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PHARMACOLOGY NOTES - KATZUNG 16th Edition

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SECTION 1: ANTIPSYCHOTIC DRUGS (Chapter 29)

Receptor Binding Profile (Katzung Table 29-1)

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1. CHLORPROMAZINE (Thorazine)

• Blocks D2 receptors (requires ~60% D2 occupancy for antipsychotic effect; EPS occurs at ≥80%)
• Also potently blocks α1-adrenoceptors and 5-HT2A receptors
• Significant H1, muscarinic, and α-adrenergic blockade

• Oral bioavailability variable (first-pass metabolism)
• Highly lipophilic, large volume of distribution
• Hepatic metabolism (CYP2D6, CYP1A2)
• Long t½; active metabolites

• Schizophrenia (positive symptoms primarily)
• Mania (adjunct)
• Nausea/vomiting (antiemetic via D2 blockade in CTZ)
• Intractable hiccups

• Autonomic: Orthostatic hypotension (prominent - α1 blockade), dry mouth, urinary retention, constipation (muscarinic blockade), impotence, failure to ejaculate (α-blockade)
• CNS: EPS (acute dystonia, akathisia, Parkinsonism, tardive dyskinesia with long-term use), sedation (H1 blockade)
• Endocrine: Hyperprolactinemia (D2 block in tuberoinfundibular pathway) - galactorrhea, amenorrhea, gynecomastia
• Metabolic: Weight gain
• Other: Jaundice (cholestatic), photosensitivity, skin pigmentation, agranulocytosis (rare), lowered seizure threshold, Neuroleptic Malignant Syndrome (NMS)

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2. HALOPERIDOL (Haldol)

• Highly selective, potent D2 receptor antagonist
• Minimal muscarinic or histamine blockade
• Some α1 blockade

• Oral and IM formulations; long-acting decanoate injection (monthly)
• Hepatic metabolism; t½ ~18 hours
• Therapeutic plasma level: 5-15 ng/mL

• Schizophrenia (first-line typical)
• Acute agitation (IM - ICU, emergency settings)
• Tourette syndrome
• Delirium management
• Nausea/vomiting
• Second-line for acute mania

• EPS (most common and severe): Acute dystonias, akathisia, drug-induced Parkinsonism, tardive dyskinesia (long-term)
• Minimal: Sedation, orthostatic hypotension (less than chlorpromazine due to less α1 blockade)
• Endocrine: Hyperprolactinemia
• Cardiac: QTc prolongation (less than thioridazine)
• NMS (rare but life-threatening)

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3. ARIPIPRAZOLE (Abilify)

• Partial agonist at D2 and D3 receptors (NOT a pure antagonist - acts as functional antagonist in hyperdopaminergic states; agonist in hypodopaminergic states)
• Partial agonist at 5-HT1A
• Antagonist at 5-HT2A
• PET studies: very high D2 occupancy but NO EPS because it is a partial agonist, not a full antagonist
• Gains antipsychotic efficacy via 5-HT2A antagonism and possibly 5-HT2B partial agonism

• Excellent oral bioavailability (~87%)
• Long t½ ~75 hours (once-daily dosing)
• Hepatic metabolism (CYP2D6, CYP3A4)
• Monthly long-acting injectable (Abilify Maintena)

• Schizophrenia (acute and maintenance)
• Bipolar disorder (manic and mixed episodes; maintenance)
• Adjunct in major depression (FDA-approved)
• Irritability in autism spectrum disorder
• Tourette syndrome

• Minimal EPS (partial agonism avoids EPS)
• Minimal prolactin elevation (actually may lower prolactin)
• Akathisia (can occur)
• Insomnia, agitation (activating side effects)
• Mild weight gain (less than olanzapine/clozapine)
• Minimal metabolic syndrome
• Minimal QTc prolongation
• No significant sedation

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4. CLOZAPINE (Clozaril)

• Very high affinity for D4 receptors, 5-HT2A, α1 (D4 = α1 > 5-HT2A > D2 = D1)
• Low affinity for D2 (explains absence of EPS)
• 5-HT2 antagonism at lower D2 occupancy levels (30-50%) than typical agents
• Achieves efficacy through high 5-HT2A occupancy even at low D2 occupancy
• Also a 5-HT2 antagonist - may be partly responsible for efficacy against negative symptoms

• Oral only; t½ ~12 hours
• Hepatic metabolism; active metabolite norclozapine
• Requires REMS program (Risk Evaluation and Mitigation Strategy) due to agranulocytosis risk

• Treatment-resistant schizophrenia (failed 2+ antipsychotics) - gold standard
• Reducing suicidal behavior in schizophrenia/schizoaffective disorder (FDA-approved)
• Psychosis in Parkinson disease (does not worsen motor symptoms due to low D2 affinity)

