drugs | Small dose changes → large level changes |
| Key example | Most AEDs, most drugs | Phenytoin (saturates at therapeutic doses), ethanol, aspirin (high dose) |
- Phenytoin is the classic board example: follows first-order at low concentrations but switches to zero-order at therapeutic doses because hepatic hydroxylation enzymes become saturated
- A small increase in phenytoin dose (e.g., 300 → 400 mg) can cause disproportionately large increases in serum levels → toxicity (nystagmus → ataxia → confusion)
Protein Binding
- Phenytoin: ~90% protein bound — only free (unbound) drug is active
- In hypoalbuminemia (liver disease, nephrotic syndrome, critical illness): total phenytoin level underestimates free level → use corrected phenytoin or measure free level directly
- Corrected phenytoin = measured level / (0.2 × albumin + 0.1)
- Valproate: ~90% protein bound; displaces phenytoin from albumin → increases free phenytoin
Clinical Pearl
A patient with low albumin (e.g., 2.0 g/dL) has a reported phenytoin level of 8 mcg/mL (subtherapeutic). Corrected level = 8 / (0.2 × 2.0 + 0.1) = 8 / 0.5 = 16 mcg/mL (therapeutic). Always correct for albumin or check a free phenytoin level before increasing the dose.
Blood-Brain Barrier Pharmacology
BBB Permeability Principles
| Crosses BBB Readily | Crosses BBB Poorly |
|---|---|
| Lipophilic drugs (diazepam, phenytoin, carbamazepine) | Hydrophilic/charged molecules (dopamine, serotonin, most antibiotics) |
| Small molecular weight (<400–500 Da) | Large molecules (antibodies, proteins) |
| Uncharged at physiologic pH | Quaternary amines (neostigmine, edrophonium) |
| L-DOPA (via large neutral amino acid transporter) | Dopamine (hence give L-DOPA, not DA itself) |
CNS Antibiotic Penetration
| Good CNS Penetration | Moderate (improved with inflamed meninges) | Poor CNS Penetration |
|---|---|---|
| Metronidazole, chloramphenicol, TMP-SMX, isoniazid, pyrazinamide, linezolid, fluconazole | Penicillins (high dose), ceftriaxone, cefotaxime, meropenem, amphotericin B, acyclovir | Aminoglycosides, 1st-gen cephalosporins, clindamycin, itraconazole, doxycycline (variable) |
P-Glycoprotein (P-gp) Efflux Pump
- ATP-dependent efflux transporter on BBB endothelial luminal surface — actively pumps drugs out of CNS
- P-gp substrates: many AEDs, loperamide (hence no CNS opioid effect at normal doses), digoxin, cyclosporine
- P-gp inhibitors: verapamil, quinidine, cyclosporine — may increase CNS drug penetration
- P-gp inducers: rifampin, St. John's wort, carbamazepine — may decrease CNS drug levels
- Loperamide is a mu-opioid agonist but does not cause CNS effects because P-gp efficiently effluxes it from the brain; overdose with P-gp inhibitors can cause CNS opioid effects
BBB Disruption in Disease
- Meningitis, brain tumors, MS plaques, and ischemia disrupt the BBB → increased drug penetration
- This is why penicillin/cephalosporins achieve adequate CNS levels in meningitis (inflamed meninges increase permeability) but not in healthy individuals
- Mannitol and focused ultrasound are used experimentally to transiently open the BBB for drug delivery
Board Pearl
L-DOPA crosses the BBB via the large neutral amino acid transporter; dopamine cannot cross. This is why Parkinson's disease is treated with L-DOPA (a precursor) rather than dopamine itself. Carbidopa is added to block peripheral DOPA decarboxylase, preventing peripheral conversion and increasing CNS delivery.
