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Pharmacology Study Notes

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ANTIPSYCHOTICS

General Background

• Chlorpromazine: α1 = 5-HT2A > D2 > D1
• Haloperidol: D2 > α1 > D4 > 5-HT2A > D1 > H1
• Clozapine: D4 = α1 > 5-HT2A > D2 = D1
• Olanzapine: 5-HT2A > H1 > D4 > D2 > α1 > D1
• Aripiprazole: D2 = 5-HT2A > D4 > α1

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1. Chlorpromazine (Thorazine)

• Blocks D2 dopamine receptors in mesolimbic, mesocortical, nigrostriatal, and tuberoinfundibular pathways
• Also blocks α1-adrenergic, H1-histamine, muscarinic cholinergic, and 5-HT2A receptors
• Low D2 potency means higher doses are needed compared to haloperidol

• Schizophrenia (positive symptoms: hallucinations, delusions, disorganization)
• Acute mania (adjunctive)
• Nausea/vomiting (antiemetic via D2 blockade in chemoreceptor trigger zone)
• Intractable hiccups
• Agitation in psychiatric emergencies

• EPS (less than haloperidol due to lower potency, but still significant): akathisia, dystonia, parkinsonism, tardive dyskinesia (long-term)
• Sedation (prominent - H1 blockade)
• Orthostatic hypotension (significant - α1 blockade)
• Anticholinergic effects: dry mouth, urinary retention, blurred vision, constipation
• Photosensitivity and skin pigmentation
• QTc prolongation
• Hyperprolactinemia: galactorrhea, amenorrhea, gynecomastia (D2 blockade in tuberoinfundibular pathway)
• Agranulocytosis (rare)
• Weight gain
• Neuroleptic malignant syndrome (NMS) - rare but life-threatening

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2. Haloperidol (Haldol)

• Potent and selective D2 receptor antagonist - highest D2 affinity among the typicals
• Minimal anticholinergic, antihistamine, or α1 activity
• Blocks dopamine in all four pathways

• Schizophrenia (most effective for positive symptoms)
• Acute psychosis and agitation (IV/IM available)
• Delirium in ICU/postoperative settings
• Tourette syndrome (tics)
• Huntington disease (chorea)
• Adjunct in bipolar disorder mania
• Intractable hiccups

• High EPS risk (highest among antipsychotics due to high D2 potency): acute dystonia, akathisia, parkinsonism, tardive dyskinesia
• Hyperprolactinemia
• QTc prolongation (especially IV administration)
• NMS risk
• Minimal sedation, minimal hypotension, minimal anticholinergic effects (distinguishes it from chlorpromazine)
• Less metabolic side effects than atypicals

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3. Aripiprazole (Abilify)

• Partial agonist at D2 and D3 receptors - acts as functional antagonist in dopamine-excess states (mesolimbic), and functional agonist in dopamine-deficient states (mesocortical)
• Partial agonist at 5-HT1A receptors
• Antagonist at 5-HT2A receptors
• High D2 receptor occupancy (~90%) but does NOT cause EPS because it is a partial agonist, not a full antagonist
• This "dopamine system stabilizer" mechanism is unique among antipsychotics

• Schizophrenia (positive and negative symptoms)
• Bipolar I disorder (acute mania, maintenance)
• Adjunct in major depressive disorder (MDD)
• Irritability associated with autism spectrum disorder
• Tourette syndrome

• Minimal EPS (due to partial agonism)
• Minimal sedation (low H1 affinity)
• Minimal weight gain and minimal metabolic effects (advantage over olanzapine/clozapine)
• Akathisia (can be bothersome)
• Nausea, insomnia
• No significant QTc prolongation
• Hyperprolactinemia is rare (partial agonism may actually normalize prolactin)
• Impulse control problems (compulsive gambling, hypersexuality) - rare but notable

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4. Clozapine (Clozaril)

• Low D2 affinity but high D4 affinity; also blocks D1
• Potent 5-HT2A antagonist (thought to contribute to efficacy without EPS)
• Blocks α1, α2, H1, and muscarinic receptors
• Does NOT require high D2 occupancy for efficacy (30-50% is sufficient)
• Unique mechanism possibly involving serotonin-dopamine balance

• Treatment-resistant schizophrenia (first-line when 2+ antipsychotics have failed) - the only antipsychotic proven superior for this
• Reduces suicidal behavior in schizophrenia/schizoaffective disorder (FDA-approved indication)
• Psychosis in Parkinson disease (does not worsen motor symptoms)
• Refractory bipolar disorder

• Agranulocytosis (1-2%) - MANDATORY weekly WBC monitoring for 6 months, then every 2 weeks; this is the most dangerous side effect
• Seizures (dose-dependent, up to 5% at high doses)
• Metabolic syndrome: significant weight gain, hyperglycemia, dyslipidemia
• Myocarditis (rare but potentially fatal)
• Hypersalivation (paradoxical - muscarinic agonism at M4)
• Sedation (very prominent - H1)
• Orthostatic hypotension (α1 blockade)
• Constipation, urinary retention (anticholinergic)
• No tardive dyskinesia - does NOT cause EPS at therapeutic doses
• No significant hyperprolactinemia

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5. Olanzapine (Zyprexa)

• Blocks 5-HT2A > D2 (higher serotonin than dopamine affinity)
• Also blocks H1, muscarinic, α1, and D1/D4 receptors
• Lower EPS risk due to high 5-HT2A/D2 ratio
• Similar receptor profile to clozapine but without the agranulocytosis risk

• Schizophrenia (positive and negative symptoms)
• Bipolar I disorder (mania, mixed episodes, maintenance)
• Agitation in psychosis (IM form)
• Bipolar depression (in combination with fluoxetine - Symbyax)
• Adjunct in treatment-resistant depression
• Used in delirium management

• Significant weight gain - one of the worst among antipsychotics
• Metabolic syndrome: diabetes (hyperglycemia), dyslipidemia - major long-term concern
• Sedation (H1 blockade)
• Orthostatic hypotension (α1 blockade)
• Anticholinergic effects
• Low but possible EPS (much less than typicals)
• Hyperprolactinemia (mild)
• QTc prolongation (modest)

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6. Risperidone (Risperdal)