• Agranulocytosis (1-2%) - most dangerous; fatal if untreated; requires mandatory weekly CBC for first 6 months, then bi-weekly
  • Must stop immediately if ANC < 1000/mm³
• Seizures (dose-dependent, ~3% at doses >600 mg/day) - lowers seizure threshold significantly
• Metabolic syndrome - severe weight gain, hyperglycemia, hyperlipidemia (MOST likely of all antipsychotics)
• Sedation (prominent - H1 blockade)
• Hypersalivation (paradoxical - muscarinic agonism at M4?)
• Orthostatic hypotension (α1 blockade)
• Tachycardia
• Myocarditis (rare but serious)
• No EPS, no tardive dyskinesia (major advantage)
• No hyperprolactinemia

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5. OLANZAPINE (Zyprexa)

• 5-HT2A > H1 > D4 > D2 > α1 > D1
• Like clozapine in pharmacology but less potent D4 affinity
• Effective at 30-50% D2 occupancy due to high 5-HT2A blockade
• Broad receptor blockade (dopamine, serotonin, histamine, muscarinic, adrenergic)

• Good oral bioavailability; t½ ~30 hours (once daily)
• Hepatic metabolism (CYP1A2 primarily, CYP2D6)
• IM form for acute agitation (less EPS than haloperidol IM)
• Long-acting IM: Zyprexa Relprevv (risk of post-injection delirium/sedation syndrome - PDSS)

• Schizophrenia (positive and negative symptoms)
• Bipolar mania (acute and maintenance)
• Bipolar depression (in combination with fluoxetine - Symbyax)
• Adjunct in treatment-resistant depression
• Acute agitation (IM)

• Metabolic syndrome - MOST significant; weight gain (most pronounced), hyperglycemia, dyslipidemia
• Sedation (prominent H1 blockade)
• Orthostatic hypotension (α1 blockade)
• Minimal EPS
• No agranulocytosis (unlike clozapine)
• Hyperprolactinemia (minimal - less than typicals)
• Anticholinergic effects (dry mouth, constipation)

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6. RISPERIDONE (Risperdal)

• High affinity for D2 AND 5-HT2A receptors (D2/5-HT2A antagonist)
• Also blocks α1, α2, and H1
• At higher doses, D2 occupancy increases and EPS risk rises (dose-dependent EPS - unlike other atypicals)

• Oral, IM (Risperdal Consta - 2-week long-acting injection), and subcutaneous (Perseris - monthly)
• Active metabolite: 9-hydroxyrisperidone (paliperidone) - equally active
• t½ ~20 hours (risperidone); paliperidone t½ ~23 hours
• Renal excretion of metabolite

• Schizophrenia
• Bipolar disorder (manic and mixed episodes)
• Irritability in autism
• Adjunct in bipolar maintenance

• Hyperprolactinemia (most potent prolactin-elevating atypical - behaves like typical in this regard); galactorrhea, sexual dysfunction
• EPS at higher doses (unlike clozapine/olanzapine)
• QTc prolongation
• Weight gain (moderate)
• Orthostatic hypotension (α1)
• Minimal sedation at low doses

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Adverse Effects Comparison Table

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SECTION 2: PARKINSON'S DISEASE DRUGS (Chapter 28)

Pathophysiology Background (Katzung)

• Loss of dopaminergic neurons in the substantia nigra pars compacta - reduced dopamine in striatum
• Lewy bodies (α-synuclein inclusions) are the pathologic hallmark
• Normal balance: dopamine (inhibitory) vs. acetylcholine (excitatory) in basal ganglia
• Braak staging: pathology begins in olfactory nucleus and medulla, reaches substantia nigra at stage 3 (when motor symptoms appear)
• Cardinal features: TRAP - Tremor (resting), Rigidity, Akinesia/bradykinesia, Postural instability

1. Increase dopamine (levodopa, dopamine agonists)
2. Decrease dopamine catabolism (MAO-B inhibitors, COMT inhibitors)
3. Reduce cholinergic excess (antimuscarinics)
4. Other (amantadine - NMDA antagonist)

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7. LEVODOPA (with Carbidopa)

• Levodopa is the immediate precursor of dopamine; crosses the blood-brain barrier (dopamine itself cannot)
• Converted to dopamine by aromatic L-amino acid decarboxylase (DOPA decarboxylase) in CNS neurons
• Carbidopa is a peripheral DOPA decarboxylase inhibitor that does NOT cross the BBB
  • Carbidopa reduces peripheral conversion of levodopa → dopamine (reduces nausea, vomiting, cardiac arrhythmias)
  • Increases levodopa bioavailability to the brain by ~75%
  • Allows 75% dose reduction of levodopa

• Carbidopa/levodopa (Sinemet): standard immediate-release
• Carbidopa/levodopa/entacapone (Stalevo): triple combination
• Rytary (carbidopa/levodopa ER): extended-release capsule (substitution table available in Katzung)

• Absorbed via large neutral amino acid transporter (competes with dietary amino acids)
• Taken 30-60 min before meals to maximize absorption
• Short plasma t½ (~1-2 hours) - leads to motor fluctuations with chronic use
• 70-80% eliminated as dopamine metabolites in urine

