Neuropharmacology Principles
Neuropharmacology Principles
What You'll Learn
- 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
HighYield Pearls
- 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.
🔍 Quick ReferencePK / 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"
Continue reading — sign in
The full note has more clinical pearls, tables, and board-focused tips. Free account, no fee.