• Potent 5-HT2A antagonist > D2 antagonist
• Blocks α1, α2, and H1 receptors
• Minimal anticholinergic activity
• At low doses: low EPS due to 5-HT2A > D2 blockade
• At high doses: behaves more like a typical (D2 occupancy increases, EPS risk rises)

• Schizophrenia
• Bipolar I disorder (acute mania, maintenance)
• Irritability/agitation in autism spectrum disorder
• Tourette syndrome
• Available as long-acting injectable (Risperdal Consta) for adherence
• Adjunct in dementia-related behavioral disturbances (controversial - increases mortality)

• Highest hyperprolactinemia among atypicals (due to significant D2 blockade)
• EPS (dose-dependent - significant at high doses)
• Orthostatic hypotension (α1, α2 blockade)
• Weight gain and metabolic effects (less than olanzapine/clozapine)
• QTc prolongation
• Sedation (moderate)
• No significant anticholinergic effects

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ANTIPARKINSONIAN DRUGS

7. Levodopa (L-DOPA, often given with Carbidopa as Sinemet)

• Dopamine precursor - converted to dopamine by aromatic L-amino acid decarboxylase (AADC/DOPA decarboxylase) in the brain
• Crosses the blood-brain barrier (dopamine itself cannot)
• Replenishes depleted striatal dopamine in Parkinson disease
• Given with carbidopa (peripheral DOPA decarboxylase inhibitor) to prevent peripheral conversion, reducing side effects and increasing CNS bioavailability
• Combined with entacapone (Stalevo) to further reduce peripheral breakdown

• Parkinson disease - most effective drug; cornerstone of therapy
• Best for bradykinesia and rigidity (tremor responds less well)
• Drug-induced parkinsonism does NOT respond (avoid in this case)

• Nausea/vomiting (reduced by carbidopa)
• Orthostatic hypotension
• "On-Off" fluctuations - wearing off, on-off phenomenon after years of use
• Dyskinesias (involuntary movements) - with long-term use
• Neuropsychiatric effects: hallucinations, confusion, psychosis (dopamine excess in limbic system)
• Impulse control disorders: hypersexuality, gambling
• Darkening of urine/sweat (melanin synthesis)
• Contraindicated in narrow-angle glaucoma and with non-selective MAOIs (hypertensive crisis risk)

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8. Pramipexole (Mirapex)

• Direct D2 and D3 receptor agonist in the striatum
• Does not require conversion to active form (unlike levodopa)
• Stimulates dopamine receptors regardless of nigrostriatal neuron degeneration
• Preferential affinity for D3 receptors

• Parkinson disease: early monotherapy (delays need for levodopa) and adjunct with levodopa in advanced disease
• Restless legs syndrome (RLS)
• Sometimes used in bipolar depression

• Nausea, orthostatic hypotension (dopamine-mediated)
• Somnolence/sudden sleep attacks (driving warning required)
• Impulse control disorders: pathological gambling, compulsive eating, hypersexuality
• Hallucinations and psychosis (more than levodopa in elderly)
• Peripheral edema
• Less dyskinesia than levodopa
• Does NOT cause wearing-off fluctuations (long-acting)

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9. Rasagiline (Azilect)

• Irreversibly inhibits MAO-B, the enzyme that degrades dopamine in the striatum
• Inhibiting MAO-B increases dopamine availability in the synapse
• Selective for MAO-B at therapeutic doses (unlike older, non-selective MAOIs)
• Unlike selegiline, does NOT produce amphetamine metabolites

• Early Parkinson disease (monotherapy - may have neuroprotective effects, though unproven clinically)
• Adjunct to levodopa in advanced PD to extend "on" time and reduce wearing-off
• Once-daily dosing (advantage over selegiline)

• Generally well tolerated
• Mild nausea, headache
• Insomnia (less than selegiline)
• Dyskinesia when used with levodopa
• Drug interactions: Avoid with meperidine, tramadol, SSRIs, SNRIs, cyclobenzaprine (risk of serotonin syndrome); avoid tyramine-rich foods in high doses (though selective MAO-B inhibition makes this less of a concern at standard doses)
• Avoid with other MAOIs

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10. Entacapone (Comtan)

• Inhibits COMT, an enzyme that metabolizes levodopa and dopamine in the periphery
• Prolongs the half-life of levodopa by blocking its peripheral degradation to 3-O-methyldopa
• Increases the duration and bioavailability of levodopa reaching the brain
• Acts only peripherally (unlike tolcapone, which has central and peripheral effects)
• Always used in combination with levodopa/carbidopa (never as monotherapy)

• Parkinson disease with motor fluctuations ("wearing off") while on levodopa
• Available as Stalevo (levodopa + carbidopa + entacapone in one tablet)
• Extends "on" time by 1-2 hours per day

• Orange-brown discoloration of urine (harmless)
• Diarrhea (can be significant)
• Dyskinesias increase (because more levodopa reaches the brain - dose of levodopa often needs reduction)
• Nausea, abdominal pain
• No hepatotoxicity (unlike tolcapone - this is entacapone's safety advantage)
• Not used alone; side effects largely reflect amplified levodopa effects

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ANTIEPILEPTIC DRUGS (AEDs)

11. Phenytoin (Dilantin)

• Sodium channel blocker - blocks voltage-gated Na+ channels in the inactivated state
• Slows recovery of Na+ channels from inactivation, reducing high-frequency neuronal firing
• Does NOT affect normal low-frequency neuronal activity
• Also inhibits calcium channels and decreases synaptic transmission

• Partial (focal) seizures and secondarily generalized tonic-clonic seizures
• Status epilepticus (IV fosphenytoin preferred)
• Trigeminal neuralgia
• Cardiac arrhythmias (historically, Class IB antiarrhythmic)

• Nystagmus (early sign of toxicity)
• Ataxia, diplopia, sedation (dose-related CNS effects)
• Gingival hyperplasia (characteristic - especially in children)
• Hirsutism (excessive hair growth)
• Coarsening of facial features
• Peripheral neuropathy (chronic use)
• Megaloblastic anemia (folate deficiency)
• Osteomalacia (vitamin D metabolism impairment)
• Teratogenicity - fetal hydantoin syndrome (cleft palate, cardiac defects, digital anomalies)
• Steven-Johnson syndrome (rare hypersensitivity)
• Hepatotoxicity (rare)
• Drug interactions: potent inducer of CYP enzymes (CYP2C9, CYP3A4) - reduces levels of many drugs
• Zero-order kinetics at therapeutic doses (small dose increases can cause large toxicity spikes)