• Wearing off (end-of-dose deterioration): drug effect wanes before next dose; managed by increasing dose frequency, adding COMT inhibitor, or MAO-B inhibitor
• On-Off phenomenon: abrupt, unpredictable fluctuations between mobile ("on") and akinetic ("off") states
• Peak-dose dyskinesia: involuntary choreiform movements at peak plasma level
• Delayed "on" or "no-on": failure of dose to take effect

• Peripheral (reduced by carbidopa): Nausea, vomiting, orthostatic hypotension, cardiac arrhythmias
• Central: Dyskinesias, on-off fluctuations, psychiatric effects (hallucinations, confusion, psychosis - especially in elderly), impulse control disorders (gambling, hypersexuality), vivid dreams
• Contraindicated with: Non-selective MAO inhibitors (risk of hypertensive crisis); narrow-angle glaucoma

• Most effective symptomatic treatment of Parkinson disease
• Still the "cornerstone" of treatment despite newer agents
• Early initiation may be preferred in older patients (>70) or those with significant disability

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8. PRAMIPEXOLE (Mirapex)

• Direct agonist at D2 and D3 receptors (preferential D3 affinity)
• Does NOT require conversion; acts directly on post-synaptic dopamine receptors
• Bypasses degenerating presynaptic dopaminergic neurons

• Oral bioavailability ~90%
• Renal excretion (dose adjust in renal impairment)
• t½ ~8-12 hours; ER formulation available (once daily)

• Parkinson disease (early monotherapy OR adjunct with levodopa in advanced disease)
• Restless legs syndrome (RLS)
• Depression (off-label, especially bipolar depression)

• Longer duration of action (fewer wearing-off episodes)
• Less motor fluctuations and dyskinesias
• May have neuroprotective potential (controversial)
• Used early in disease to delay levodopa initiation (especially in younger patients)

• Impulse control disorders - pathologic gambling, hypersexuality, binge eating (class effect of dopamine agonists)
• Nausea, orthostatic hypotension
• Sedation ("sleep attacks" - sudden onset sleep while driving)
• Peripheral edema
• Hallucinations and confusion (more than levodopa in elderly)
• Dyskinesias (less than levodopa)

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9. RASAGILINE (Azilect)

• Irreversibly inhibits monoamine oxidase type B (MAO-B) in the CNS
• MAO-B is the predominant enzyme responsible for dopamine catabolism in the striatum
• Inhibition → reduced dopamine breakdown → increased dopamine levels in synapse
• Does NOT inhibit MAO-A at therapeutic doses (unlike older selegiline analogs)
• Possible neuroprotective effect (reduces oxidative stress from dopamine catabolism) - debated

• Oral; t½ ~1.3 hours (but MAO-B inhibition is irreversible - effect lasts weeks until new MAO-B synthesized)
• Hepatic metabolism (CYP1A2)

• Early Parkinson disease (monotherapy)
• Adjunct to levodopa in advanced disease (reduces wearing-off)

• Generally well-tolerated
• May cause serotonin syndrome if combined with SSRIs, meperidine, or tramadol
• Hypertensive crisis with tyramine-rich foods is NOT a concern at selective MAO-B doses (unlike non-selective MAOIs)
• Dyskinesias when used with levodopa (dose reduction may be needed)
• Nausea, insomnia

• SSRIs/SNRIs: risk of serotonin syndrome
• Meperidine: contraindicated (serotonin syndrome)
• Non-selective MAOIs: contraindicated (hypertensive crisis)
• Sympathomimetics: avoid

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10. ENTACAPONE (Comtan)

• Inhibits COMT in peripheral tissues, blocking the major alternative metabolic pathway of levodopa (conversion to 3-O-methyldopa)
• Increases levodopa bioavailability and plasma half-life
• Does NOT cross BBB significantly (peripheral action only)
• Combination: Carbidopa/levodopa/entacapone = Stalevo

• Oral; short t½ (~2 hours); must be given with each dose of levodopa (5x/day typically)
• Hepatic glucuronidation; excreted in bile/feces

• Adjunct to carbidopa/levodopa in patients experiencing "wearing off" episodes
• NOT used as monotherapy (requires levodopa to work)

• Increased dopaminergic effects: dyskinesias (may need to reduce levodopa dose), nausea, orthostatic hypotension, hallucinations
• Orange discoloration of urine (harmless - due to catechol metabolites)
• Diarrhea (can be severe - up to 10% discontinuation)
• Hepatotoxicity (rare, unlike tolcapone - a centrally-acting COMT inhibitor)

• Tolcapone acts both centrally and peripherally (more effective but requires LFT monitoring due to fatal hepatotoxicity risk)
• Entacapone: peripheral only, safer hepatic profile, no LFT monitoring needed

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SECTION 3: ANTISEIZURE DRUGS (Chapter 24)

General Mechanism Overview

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11. PHENYTOIN (Dilantin)