Pharmacokinetics Essentials
Board-Tested PK Concepts
| Concept | Definition | Clinical Relevance |
|---|---|---|
| Bioavailability (F) | Fraction of drug reaching systemic circulation | IV = 100%; oral < 100% due to first-pass metabolism; phenytoin oral F ~95% (unusually high) |
| Half-life (t1/2) | Time for plasma concentration to fall by 50% | Determines dosing interval; diazepam ~40 hr (long), lorazepam ~12 hr (shorter) |
| Steady state | Rate in = rate out; reached in ~5 half-lives | Lamotrigine t1/2 ~25 hr → steady state in ~5 days; phenobarbital t1/2 ~100 hr → ~3 weeks |
| Volume of distribution (Vd) | Apparent volume drug distributes into | High Vd = tissue-bound (not removed by dialysis); low Vd = plasma-confined (dialyzable) |
| Loading dose | = Vd × target concentration / F | Achieves therapeutic level immediately; phenytoin load = 20 mg/kg IV |
| Maintenance dose | = Clearance × target concentration / F | Maintains steady state; determined by clearance, not Vd |
| Clearance | Volume of plasma cleared of drug per unit time | Renal or hepatic; adjust in organ failure |
- Dialyzable drugs: low Vd, low protein binding, water-soluble (lithium, valproate, phenobarbital, salicylates)
- Not dialyzable: high Vd, high protein binding (phenytoin, carbamazepine, diazepam)
Therapeutic Drug Monitoring — Key AED Levels
| Drug | Therapeutic Range | Half-Life | Special Considerations |
|---|---|---|---|
| Phenytoin | 10–20 mcg/mL (free: 1–2) | ~22 hr (variable, dose-dependent) | Zero-order; correct for albumin; monitor free level |
| Carbamazepine | 4–12 mcg/mL | ~12–17 hr (after autoinduction) | Autoinduction over 3–5 weeks; active epoxide metabolite |
| Valproate | 50–100 mcg/mL | ~9–16 hr | Check ammonia if encephalopathy; monitor LFTs, CBC |
| Phenobarbital | 15–40 mcg/mL | ~80–120 hr | Very long t1/2; steady state ~3 weeks; dialyzable |
| Lamotrigine | 3–14 mcg/mL | ~25 hr (alone); ~60–70 hr (with VPA) | Halve dose with VPA; double dose with enzyme inducers |
| Levetiracetam | 12–46 mcg/mL | ~6–8 hr | Renal elimination; no CYP interactions; adjust in renal failure |
Board Pearl
Steady state is reached at ~5 half-lives regardless of dose. A loading dose achieves the target level immediately but does not change the time to steady state. It takes ~5 days for lamotrigine and ~3 weeks for phenobarbital to reach steady state after any dose change.
Drug Interactions in Neurology
Enzyme Inducers vs Inhibitors — Key AEDs
| Category | Drugs | Effect on Other Drug Levels |
|---|---|---|
| Potent inducers | Carbamazepine, phenytoin, phenobarbital, primidone | ↓ Levels of OCPs, warfarin, statins, steroids, lamotrigine, other AEDs, apixaban |
| Moderate inducers | Oxcarbazepine, topiramate (>200 mg), eslicarbazepine, felbamate | ↓ OCP efficacy (use alternative contraception) |
| Enzyme inhibitors | Valproate, felbamate, stiripentol (CYP2C19/3A4 inhibitor — raises norclobazam in Dravet), cannabidiol (CBD) (CYP2C19 inhibitor) | ↑ Lamotrigine, phenobarbital, carbamazepine-epoxide, N-desmethylclobazam (norclobazam) |
| No significant interaction | Levetiracetam, lacosamide, gabapentin, pregabalin, brivaracetam | Preferred when drug interactions are a concern |
High-Yield Drug Interactions
| Interaction | Mechanism | Clinical Consequence |
|---|---|---|
| Valproate + lamotrigine | Valproate inhibits lamotrigine glucuronidation (UGT) | ↑ Lamotrigine levels 2× → SJS/TEN risk; must halve lamotrigine dose |
| Carbamazepine + OCPs | CBZ induces CYP3A4 → ↑ OCP metabolism | Contraceptive failure; use IUD or depot medroxyprogesterone |
| Carbamazepine + erythromycin | Erythromycin inhibits CYP3A4 | ↑ CBZ levels → toxicity (diplopia, ataxia) |
| Phenytoin + warfarin | Both CYP2C9 substrates; complex interaction | Initial ↑ warfarin effect (displacement); chronic ↓ warfarin effect (induction) |
| Valproate + phenytoin | VPA displaces PHT from albumin + inhibits metabolism | ↑ Free phenytoin (total may appear unchanged); risk of toxicity |
| Grapefruit + CYP3A4 substrates | Grapefruit inhibits intestinal CYP3A4 | ↑ Levels of carbamazepine, midazolam, statins |
| SSRI + MAOI | ↑↑ Serotonin (blocked reuptake + blocked degradation) | Serotonin syndrome; washout period required (5 weeks for fluoxetine) |
| Fluvoxamine + clozapine/olanzapine | Fluvoxamine inhibits CYP1A2 | ↑ Clozapine/olanzapine levels → toxicity |
| Carbamazepine autoinduction | CBZ induces its own metabolism via CYP3A4 | Levels fall over 3–5 weeks; requires dose increase to maintain therapeutic levels |
Board Pearl
Valproate + lamotrigine is the most commonly tested AED interaction. Valproate doubles lamotrigine levels by inhibiting glucuronidation. The lamotrigine dose must be halved when adding valproate. Rapid lamotrigine titration with valproate co-therapy is a major risk factor for Stevens-Johnson syndrome.