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12. Carbamazepine (Tegretol)

• Sodium channel blocker - same mechanism as phenytoin (blocks inactivated state of voltage-gated Na+ channels)
• Also modulates calcium channels and reduces release of excitatory neurotransmitters
• May enhance GABA transmission

• Partial (focal) seizures - drug of choice for complex partial seizures
• Generalized tonic-clonic seizures
• Trigeminal neuralgia - drug of choice
• Bipolar disorder (acute mania and prophylaxis - mood stabilizer)
• Neuropathic pain

• Diplopia, ataxia, sedation (dose-related)
• Nausea, vomiting
• Hyponatremia/SIADH (especially in elderly)
• Aplastic anemia (rare, but serious - monitor CBC)
• Agranulocytosis (rare)
• Hepatotoxicity (monitor LFTs)
• Rash, Stevens-Johnson syndrome (especially in HLA-B*1502 carriers - Asian populations; genetic testing recommended)
• Teratogenicity - neural tube defects (folic acid supplementation needed)
• Autoinduction of CYP3A4 (induces its own metabolism - tolerance develops, doses need adjustment)
• Potent CYP inducer - reduces levels of oral contraceptives, warfarin, other AEDs
• Not effective for absence or myoclonic seizures (may worsen them)

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13. Valproate (Valproic Acid / Depakote)

• Multiple mechanisms (broadest spectrum AED):
  1. Sodium channel blockade (like phenytoin/carbamazepine)
  2. Increases GABA - inhibits GABA transaminase (enzyme that degrades GABA) and stimulates glutamic acid decarboxylase (enzyme that synthesizes GABA)
  3. Calcium channel blockade (T-type channels) - relevant for absence seizures
  4. Inhibits NMDA receptor function

• Broadest spectrum antiepileptic - effective for most seizure types:
  • Absence seizures
  • Generalized tonic-clonic
  • Myoclonic seizures
  • Partial/focal seizures
• Bipolar disorder - mood stabilizer (acute mania and prophylaxis)
• Migraine prophylaxis

• Hepatotoxicity - potentially fatal; highest risk in children <2 years on polytherapy; monitor LFTs
• Pancreatitis (rare but serious)
• Teratogenicity - neural tube defects (spina bifida - highest risk among AEDs; 1-2%), fetal valproate syndrome; also associated with lower IQ in children of exposed mothers
• Weight gain
• Thrombocytopenia, platelet dysfunction
• Hair loss (alopecia) - can add zinc/selenium
• Tremor
• Polycystic ovarian syndrome (PCOS) with chronic use in women
• Hyperammonemia (with or without encephalopathy)
• Drug interactions: inhibits CYP enzymes (opposite of phenytoin/carbamazepine) - increases levels of lamotrigine, phenobarbital, phenytoin (free fraction)
• Nausea, GI upset (use enteric-coated form)

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14. Lamotrigine (Lamictal)

• Sodium channel blocker (stabilizes inactivated state)
• Also blocks voltage-gated calcium channels
• Inhibits release of excitatory neurotransmitters (especially glutamate and aspartate) - this distinguishes it from phenytoin/carbamazepine
• Net effect: reduces presynaptic release of excitatory amino acids

• Broad-spectrum AED:
  • Partial (focal) seizures
  • Generalized tonic-clonic
  • Absence seizures (particularly juvenile absence epilepsy)
  • Lennox-Gastaut syndrome (adjunct)
  • Myoclonic seizures (some forms)
• Bipolar disorder - mood stabilizer (especially effective for bipolar depression and maintenance; less effective for acute mania)
• Preferred AED in pregnancy among women with childbearing potential (lower teratogenic risk than valproate)

• Serious rash - including Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN) - most dangerous; risk reduced by slow dose titration
• Dizziness, diplopia, ataxia
• Headache, nausea
• Insomnia
• Generally well tolerated; minimal sedation
• No hepatotoxicity, no blood dyscrasias, no weight gain
• Drug interaction: Valproate markedly increases lamotrigine levels (start at lower dose and titrate more slowly); enzyme inducers (phenytoin, carbamazepine) decrease lamotrigine levels
• Aseptic meningitis (rare)

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15. Gabapentin (Neurontin)

• Despite the name, does NOT directly act on GABA receptors or enhance GABA synthesis significantly
• Binds to the α2δ subunit of voltage-gated calcium channels - reduces calcium influx and decreases release of excitatory neurotransmitters (glutamate, substance P, norepinephrine)
• May have some GABA-mimetic effects through indirect mechanisms
• Does NOT block sodium channels (unlike most other AEDs)

• Partial (focal) seizures (adjunct)
• Neuropathic pain - first-line for diabetic peripheral neuropathy, postherpetic neuralgia
• Restless legs syndrome
• Fibromyalgia
• Hot flashes
• Anxiety disorders (off-label)
• Alcohol withdrawal (off-label)

• Sedation/drowsiness (very common)
• Dizziness, ataxia
• Weight gain
• Peripheral edema
• Fatigue
• Abuse potential - increasing recognition; risk of misuse, especially in opioid-dependent patients
• GI: nausea, constipation
• Minimal drug interactions - not metabolized by liver (renally excreted unchanged), not protein-bound, does NOT induce/inhibit CYP enzymes
• Dose reduction needed in renal impairment

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ANXIOLYTICS / SEDATIVE-HYPNOTICS

16. Alprazolam (Xanax)

• Positive allosteric modulator of GABA-A receptors - binds to the benzodiazepine site (between α and γ subunits) and increases the frequency of Cl- channel opening in response to GABA
• Does NOT open channels on its own (requires GABA to be present)
• Enhances GABAergic inhibitory neurotransmission
• High potency, short to intermediate half-life (~11 hours)

• Panic disorder (one of the preferred drugs)
• Generalized anxiety disorder (GAD)
• Social anxiety disorder
• Short-term anxiety relief
• Agoraphobia