• Blocks voltage-gated Na+ channels in a use-dependent (frequency-dependent) manner
• Preferentially binds to and stabilizes the inactivated state of Na+ channels
• Prevents repetitive high-frequency neuronal firing (normal firing unaffected)
• No significant effect on GABA

• Oral; highly protein-bound (90%)
• Zero-order (saturation) kinetics at therapeutic doses - small dose increases can cause disproportionate rise in plasma levels (NARROW THERAPEUTIC INDEX)
• Therapeutic plasma level: 10-20 mcg/mL
• t½: 22 hours but varies widely (dose-dependent: increases as dose increases)
• Hepatic metabolism: CYP2C9, CYP2C19 (strong inducer of CYP enzymes)
• IV form: fosphenytoin sodium (water-soluble prodrug) preferred over phenytoin sodium injection

• Start adults at 300 mg/day
• Increase in increments of no more than 25-30 mg/day (common error: jumping from 300→400 mg causes toxicity)
• Loading dose: oral or IV (fosphenytoin preferred IV)

• Focal (partial) seizures
• Generalized tonic-clonic seizures
• Status epilepticus (IV fosphenytoin)
• NOT effective for absence seizures (may worsen)

• Nystagmus (early sign - not indication to reduce dose)
• Diplopia and ataxia (most common dose-related requiring dose adjustment)
• Sedation (at high levels)
• Gingival hyperplasia (long-term)
• Hirsutism (especially troublesome in women)
• Coarsening of facial features (long-term)
• Peripheral neuropathy (diminished DTRs)
• Osteomalacia (vitamin D metabolism impairment)
• Megaloblastic anemia (folate deficiency)

• Skin rash (hypersensitivity)
• Lymphadenopathy (distinguish from malignant lymphoma)
• Agranulocytosis (with fever/rash - rare)
• Stevens-Johnson syndrome (severe)

• Strong enzyme inducer (CYP2C9, CYP3A4) - reduces levels of many drugs
• Valproate displaces phenytoin from protein binding (monitor free levels)
• Carbamazepine, phenobarbital: reduce phenytoin levels

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12. CARBAMAZEPINE (Tegretol)

• Blocks voltage-gated Na+ channels (use-dependent) - same mechanism as phenytoin
• Stabilizes inactivated state of Na+ channels
• Active metabolite: carbamazepine-10,11-epoxide (also pharmacologically active)

• Oral; t½ initially ~36 hours, decreases to 8-12 hours with autoinduction (induces its own metabolism via CYP3A4)
• Hepatic metabolism: CYP3A4 (strong inducer of CYP3A4, CYP2C9, CYP2C19)
• Therapeutic level: 4-12 mcg/mL (some sources 6-12 mcg/mL)

• Focal (partial) seizures - drug of choice (along with lamotrigine)
• Generalized tonic-clonic seizures
• Trigeminal neuralgia (drug of choice)
• Bipolar disorder (mood stabilizer)
• NOT effective for absence, myoclonic, or atonic seizures (may worsen)

• Diplopia, ataxia, dizziness, sedation (dose-related)
• Nausea, vomiting (GI)
• Hyponatremia (SIADH-like effect - inappropriate ADH secretion)
• Aplastic anemia and agranulocytosis (rare but serious - CBC monitoring required)
• Rash; Stevens-Johnson syndrome (HLA-B*1502 in Asian patients)
• Teratogenicity: neural tube defects (spina bifida)
• Autoinduction - dose may need to be increased over first weeks

• Strong enzyme inducer: reduces levels of many drugs (warfarin, OCP, lamotrigine, valproate)
• Valproate increases carbamazepine-10,11-epoxide (toxic metabolite)
• Many drugs increase carbamazepine levels (erythromycin, verapamil, fluoxetine)

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13. VALPROATE (Depakote, Depakene)

• Blocks voltage-gated Na+ channels (use-dependent)
• Increases brain GABA levels (may inhibit GABA transaminase and succinic semialdehyde dehydrogenase)
• Blocks T-type calcium channels (relevant for absence seizures)
• Possible effects on GABA-A receptor
• Broad-spectrum agent - widest clinical spectrum of all antiseizure drugs

• Oral; well absorbed; highly protein bound (~90%)
• Hepatic metabolism (CYP2C9, glucuronidation, β-oxidation)
• t½: 8-17 hours; therapeutic level: 50-100 mcg/mL (some sources up to 150 mcg/mL)
• Inhibits metabolism of many drugs (opposite of carbamazepine)

• Generalized seizures (tonic-clonic, absence, myoclonic, atonic) - broad spectrum
• Focal seizures
• Bipolar disorder (acute mania and prophylaxis)
• Migraine prophylaxis
• Juvenile myoclonic epilepsy (drug of choice)
• Lennox-Gastaut syndrome