Clinical Pearl
When a woman of childbearing potential needs an AED, avoid potent enzyme inducers (carbamazepine, phenytoin, phenobarbital) if she is on OCPs. Levetiracetam, lamotrigine, and lacosamide do not significantly affect OCP efficacy. If an inducer is necessary, recommend non-oral contraception (IUD, depot injection).
Board Pearl
CYP2D6 is not inducible — unlike other CYP enzymes, 2D6 cannot be upregulated by drugs. Instead, genetic polymorphisms determine phenotype: Poor metabolizers (PM) get no analgesic effect from codeine (cannot convert to morphine) and accumulate TCA toxicity. Ultra-rapid metabolizers (UM) convert codeine to morphine excessively → respiratory depression and death (FDA boxed warning; contraindicated in children post-tonsillectomy and in breastfeeding mothers). Pharmacogenomic testing for CYP2D6 is increasingly board-relevant.
Clinical Pearl
Carbamazepine autoinduction is a common pitfall: a patient starts CBZ and initially achieves therapeutic levels, but over 3–5 weeks the level drops as CBZ induces its own CYP3A4 metabolism. Dose increases are routinely needed. Recheck levels 4–6 weeks after any dose change.
Quick Reference Table
Neuropharmacology Principles — At a Glance
| Concept | Key Point | Board-Yield Detail |
|---|---|---|
| Ionotropic receptors | Fast, ligand-gated ion channels | Nicotinic, NMDA, AMPA, GABA-A, 5-HT3, glycine |
| Metabotropic receptors | Slow, G-protein coupled | Muscarinic, GABA-B, dopamine, most 5-HT subtypes, adrenergic |
| CYP3A4 | Most important CYP; metabolizes most drugs | Induced by CBZ/PHT/PB; inhibited by grapefruit, azoles, macrolides |
| CYP2D6 | TCAs, codeine, tramadol, tamoxifen, metoprolol | Not inducible; inhibited by fluoxetine, paroxetine (these are inhibitors, not substrates) |
| Phenytoin kinetics | Zero-order at therapeutic doses | Small dose ↑ → disproportionate level ↑; correct for albumin |
| Protein binding | Phenytoin ~90% bound | Corrected PHT = measured / (0.2 × albumin + 0.1) |
| BBB crossing | Lipophilic, small, uncharged | L-DOPA crosses (transporter); dopamine does not |
| P-glycoprotein | Efflux pump at BBB | Keeps loperamide out of CNS; inhibitors can cause toxicity |
| Steady state | 5 half-lives | Loading dose achieves target immediately; does not change time to steady state |
| VPA + LTG | VPA doubles LTG levels | Halve LTG dose; SJS risk with rapid titration |
| CBZ + OCPs | CBZ induces CYP3A4 | Contraceptive failure; use IUD or depot |
| CBZ autoinduction | Induces own CYP3A4 metabolism | Levels fall over 3–5 weeks; may need dose increase |
| Enzyme-neutral AEDs | LEV, LCM, GBP, PGB, BRV | Preferred when drug interactions are a concern |
| SSRI + MAOI | Serotonin syndrome | 5-week washout for fluoxetine (long t1/2 of norfluoxetine) |
| Dialyzable drugs | Low Vd, low protein binding | Lithium, valproate, phenobarbital; phenytoin is NOT dialyzable |
| CYP2D6 polymorphisms | Genetic, not inducible | Poor metabolizers: TCA toxicity + no codeine analgesia; ultra-rapid: codeine → morphine overdose (FDA boxed warning; contraindicated post-tonsillectomy in children, in breastfeeding mothers) |
| CNS antibiotic penetration | Lipophilic agents cross best | Metronidazole, TMP-SMX, chloramphenicol cross well; aminoglycosides do not |
| Meningeal inflammation | Disrupts BBB → ↑ drug entry | Penicillins/cephalosporins reach CNS only with inflamed meninges |
| Gs / Gi / Gq | Three major G-protein families | Gs: ↑ cAMP (D1, β); Gi: ↓ cAMP (D2, M2, α2); Gq: IP3/Ca2+ (M1, α1, 5-HT2) |
References
- Bhatt A. Ultimate Review for the Neurology Boards. 3rd ed. Demos Medical; 2016.
- Patsalos PN, et al. Antiepileptic drugs — best practice guidelines for therapeutic drug monitoring. Epilepsia. 2008;49(7):1239–1276.
- Perucca E. Clinically relevant drug interactions with antiepileptic drugs. Br J Clin Pharmacol. 2006;61(3):246–255.
- Ropper AH, Samuels MA, Klein JP, Prasad S. Adams and Victor’s Principles of Neurology. 12th ed. McGraw-Hill; 2023.
- Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics. 14th ed. McGraw-Hill; 2023.
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