• Sedation, drowsiness, cognitive impairment
• Dependence and withdrawal (especially with short-acting benzodiazepines like alprazolam - more severe withdrawal)
• Tolerance develops rapidly
• Respiratory depression (especially with CNS depressants, opioids - synergistic)
• Anterograde amnesia
• Rebound anxiety upon discontinuation
• Paradoxical excitation (elderly, children)
• Teratogenicity (avoid in pregnancy)

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17. Diazepam (Valium)

• Same as alprazolam: positive allosteric modulator of GABA-A receptors - increases Cl- channel opening frequency
• Long half-life (~20-100 hours) due to active metabolites (desmethyldiazepam, oxazepam)

• Anxiety disorders (GAD, acute anxiety)
• Alcohol withdrawal (first-line for preventing seizures and delirium tremens)
• Status epilepticus (IV/rectal diazepam)
• Muscle relaxation (spasticity, skeletal muscle spasm)
• Pre-anesthetic medication (reduces anxiety before procedures)
• Catatonia (IV formulation)
• Acute vertigo

• Same class effects as alprazolam: sedation, dependence, respiratory depression
• Accumulation in elderly (long half-life + active metabolites - avoid per Beers criteria)
• Long-acting sedation (hangover effect)
• Paradoxical disinhibition (increased aggression, excitement)
• Injection site pain (IV form - propylene glycol vehicle)
• Less severe withdrawal than short-acting benzodiazepines (self-tapering nature helpful in alcohol withdrawal)

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18. Flumazenil (Romazicon)

• Competitive antagonist at the benzodiazepine site on GABA-A receptors
• Reverses benzodiazepine-induced sedation, respiratory depression, and amnesia
• Short half-life (~1 hour) - much shorter than most benzodiazepines

• Reversal of benzodiazepine overdose (sedation, respiratory depression)
• Reversal of benzodiazepine sedation after procedures
• Diagnosis: helps differentiate benzodiazepine overdose from other causes of coma

• Re-sedation - because flumazenil wears off before the benzodiazepine; repeated dosing required
• Precipitates acute withdrawal in benzodiazepine-dependent patients (seizures, agitation)
• Seizures in mixed overdoses (e.g., if TCAs were also ingested)
• Nausea, vomiting, dizziness
• Does NOT reverse other CNS depressants (barbiturates, opioids, alcohol)

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19. Zolpidem (Ambien)

• Binds to the benzodiazepine site on GABA-A receptors - but selective for ω1 (BZ1) receptors containing α1 subunits
• Increases Cl- channel opening frequency (same as benzodiazepines)
• Selectivity for α1 subunits confers primarily hypnotic (sedative) effects with less anxiolytic, anticonvulsant, and muscle-relaxant activity compared to classical benzodiazepines
• Short half-life (~2.5 hours)

• Short-term treatment of insomnia (sleep onset problems)
• Extended-release form for sleep maintenance insomnia

• Residual daytime sedation (especially in elderly and women - lower dosing recommended in women)
• Amnesia and complex sleep behaviors: sleep-walking, sleep-driving, sleep-eating (without memory)
• Rebound insomnia upon discontinuation
• Dizziness, headache
• Dependence potential (Schedule IV controlled substance)
• Respiratory depression (less than benzodiazepines but possible with other CNS depressants)
• Can be reversed by flumazenil (since it acts on benzodiazepine site)
• Lacks anticonvulsant and muscle relaxant effects (unlike benzodiazepines)

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20. Buspirone (Buspar)

• Partial agonist at 5-HT1A receptors (presynaptic and postsynaptic) - reduces serotonergic activity
• Also has some D2 receptor antagonist/partial agonist activity (weak)
• Does NOT interact with GABA-A receptors - completely different mechanism from benzodiazepines
• Delayed onset: therapeutic effect takes 2-4 weeks (not useful for acute anxiety)

• Generalized anxiety disorder (GAD) - first-line alternative to benzodiazepines
• Head-to-head studies show similar efficacy to alprazolam and diazepam for GAD
• Not effective for panic disorder
• Not effective for acute anxiety episodes

• No sedation (major advantage)
• No dependence or withdrawal (major advantage)
• No respiratory depression
• No interaction with alcohol/CNS depressants
• Nausea, dizziness, headache
• Restlessness/dysphoria (reported)
• Does NOT work if patient has previously used benzodiazepines long-term (negative predictor of response)
• Cannot be used PRN (as-needed) - requires regular dosing
• Drug interactions: avoid with MAOIs (serotonin syndrome risk)

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OPIOID AGONISTS AND ANTAGONISTS

Opioid Receptor Types

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Opioid Agonists

• Prototype full μ-opioid agonist
• Mechanism: Binds μ receptors → activates Gi protein → decreases cAMP → reduces neuronal excitability, inhibits neurotransmitter release (opens K+ channels, closes Ca2+ channels)
• Clinical uses: Moderate-severe pain, acute pulmonary edema (reduces preload/anxiety), palliative care
• Side effects: Respiratory depression (most dangerous), constipation (no tolerance develops), nausea/vomiting, sedation, miosis (pinpoint pupils), pruritus (histamine release), urinary retention, physical dependence

• Prodrug - converted to morphine by CYP2D6 (~10% converted)
• Weak μ agonist in its own right
• Clinical uses: Mild-moderate pain, antitussive (cough suppression)
• Poor metabolizers (CYP2D6) get no analgesic effect; ultra-rapid metabolizers face toxicity risk
• Side effects: Similar to morphine but less potent; constipation, nausea, sedation

• Full μ agonist, ~100x more potent than morphine
• Highly lipophilic - rapid onset (IV, transdermal, transmucosal)
• Used in anesthesia, chronic pain (patches), procedural sedation, palliative care
• Short duration of action IV (rapid redistribution)
• Side effects: Respiratory depression, chest wall rigidity (at high doses), constipation

• Full μ agonist + NMDA receptor antagonist
• Long half-life (24-36 hours) - used for opioid use disorder maintenance and chronic pain
• Clinical uses: Opioid dependence treatment, neuropathic pain
• Side effects: QTc prolongation (torsades risk), respiratory depression, sedation, drug interactions (CYP3A4 substrate)