• Hepatotoxicity (idiosyncratic, potentially fatal, highest risk <2 years old on polytherapy) - LFT monitoring required
• Pancreatitis (rare)
• Teratogenicity: most teratogenic antiseizure drug - neural tube defects, fetal valproate syndrome (cognitive impairment - IQ reduction documented), spina bifida (1-2%); avoid in women of childbearing age if possible; supplement folic acid
• Tremor (dose-related)
• Weight gain
• Hair loss (alopecia) - transient; zinc/selenium supplements may help
• Nausea, vomiting (GI)
• Thrombocytopenia, inhibition of platelet aggregation (watch with surgery)
• Sedation (less than phenytoin/carbamazepine)

• Dramatically increases lamotrigine levels (by inhibiting glucuronidation) - must reduce lamotrigine dose by 50%
• Increases phenytoin free levels (displaces from protein)
• Inhibits metabolism of many drugs
• Does NOT increase carbamazepine itself but increases its toxic epoxide metabolite

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14. LAMOTRIGINE (Lamictal)

• Blocks voltage-gated Na+ channels (use-dependent)
• Also blocks high-voltage-activated (N- and P-type) Ca2+ channels
• Reduces presynaptic release of glutamate (excitatory neurotransmitter)

• Oral; well absorbed; t½ ~24 hours (monotherapy)
• Hepatic glucuronidation (UGT enzymes)
• Critical interactions:
  • Valproate DECREASES lamotrigine clearance → t½ increases to ~60 hours (plasma levels double/triple - toxic)
  • CYP inducers (phenytoin, carbamazepine, phenobarbital) INCREASE lamotrigine clearance → t½ decreases to ~12-15 hours

• Focal (partial) seizures (drug of choice along with carbamazepine)
• Generalized tonic-clonic seizures
• Absence seizures
• Juvenile myoclonic epilepsy
• Lennox-Gastaut syndrome
• Bipolar disorder (especially bipolar depression - mood stabilizer)

• Serious Rash/Stevens-Johnson syndrome (risk reduced by slow titration; higher risk in children and with valproate co-administration)
• Diplopia, ataxia, dizziness, headache
• Nausea
• Insomnia
• Generally well-tolerated compared to older AEDs
• Safer in pregnancy than valproate or carbamazepine (breast milk concentrations 18.3% of maternal levels)

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15. GABAPENTIN (Neurontin)

• Binds to α2δ subunit of voltage-gated calcium channels (NOT GABA receptors despite name/structure)
• Reduces calcium influx → decreases release of excitatory neurotransmitters (glutamate, substance P, norepinephrine)
• Does NOT enhance GABA activity directly
• Does NOT block Na+ channels

• Oral; absorption is saturable (uses active transporter - large neutral amino acid transporter L-system)
• NOT hepatically metabolized; renally excreted unchanged (dose adjustment in renal impairment essential)
• No protein binding; no drug-drug interactions (major advantage)
• t½: ~5-7 hours (must be dosed 3x/day; ER formulation: Gralise)

• Focal (partial) seizures (adjunctive)
• Postherpetic neuralgia (FDA-approved)
• Neuropathic pain (diabetic neuropathy, off-label)
• Restless legs syndrome
• Fibromyalgia (pregabalin more commonly)
• Off-label: anxiety disorders, hot flashes, alcohol withdrawal, migraine prophylaxis

• Sedation, fatigue, somnolence (most common)
• Dizziness, ataxia
• Peripheral edema (especially at higher doses)
• Weight gain
• No serious organ toxicity
• No significant drug interactions (major advantage)
• Withdrawal: may cause seizures if abruptly stopped
• Abuse potential (increasingly recognized)

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SECTION 4: ANXIOLYTICS AND HYPNOTICS (Chapter 22)

Benzodiazepine Mechanism

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16. ALPRAZOLAM (Xanax)

• Oral; t½ ~12 hours (short-acting compared to diazepam)
• Hepatic metabolism: CYP3A4 → active metabolites (less than diazepam)
• Intermediate acting; onset: 1-2 hours oral

• Generalized anxiety disorder (GAD)
• Panic disorder (FDA-approved - high potency for panic)
• Social anxiety disorder

• Sedation, cognitive impairment, anterograde amnesia
• Psychomotor impairment
• Physical dependence and withdrawal (more severe than diazepam due to shorter t½; can cause seizures on abrupt discontinuation)
• Tolerance (especially sedation)
• Rebound anxiety on discontinuation
• Respiratory depression (especially with opioids/alcohol)
• Abuse potential

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17. DIAZEPAM (Valium)

• Oral, IV, IM, rectal gel
• t½: 20-70 hours; active metabolites (desmethyldiazepam t½ ~36-200 hours) - prolonged clinical effect
• Highly lipophilic → rapid CNS penetration (fast onset)
• Hepatic metabolism: CYP2C19, CYP3A4 → active metabolites (oxazepam, desmethyldiazepam)

• Anxiety disorders
• Status epilepticus (IV - first-line with lorazepam)
• Alcohol withdrawal (preferred due to long t½ - self-tapering effect)
• Muscle relaxant (spastic disorders)
• Procedural sedation/premedication
• Acute sedation

• Less rebound anxiety
• Effective for alcohol withdrawal (self-tapering)
• Once-daily dosing possible