• Weak μ agonist + inhibits reuptake of serotonin and norepinephrine (dual mechanism)
• Clinical uses: Moderate pain, neuropathic pain
• Side effects: Seizures (lowers seizure threshold), serotonin syndrome (with SSRIs/MAOIs), nausea, dizziness
• Lower dependence potential but still scheduled

• Partial μ agonist + κ antagonist (high affinity for μ receptor)
• Clinical uses: Opioid use disorder (Suboxone = buprenorphine + naloxone), chronic pain, OUD in pregnancy
• Due to ceiling effect on respiratory depression - safer than full agonists in overdose
• High receptor affinity - can precipitate withdrawal in dependent patients if given when opioids are still present
• Not readily reversed by naloxone (partial agonist, tight binding)
• Side effects: Nausea, sedation, constipation; precipitates withdrawal

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Opioid Antagonists

• Pure competitive μ-opioid receptor antagonist (also blocks κ and δ)
• Reverses ALL opioid effects: respiratory depression, sedation, miosis, analgesia
• Route: IV (immediate onset), IM, intranasal (Narcan nasal spray)
• Short half-life (~1 hour IV) - may need repeated dosing or infusion for long-acting opioids
• Clinical uses:
  • Opioid overdose reversal (primary use - lifesaving)
  • Component of Suboxone (with buprenorphine) to deter IV abuse
  • Naloxone-induced reversal in opioid-dependent patients precipitates acute withdrawal (agitation, tachycardia, hypertension, piloerection, severe pain)
• No agonist activity - ineffective in non-opioid overdose
• Side effects: Acute opioid withdrawal, tachycardia, hypertension, pulmonary edema (rare)

• Pure opioid antagonist - competitive at μ, κ, δ receptors
• Long-acting (oral ~24 hours; extended-release IM monthly injection - Vivitrol)
• Clinical uses:
  • Alcohol use disorder (reduces craving/reward - FDA approved)
  • Opioid use disorder (prevents opioid euphoria if relapse occurs)
  • Opioid-induced constipation (peripheral action with methylnaltrexone)
• Patient must be opioid-free for at least 7-10 days before starting (prevent withdrawal)
• Side effects: Nausea, hepatotoxicity (at high doses), precipitation of withdrawal

• Peripheral-acting μ-opioid receptor antagonist (does not cross BBB)
• Does NOT reverse central opioid analgesia
• Specifically treats opioid-induced constipation in palliative care
• Side effects: Abdominal pain, diarrhea, flatulence

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Quick Reference Summary Table

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Opioid Pharmacology - Detailed Study Notes

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OPIOID RECEPTORS - Foundation

1. Inhibits adenylyl cyclase → decreases intracellular cAMP
2. Increases K+ efflux → hyperpolarization of postsynaptic neuron
3. Reduces presynaptic Ca2+ influx → decreases neurotransmitter release

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SECTION 1 - FULL OPIOID AGONISTS

1. Morphine

• Binds and fully activates μ > κ > δ receptors
• Inhibits adenylyl cyclase → ↓ cAMP → opens K+ channels (hyperpolarization) and closes presynaptic Ca2+ channels → reduces release of substance P, glutamate, and other pain neurotransmitters in the dorsal horn
• Hydrophilic - slower CNS penetration than fentanyl
• Active metabolites: morphine-6-glucuronide (M6G) = analgesic (2x more potent), morphine-3-glucuronide (M3G) = no analgesia, causes neuroexcitatory effects (myoclonus, hyperalgesia) - accumulates in renal failure

• PO (IR and SR/ER), IM, IV, SC, PR (rectal), SL, epidural (EA), intrathecal
• Oral bioavailability ~25-35% (significant first-pass metabolism)
• IV is gold standard for acute severe pain

• Moderate to severe acute pain (post-op, trauma, MI - reduces anxiety and preload in acute pulmonary edema)
• Chronic cancer pain
• Palliative care
• Acute pulmonary edema (reduces preload, dyspnea, anxiety)
• Reference standard against which all opioids are compared

• Respiratory depression (most dangerous - dose-dependent, mediated by μ receptors in brainstem respiratory centers)
• Constipation (no tolerance develops - most persistent SE)
• Nausea/vomiting (stimulates chemoreceptor trigger zone - D2 receptors)
• Sedation, cognitive impairment
• Miosis (pinpoint pupils - diagnostic sign of opioid toxicity; μ and κ mediated)
• Urinary retention (increased urethral sphincter tone)
• Histamine release → pruritus, urticaria, hypotension (especially IV)
• Euphoria (can lead to dependence)
• Tolerance and physical dependence with chronic use
• Biliary colic (spasm of sphincter of Oddi)
• Bradycardia (vagal stimulation)

• Concurrent MAOI use (risk of serotonin syndrome and severe respiratory depression)
• Severe respiratory depression / paralytic ileus
• Head trauma / raised ICP (CO2 retention causes vasodilation → worsens ICP)
• Renal impairment: reduce dose (M6G accumulates - oversedation risk)
• Pregnancy (neonatal respiratory depression, withdrawal)
• Hypersensitivity

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2. Hydromorphone (Dilaudid)

• Full μ agonist, similar to morphine
• 5-7x more potent than morphine
• Fewer active metabolites than morphine

• IV onset: 5 min; Duration: 3-4 h
• PO onset: 30-60 min; Duration: 3-6 h; SR: 12-24 h

• Severe pain (alternative to morphine, especially in renal impairment - safer than morphine as no significant active metabolite accumulation)
• Popular among recreational users (high abuse potential)

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3. Fentanyl (Sublimaze, Duragesic, Actiq)

• Potent full μ receptor agonist
• 100x more potent than morphine (by weight)
• Highly lipophilic - rapid CNS penetration, rapid onset
• No significant active metabolites (advantage over morphine)
• Short duration IV due to rapid redistribution into fat/muscle (not due to rapid metabolism)

• IV/IM (anesthesia)
• Transdermal patch (Duragesic) - for chronic pain
• Transmucosal (buccal, sublingual, nasal spray) - for breakthrough cancer pain
• Intrathecal/epidural

• Note: IV short duration is due to redistribution, not metabolism - repeated doses cause accumulation