• Sedation, cognitive impairment
• Ataxia
• Anterograde amnesia
• Respiratory depression (especially IV, or combined with opioids/alcohol)
• Physical dependence (with chronic use)
• Accumulation with repeated doses (long t½ and active metabolites)

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18. FLUMAZENIL (Romazicon)

• Competitive antagonist at the benzodiazepine binding site on the GABA-A receptor
• Reverses all effects of benzodiazepines (sedation, amnesia, respiratory depression)
• Also reverses effects of zolpidem, zaleplon (non-BZD hypnotics that act at same site)

• IV only (not effective orally - extensive first-pass)
• Short t½: 1 hour (much shorter than all benzodiazepines)
• Hepatic metabolism

• Reversal of benzodiazepine overdose/excess sedation
• Diagnostic use: to differentiate BZD-induced vs other causes of CNS depression
• Post-procedural reversal

• Short duration of action (1 hour) - patient may re-sedate after flumazenil wears off; requires monitoring and possible repeat dosing
• Does NOT reverse opioid effects (naloxone required for opioids)
• CONTRAINDICATED in patients with benzodiazepine dependence (precipitates acute withdrawal seizures)
• CONTRAINDICATED in patients who received BZD for seizure control (may re-precipitate seizures)
• Not useful for chronic BZD toxicity due to short duration

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19. ZOLPIDEM (Ambien)

• Acts at benzodiazepine binding site on GABA-A receptor (same site as BZDs)
• Selective for GABA-A receptors containing α1 subunit (mediates sedation/hypnosis)
• Unlike BZDs: minimal effects on α2 (anxiolysis) and α3 (muscle relaxation, anticonvulsant) subunits
• Effect reversed by flumazenil

• Oral; t½ ~2.5 hours (very short - designed for sleep onset)
• No active metabolites (avoids accumulation - unlike BZDs such as diazepam/flurazepam)
• Hepatic metabolism: CYP3A4 primarily
• Formulations: immediate-release (Ambien), CR (Ambien-CR for sleep maintenance), sublingual (Intermezzo)
• Extended-release allows sleep onset AND maintenance

• Short-term treatment of insomnia (sleep onset and maintenance)
• Preferred over benzodiazepines for insomnia due to selectivity and shorter t½

• Sedation, dizziness, headache
• Anterograde amnesia (can impair next-day driving)
• Parasomnia behaviors: sleepwalking, sleep-eating, sleep-driving (unconscious complex behaviors - FDA black box warning)
• Less tolerance than BZDs (due to receptor selectivity)
• Less respiratory depression than BZDs
• Physical dependence possible with prolonged use
• Withdrawal syndrome if abruptly stopped

• No accumulation (no active metabolites, short t½)
• Less daytime sedation (zaleplon even shorter t½ for pure sleep onset)
• Less tolerance and dependence
• Minimal anxiolytic, anticonvulsant, muscle-relaxant effects (more selective)

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20. BUSPIRONE (BuSpar)

• Partial agonist at 5-HT1A receptors (both pre- and post-synaptic)
• NO benzodiazepine receptor activity
• NO GABA receptor activity
• Weak D2 antagonist
• Does NOT cause sedation, addiction, or respiratory depression

• Oral; extensive first-pass metabolism; t½ ~2-3 hours
• Active metabolite: 1-pyrimidinylpiperazine (1-PP) - contributes to effect
• Onset of anxiolytic effect: 2-4 weeks (cannot be used PRN for acute anxiety)

• Generalized anxiety disorder (GAD) - equal efficacy to BZDs in head-to-head studies
• NOT effective for: panic disorder, social anxiety, acute situational anxiety

• No dependence or addiction (no abuse potential)
• No sedation
• No respiratory depression
• No withdrawal syndrome
• No interaction with alcohol
• Safe in elderly

• 2-4 week onset delay (BZDs work immediately)
• NOT effective PRN
• Negative predictor: prior BZD users respond poorly (do not experience the BZD "effect")
• Ineffective for acute/situational anxiety or panic

• MAOIs: risk of hypertensive crisis (avoid)
• CYP3A4 inhibitors increase buspirone levels (e.g., fluconazole, erythromycin)

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SECTION 5: OPIOID AGONISTS AND ANTAGONISTS (Chapter 31)

Opioid Receptors

Pharmacodynamic Principles

• Full agonists: produce maximum receptor activation (morphine, fentanyl, meperidine, oxycodone, methadone, heroin)
• Partial agonists: submaximal efficacy even at full receptor occupancy; can displace full agonists and precipitate withdrawal (buprenorphine)
• Mixed agonist-antagonists: agonist at one receptor type, antagonist at another (nalbuphine: κ agonist + μ antagonist)
• Pure antagonists: no intrinsic activity, block all receptor types (naloxone, naltrexone)
• Partial agonists must occupy a greater fraction of functional receptors than full agonists to achieve equivalent effect