• Intraoperative analgesia and anesthesia (primary agent)
• Procedural sedation (intubation, colonoscopy)
• Chronic cancer pain (transdermal patch)
• Breakthrough cancer pain (transmucosal forms)
• Epidural/spinal analgesia (obstetrics, post-op)
• ICU sedation and analgesia

• Respiratory depression (severe; dose-related)
• Chest wall rigidity / wooden chest syndrome - at high IV doses given rapidly; prevents ventilation; requires neuromuscular blockade
• Bradycardia
• Constipation
• Minimal histamine release (advantage over morphine)
• Sedation
• Transdermal: local skin reaction, risk of accidental exposure to others

• Opioid-naive patients for transdermal patch (minimum 60 mg/day oral morphine equivalent required before switching)
• Concurrent MAOIs
• Significant respiratory impairment
• Hyperthermia (increases fentanyl release from patch)
• Avoid applying heat to transdermal site

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4. Oxycodone (OxyContin, Percocet)

• Full μ agonist; also binds κ receptors
• Converted in part to oxymorphone (active) by CYP2D6
• ~1.5x more potent than oral morphine
• Higher oral bioavailability than morphine (~60-80%)
• Greater euphoric effect than morphine (making it high abuse potential)

• Moderate to severe pain
• Often combined with acetaminophen (Percocet) or aspirin (Percodan)
• ER form for chronic cancer/non-cancer pain requiring around-the-clock analgesia

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5. Codeine

• Prodrug - must be converted to morphine by CYP2D6 (10% converted)
• Also acts as a weak μ agonist independently
• Antitussive effect at lower doses (may be non-opioid receptor mediated)
• ~10x less potent than morphine

• Mild to moderate pain
• Antitussive (cough suppression) - though non-opioid dextromethorphan often preferred now
• Often in combinations (Tylenol with Codeine)

• Similar to morphine but generally milder
• Constipation, nausea, sedation
• Codeine-specific issue: genetic variability in CYP2D6:
  • Poor metabolizers (~10% Caucasians): no analgesic effect (no conversion to morphine)
  • Ultra-rapid metabolizers: life-threatening toxicity (overdose levels of morphine); contraindicated in children post-tonsillectomy (FDA black box warning)

• Children post-tonsillectomy/adenoidectomy (FDA black box)
• Ultra-rapid CYP2D6 metabolizers (risk of fatal respiratory depression)
• Concurrent MAOIs

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6. Meperidine (Pethidine / Demerol)

• Full μ agonist, ~10x less potent than morphine
• Also has local anesthetic-like properties (Na+ channel blockade)
• Toxic metabolite: normeperidine (N-demethylation by CYP3A4) - accumulates in renal impairment, causes CNS excitability

• Acute pain (historically common, now largely replaced by safer alternatives)
• Post-operative shivering/rigors - unique indication (most effective drug)
• IV PCA (patient-controlled analgesia)
• Labor analgesia

• Standard opioid effects PLUS:
• Normeperidine toxicity: tremors, myoclonus, seizures (especially in renal impairment, elderly, or with high doses - CNS excitatory, NOT reversed by naloxone)
• Less constipation than morphine
• Serotonin syndrome risk (especially with MAOIs, SSRIs) - more than other opioids
• Tachycardia (atropine-like effect - distinguishes it from other opioids which cause bradycardia)
• Less pupillary constriction

• MAOIs (absolute - risk of fatal serotonin syndrome / hyperpyrexic crisis)
• Renal impairment (normeperidine accumulation → seizures)
• Epilepsy
• Avoid in elderly (Beers criteria)
• Chronic pain (avoid repeated doses)

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7. Methadone (Methadose, Dolophine)

• Full μ agonist (pure agonist at μ; negligible κ/δ activity)
• Also NMDA receptor antagonist - reduces opioid tolerance and treats neuropathic pain component
• Also inhibits serotonin and norepinephrine reuptake
• Long, variable half-life (24-36 hours; range 8-59 hours)
• High oral bioavailability (~80%)
• Racemic mixture (R-methadone is pharmacologically active)
• Complex pharmacokinetics - takes 5-7 days to reach steady state

• Opioid use disorder (OUD) maintenance treatment - only through licensed methadone maintenance treatment programs (MMTPs) in the US
• Short-term (7-30 days) and long-term (>180 days) OUD detoxification and maintenance
• Chronic severe pain (cancer, neuropathic pain)
• Reduces mortality by 70% in opioid-dependent patients when used for maintenance
• Reduces HIV/hepatitis B/C transmission
• Neuropathic pain (NMDA antagonism)

• Standard opioid effects PLUS:
• QTc prolongation → risk of torsades de pointes (ECG monitoring required at higher doses)
• Delayed respiratory depression (half-life mismatch with analgesic duration - overdose risk with dose escalation)
• Drug accumulation with repeated dosing (steady state takes days)
• Sweating (prominent)
• Peripheral edema

• Concurrent QTc-prolonging drugs (significant interaction)
• Concurrent MAOIs
• Significant respiratory depression
• Caution with CYP3A4 inducers/inhibitors (carbamazepine, rifampin, fluconazole, etc.) - methadone is a CYP substrate with complex interactions

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8. Hydrocodone (Vicodin, Norco, Hysingla ER)

• Moderate to severe pain (most prescribed opioid in the US historically)
• Often in combination with acetaminophen (Vicodin, Norco) or ibuprofen (Vicoprofen)
• ER form (Hysingla) for around-the-clock pain management

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SECTION 2 - PARTIAL OPIOID AGONIST

9. Buprenorphine (Subutex, Suboxone, Butrans, Belbuca)

• Partial agonist at μ receptors: binds with very high affinity but activates the receptor only partially → produces a ceiling effect on respiratory depression (ceiling does NOT apply to analgesia)
• Potent antagonist at κ receptors (which may contribute to antidepressant effects)
• Agonist at NOP/ORL1 receptors
• Very high receptor affinity → displaces full agonists from receptors; can precipitate acute withdrawal if given to a patient actively on full agonists
• Dissociates slowly from receptor → long duration despite moderate half-life; can be dosed every 24-48 h for OUD