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OPIOID AGONISTS

MORPHINE

• Oral (significant first-pass), IV, IM, SC, epidural, intrathecal
• Poor oral bioavailability (25-35%) → higher doses needed PO vs IV
• Hepatic glucuronidation: morphine-6-glucuronide (M6G - active, potent analgesic), morphine-3-glucuronide (M3G - inactive, neuroexcitatory)
• M6G accumulates in renal failure - can cause prolonged respiratory depression
• t½ ~2-4 hours; analgesia 4-6 hours

• Analgesia (primary therapeutic use)
• Euphoria (via mesolimbic pathway)
• Sedation, drowsiness
• Respiratory depression (dose-dependent, mediated via μ2 receptors in respiratory centers) - primary cause of opioid overdose death
• Cough suppression (antitussive)
• Miosis (pinpoint pupils - diagnostic sign of opioid use)
• Nausea/vomiting (stimulates CTZ)
• Constipation (reduces peristalsis via μ receptors in gut) - does NOT develop tolerance
• Urinary retention
• Histamine release (causes pruritus, vasodilation) - due to non-receptor mechanism
• Biliary spasm (increases biliary duct pressure)

• Head injury (increases ICP, CO2 retention worsens vasodilation)
• Respiratory depression
• MAOIs
• Renal failure (M6G accumulation)

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FENTANYL

• 100 times more potent than morphine
• Highly lipophilic → rapid CNS penetration; very short duration IV (30-60 min)
• Formulations: IV, transdermal (Duragesic patch - 72-hour patch), transmucosal (Actiq lollipop for breakthrough cancer pain, burned children), intranasal, sublingual, buccal
• Transmucosal form promising for anxiety/pain in burned children (Katzung)
• Major metabolic pathway: CYP3A4 → inactive metabolites (no M6G problem)
• Used in anesthesia, cancer pain, procedural sedation

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CODEINE

• Prodrug; metabolized to morphine by CYP2D6 (10% conversion)
• Poor analgesic in CYP2D6 poor metabolizers (reduced efficacy)
• Ultra-rapid metabolizers: toxic morphine levels (fatal cases in children)
• Used: mild pain, antitussive

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OXYCODONE

• Semisynthetic μ-agonist; oral bioavailability better than morphine (~87%)
• Abuse-deterrent formulations (OxyContin ER)

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MEPERIDINE (Pethidine)

• Full μ-agonist; t½ ~3 hours
• Active metabolite: normeperidine - accumulates in renal failure; causes seizures, myoclonus (CNS excitation - NOT reversed by naloxone)
• Serotonin syndrome risk with MAOIs - CONTRAINDICATED
• No longer recommended for chronic pain management

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METHADONE

• Long-acting full μ-agonist; also NMDA receptor antagonist
• Long and unpredictable t½: 24-36 hours (range 15-190 hours) - accumulation risk
• Used for: opioid use disorder (OUD) maintenance treatment, chronic pain
• QTc prolongation risk

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TRAMADOL

• Weak μ-agonist + inhibits norepinephrine/serotonin reuptake (dual mechanism)
• Serotonin syndrome risk with SSRIs/MAOIs
• Lowers seizure threshold
• Less potent analgesic; less abuse potential (scheduled but lower risk)

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BUPRENORPHINE

• Partial μ-agonist: ceiling effect on respiratory depression (safer in overdose)
• Very high receptor affinity → difficult to displace with full agonists
• Long t½: 24-36 hours (sublingual)
• Formulations:
  • Buprenorphine/naloxone (Suboxone) - sublingual; naloxone is added to deter IV abuse (naloxone not absorbed sublingually but active if injected)
  • Buprenorphine alone (Subutex) - used in pregnancy
• Uses: OUD treatment (medication-assisted treatment - MAT), chronic pain

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NALBUPHINE

• Mixed agonist-antagonist: κ-agonist + μ-antagonist
• Analgesic (via κ) with ceiling effect on respiratory depression
• Can precipitate withdrawal in morphine-dependent patients (due to μ antagonism)

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OPIOID ANTAGONISTS

NALOXONE (Narcan)

• Competitive antagonist at all three opioid receptor types
• Highest affinity for μ receptors
• Rapidly reverses: analgesia, respiratory depression, sedation, miosis, euphoria

• IV, IM, intranasal (Narcan nasal spray), subcutaneous
• Short t½: 1-4 hours (much shorter than most opioids)
• Hepatic glucuronidation; duration ~45-90 min (IV)
• NOT effective orally (extensive first-pass)

• Re-narcotization is the primary clinical danger - patient may relapse into respiratory depression as naloxone wears off; MUST monitor for 4-6 hours and may need repeat doses or infusion
• Dose: 0.4-2 mg IV; may repeat every 2-3 min (up to 10 mg)
• In opioid-dependent patients: precipitates acute opioid withdrawal (within minutes) - extreme caution
• Naloxone reversal of fentanyl may require larger doses; reversal of methadone requires prolonged monitoring
• Does NOT reverse benzodiazepine effects (flumazenil required)
• Does NOT work against non-opioid CNS depressants