• Note: Buprenorphine has very low oral bioavailability (near zero) due to extensive first-pass metabolism → must be given SL/buccal/transdermal/parenteral

• SL/buccal: Onset 30-60 min; Duration 8-12 h (OUD dosing); analgesic duration 6-8 h
• Transdermal: Onset 12-24 h; Duration 7 days
• IV/IM: Onset 15-30 min; Duration 6-8 h

• Opioid use disorder (OUD) - first-line treatment (Office-Based Opioid Treatment, OBOT); any licensed physician can prescribe for OUD (unlike methadone for OUD)
• Moderate to severe chronic pain
• Acute pain (parenteral)
• Partial agonist → useful for patients requiring both pain control and reduced overdose risk
• Increasingly used for depression (off-label)
• Neonatal opioid withdrawal syndrome treatment

• Precipitates withdrawal if given when full agonist still occupies receptors (start only when patient is in mild-moderate withdrawal)
• Nausea, vomiting, constipation (less than full agonists)
• Headache, dizziness, diaphoresis
• QTc prolongation (buccal/SL forms - at higher doses)
• Sedation (less than full agonists)
• Elevation of hepatic enzymes (monitor LFTs)
• Ceiling effect on respiratory depression = safety advantage
• Not readily reversed by naloxone (high affinity - requires larger/repeated naloxone doses)

• Acute respiratory depression/severe asthma
• Concurrent benzodiazepines/alcohol/CNS depressants (despite ceiling, combination still dangerous - black box warning)
• Administration before patient has entered mild-moderate opioid withdrawal (COWS score ≥8 recommended before first dose)
• MAOIs

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SECTION 3 - MIXED AGONIST-ANTAGONISTS

10. Pentazocine (Talwin)

• Agonist at κ receptors (analgesia, sedation, dysphoria)
• Weak antagonist (or partial agonist) at μ receptors - can precipitate withdrawal
• The (-) enantiomer is the κ agonist; the (+) enantiomer has some σ receptor effects (psychotomimetic)
• Commercially available as Talwin NX = pentazocine + naloxone (100:1 ratio) - naloxone added in the 1970s to prevent IV abuse (naloxone is active IV but not PO)

• Moderate to severe pain (now infrequently used)
• Labor analgesia (historical)
• As part of Talwin NX formulation to deter abuse

• Dysphoria, hallucinations, nightmares (κ receptor mediation - more prominent than with full agonists)
• Psychotomimetic effects (sigma receptor activation)
• Nausea, dizziness, sedation
• Sweating, flushing
• Precipitates withdrawal in opioid-dependent patients
• Less respiratory depression than morphine at equianalgesic doses (ceiling effect due to mixed mechanism)
• Increases cardiac workload (raises pulmonary artery pressure, systemic BP, heart rate) - unlike morphine; avoid in MI

• Patients physically dependent on opioids (will precipitate withdrawal)
• Myocardial infarction (raises cardiac work - contraindicated; use morphine instead)
• MAOIs (serotonin/excitatory syndrome)
• Head trauma / raised ICP

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11. Nalbuphine (Nubain)

• Agonist at κ receptors (analgesia, sedation)
• Antagonist at μ receptors (blocks full agonist-induced respiratory depression, euphoria)
• Equianalgesic to morphine parenterally (1:1 ratio)
• Ceiling effect on respiratory depression (important safety feature)

• Moderate to severe pain (particularly useful in patients where opioid-induced pruritus or dysphoria is a concern)
• Labor and delivery analgesia
• Reversal of opioid-induced pruritus (IV nalbuphine blocks μ-mediated itch without reversing analgesia - unique use)
• Burn pain, post-op pain
• Balancing analgesia and avoiding respiratory depression in monitored settings

• Sedation (prominent)
• Nausea, vomiting, dizziness
• Less dysphoria than pentazocine (advantage)
• Sweating
• Precipitates withdrawal in opioid-dependent patients
• Less constipation than full agonists
• Less histamine release than morphine

• Opioid-dependent patients (precipitates withdrawal)
• Severe respiratory depression
• MAOIs

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12. Butorphanol (Stadol)

• Agonist at κ receptors (primary analgesic mechanism)
• Partial agonist/antagonist at μ receptors
• 5-7x more potent than morphine (parenteral)
• Ceiling effect on respiratory depression

• Migraine headache (intranasal spray - common use in ED/office setting)
• Labor analgesia
• Moderate to severe acute pain
• Pre-operative analgesia/sedation
• Opioid-induced pruritus treatment

• Dysphoria (κ mediation - but less than pentazocine)
• Sedation, dizziness, nausea
• Nasal congestion/irritation (intranasal)
• Significant abuse potential (intranasal route facilitates dependence - nasal spray associated with misuse)
• Precipitates withdrawal in opioid-dependent patients
• Psychotomimetic effects at high doses
• Increases cardiac workload (like pentazocine - caution in cardiac disease)

• Opioid-dependent patients (precipitates withdrawal)
• MAOIs
• Caution in cardiac disease (raises cardiac work)
• Caution in hepatic/renal impairment (reduce dose)

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SECTION 4 - OPIOID ANTAGONISTS

13. Naloxone (Narcan)

• Competitive antagonist at μ, κ, and δ receptors (highest affinity for μ)
• No intrinsic agonist activity - no analgesic, euphoric, or respiratory depressant effects on its own
• Displaces opioid agonists from receptors rapidly, reversing ALL opioid effects
• Short half-life (~60-90 min IV) - significantly shorter than most opioids → re-narcotization (re-sedation) is a major clinical concern
• Hepatic metabolism; no active metabolites

• Opioid overdose reversal - life-saving in community and hospital setting; treats respiratory depression, sedation, miosis
• Reversal of post-operative opioid sedation
• Diagnosis: suspected opioid intoxication (therapeutic test)
• Component of Suboxone (buprenorphine/naloxone) - oral/SL form not bioavailable so prevents IV diversion/abuse
• Component of Targiniq ER (oxycodone/naloxone) - reduces opioid-induced constipation when taken orally

• Typical overdose reversal: 0.4-2 mg IV/IM/IN; repeat every 2-3 min as needed
• Use lowest effective dose - giving too much precipitates acute withdrawal
• For long-acting opioid overdose (e.g., methadone): IV infusion (2/3 of initial effective bolus dose/hour)

• Acute opioid withdrawal syndrome in dependent patients: agitation, tachycardia, hypertension, piloerection (goosebumps), sweating, lacrimation, nausea, vomiting, abdominal cramps, diarrhea - can be life-threatening in cardiac patients
• Re-sedation (re-narcotization) - when naloxone wears off before opioid; patient must be monitored
• Nausea, vomiting
• Pulmonary edema (rare - acute catecholamine surge from withdrawal)
• Ventricular arrhythmias (rare - from catecholamine surge)
• Does NOT reverse non-opioid CNS depressants (alcohol, barbiturates, benzodiazepines)

• No absolute contraindications in life-threatening overdose
• Relative: known opioid dependence (use cautiously with small doses to avoid precipitating severe withdrawal)
• Caution in patients with cardiac disease (catecholamine surge on withdrawal)

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14. Naltrexone (ReVia, Vivitrol)

• Competitive antagonist at μ, κ, and δ receptors - similar to naloxone
• Much longer half-life than naloxone: oral ~24 h; IM extended-release (Vivitrol) ~30 days
• High oral bioavailability (~60-80%) - unlike naloxone, effective orally
• Blocks the rewarding effects of opioids (euphoria, reinforcement) → reduces craving and relapse
• In alcohol use disorder: blocks endogenous opioid-mediated reward from alcohol → reduces craving and pleasure of drinking
• No intrinsic agonist activity

• Opioid use disorder (OUD) - prevents relapse by blocking euphoria if opioids are used; IM monthly form (Vivitrol) improves adherence
• Alcohol use disorder (AUD) - FDA-approved; reduces craving and heavy drinking episodes; effective for both daily and "targeted" (event-based) use
• Smoking cessation (adjunct, off-label)
• Impulse control disorders (off-label)
• Eating disorders (off-label)

• Patient must be opioid-free for minimum 7-10 days before starting (longer for methadone: 10-14 days) to prevent precipitated withdrawal
• Naloxone challenge test can be done to confirm opioid-free status

• Hepatotoxicity - dose-dependent (at doses 5x normal); monitor LFTs; not used in acute hepatitis or liver failure
• Precipitated withdrawal if opioid-free time insufficient
• Nausea, vomiting, abdominal pain (common initially)
• Insomnia, anxiety, headache
• Injection site reactions (Vivitrol - nodule, pain, swelling - rarely serious)
• Anorexia, fatigue
• Dysphoria - some patients feel flat/anhedonic (endogenous opioid blockade)

• Active opioid use or not opioid-free (precipitates withdrawal)
• Acute hepatitis or liver failure (hepatotoxic at high doses)
• Concurrent opioid analgesic use (blocks pain relief - dangerous if patient needs emergency surgery)
• Hypersensitivity

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15. Methylnaltrexone (Relistor)

• Quaternary ammonium compound - does NOT cross the blood-brain barrier
• Blocks peripheral μ receptors in the GI tract specifically
• Does NOT antagonize central opioid effects (no reversal of analgesia, no precipitated withdrawal)

• Opioid-induced constipation (OIC) in patients with advanced illness on chronic opioid therapy (palliative care) who have not responded to laxatives
• Opioid-induced constipation in chronic non-cancer pain patients (PO form)

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SECTION 5 - ATYPICAL / DUAL-MECHANISM OPIOIDS

16. Tramadol (Ultram, ConZip)

1. Weak μ-opioid receptor agonist (1/6000 affinity of morphine for μ receptor)
2. Inhibits serotonin AND norepinephrine reuptake (SNRI-like mechanism)

• Active metabolite O-desmethyltramadol (M1): 6x stronger μ agonist than parent; produced by CYP2D6

• Moderate to moderately-severe pain
• Neuropathic pain (SNRI component helps)
• Fibromyalgia
• Premature ejaculation (off-label; serotonin reuptake mechanism)

• Nausea, dizziness, constipation, headache
• Seizures (lowers seizure threshold; dose-related; risk with TCAs, SSRIs, antipsychotics)
• Serotonin syndrome (especially with SSRIs, SNRIs, MAOIs, triptans)
• Sedation, sweating
• Less respiratory depression than full agonists at therapeutic doses

• MAOIs (serotonin syndrome)
• Seizure disorder (lowers threshold)
• Concurrent SSRIs/SNRIs (serotonin syndrome risk - use cautiously)
• Renal/hepatic impairment (reduce dose)

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17. Tapentadol (Nucynta)

1. Moderate μ-opioid receptor agonist
2. Norepinephrine reuptake inhibitor (NRI - no serotonin component; unlike tramadol)

• No active metabolites (advantage)
• ~10% as potent as morphine

• Moderate to severe acute pain
• Diabetic peripheral neuropathy (chronic pain; FDA approved for ER formulation)
• Around-the-clock chronic pain requiring opioid (ER form)

• Nausea, constipation, dizziness, somnolence
• Less GI side effects and less respiratory depression than equivalent morphine doses (purported advantage)
• Serotonin syndrome risk (lower than tramadol since no serotonin reuptake inhibition)

• MAOIs
• Maximum dose 600 mg/day

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QUICK REFERENCE COMPARISON TABLE

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OPIOID TOXIDROME & REVERSAL

1. Miosis (pinpoint pupils)
2. Respiratory depression (rate <12/min, shallow)
3. Decreased consciousness / coma

• Ensure airway / ventilatory support
• Naloxone: 0.4-2 mg IV/IM/IN; repeat q2-3 min (up to 10 mg if no response → reconsider diagnosis)
• Monitor for re-sedation - observe minimum 4 h after last naloxone dose
• Activate opioid overdose education and naloxone distribution (OEND) on discharge

• Short-acting opioids (morphine, heroin, oxycodone): starts 6-8 h after last use; peaks 36-72 h; resolves 5-10 days
• Long-acting opioids (methadone): starts 24-36 h after last use; peaks 72-96 h; can persist 2-3 weeks
• Symptoms: anxiety, yawning, lacrimation, rhinorrhea, piloerection, myalgias, nausea, vomiting, diarrhea, tachycardia, hypertension, insomnia

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