• Opioid overdose (respiratory depression reversal) - emergency medicine, community naloxone programs
• Post-operative opioid reversal
• Diagnosis: opioid vs other coma (if no response, opioids unlikely)
• Neonatal opioid depression (mother given opioids during labor)

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NALTREXONE

• Oral bioavailability (unlike naloxone)
• Long t½: ~10 hours; active metabolite 6-β-naltrexol (t½ ~13 hours)
• Available as monthly extended-release injection (Vivitrol)

• OUD treatment - blocks euphoric effects of opioids (prevents relapse)
• Alcohol use disorder (reduces craving - via endogenous opioid pathway)
  • Polymorphism in μ-opioid receptor gene (OPRM1) associated with blunted naltrexone response (genotype-guided pharmacotherapy)
• Combined with bupropion for weight loss (Contrave)

• Precipitates severe withdrawal in opioid-dependent patients - must be opioid-free for 7-10 days before starting
• Hepatotoxicity at high doses

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METHYLNALTREXONE (Relistor) & NALOXEGOL

• Peripheral μ-opioid antagonists (do NOT cross BBB)
• Used for opioid-induced constipation (OIC) in patients on opioids for cancer/chronic pain
• Reverses peripheral GI opioid effects without reversing analgesia

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Opioid Toxidrome (Overdose Triad)

1. Miosis (pinpoint pupils)
2. Respiratory depression (slow, shallow breaths - primary cause of death)
3. Coma/CNS depression

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Quick Reference: Opioid Classification

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What's Included

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Section 1 - Antipsychotics (Chapter 29)

1. Chlorpromazine - Low-potency typical; α1 > D2; high sedation/autonomic side effects, moderate EPS
2. Haloperidol - High-potency typical; D2 dominant; highest EPS, minimal sedation/autonomic effects
3. Aripiprazole - Unique D2/5-HT1A partial agonist; no EPS, no metabolic syndrome, activating
4. Clozapine - Prototype atypical; treatment-resistant schizophrenia; agranulocytosis + seizure risk; no EPS
5. Olanzapine - Broad receptor blockade; worst metabolic syndrome (after clozapine); minimal EPS
6. Risperidone - D2 + 5-HT2A antagonist; dose-dependent EPS; highest prolactin elevation among atypicals

Section 2 - Parkinson's Drugs (Chapter 28)

1. Levodopa - Dopamine precursor; gold-standard; wears off, dyskinesias, motor fluctuations
2. Pramipexole - D2/D3 agonist; impulse control disorders; sleep attacks; good for RLS
3. Rasagiline - Irreversible MAO-B inhibitor; serotonin syndrome risk; no tyramine restriction at therapeutic doses
4. Entacapone - Peripheral COMT inhibitor; extends levodopa effect; orange urine; no hepatotoxicity (unlike tolcapone)

Section 3 - Antiseizure Drugs (Chapter 24)

1. Phenytoin - Na+ channel; zero-order kinetics (narrow therapeutic window); gingival hyperplasia; hirsutism
2. Carbamazepine - Na+ channel; autoinduction; hyponatremia; aplastic anemia; Stevens-Johnson in HLA-B*1502
3. Valproate - Broadest spectrum; most teratogenic; hepatotoxicity; inhibits lamotrigine metabolism; tremor/weight gain
4. Lamotrigine - Na+ + Ca2+ channel; SJS risk (slow titration!); good for bipolar depression; safe in breastfeeding
5. Gabapentin - α2δ Ca2+ subunit (NOT GABA receptors); no drug interactions; renal excretion; neuropathic pain

Section 4 - Anxiolytics/Hypnotics (Chapter 22)

1. Alprazolam - Short-acting BZD; GABA-A α-freq increase; panic disorder; high withdrawal severity
2. Diazepam - Long-acting BZD; status epilepticus, alcohol withdrawal; active metabolites; self-tapering
3. Flumazenil - BZD competitive antagonist; short t½ (1 hour - re-sedation risk); precipitates withdrawal
4. Zolpidem - Non-BZD GABA-A α1-selective; sleep; no active metabolites; sleepwalking/sleep-driving (black box)
5. Buspirone - 5-HT1A partial agonist; GAD; no dependence/sedation; 2-4 week onset; fails in ex-BZD users

Opioids Section (Chapter 31)

• Full agonists: Morphine (prototype), Fentanyl (100x potency), Codeine (prodrug-CYP2D6), Oxycodone, Methadone (QTc, NMDA), Meperidine (normeperidine seizures/serotonin syndrome risk)
• Partial agonist: Buprenorphine (Suboxone for OUD, ceiling effect on respiratory depression)
• Mixed agonist-antagonists: Nalbuphine (κ-agonist/μ-antagonist)
• Pure antagonists: Naloxone (IV, short t½ - re-narcotization risk), Naltrexone (oral/monthly injection, OUD + alcohol use disorder), Methylnaltrexone (peripheral, OIC only)