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Antipsychotic Agents, Mood Stabilizers & Antidepressants — Complete Fast Review

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PART 1 — ANTIPSYCHOTIC AGENTS

Schizophrenia: Background

• Affects ~1% of the population; responsible for ~50% of long-term psychiatric hospitalizations
• Neurodevelopmental disorder: structural/functional brain changes present even in utero
• Genetic — high heritability; polygenic (copy number variations, deletions, insertions)
• Positive symptoms: hallucinations, delusions, disorganized thinking
• Negative symptoms: flat affect, poverty of speech, social withdrawal, cognitive deficits

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THE SEROTONIN HYPOTHESIS OF SCHIZOPHRENIA

LSD and mescaline are 5-HT agonists → searched for endogenous hallucinogens in schizophrenia patients (proved fruitless)

• 5-HT₂A-receptor stimulation underlies the hallucinatory effects of LSD/mescaline
• 5-HT₂A blockade is a key mechanism of atypical antipsychotics (e.g., clozapine, olanzapine, risperidone)
• 5-HT₂A blockade on dopaminergic neurons increases DA release in prefrontal cortex → improves negative symptoms and cognition
• 5-HT₂A blockade reduces EPS by decreasing the nigrostriatal DA imbalance caused by D2 blockade
• Atypicals show higher 5-HT₂A/D₂ affinity ratio than typicals — explains fewer EPS and better negative symptom control

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THE DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA

1. All effective antipsychotics block D₂ receptors
2. Amphetamine (releases DA) → causes amphetamine psychosis mimicking schizophrenia
3. L-DOPA can worsen psychosis
4. DA metabolite homovanillic acid (HVA) is elevated in CSF of some patients
5. PET studies: D₂ occupancy of 60–80% correlates with clinical response; >80% → EPS

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THE GLUTAMATE HYPOTHESIS OF SCHIZOPHRENIA

• NMDA receptor hypofunction hypothesis: based on observation that PCP (phencyclidine) and ketamine (NMDA antagonists) produce both positive AND negative symptoms resembling schizophrenia
• NMDA receptor hypofunction on GABAergic interneurons → disinhibition of glutamatergic and dopaminergic neurons → excess excitatory activity in limbic regions
• Glutamate dysregulation → reduced activity on mesocortical DA neurons (explains negative symptoms)
• This forms the rationale for glycine-site modulators and novel glutamatergic treatments

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BASIC PHARMACOLOGY OF ANTIPSYCHOTIC AGENTS

Classification

Mechanism of Action

• Primary: D₂ receptor blockade (all antipsychotics)
• Atypicals additionally: 5-HT₂A, 5-HT₂C, H₁, α₁, muscarinic blockade
• Aripiprazole is unique: partial D₂ agonist (dopamine system stabilizer) + 5-HT₁A partial agonist + 5-HT₂A antagonist
• Clozapine: highest affinity for D₄, also blocks 5-HT₂A/2C, α, H₁, muscarinic; almost no EPS; reserved for treatment-resistant schizophrenia due to risk of agranulocytosis

Pharmacokinetics

• Most are highly lipophilic, large Vd; extensively hepatic metabolism (CYP1A2, CYP2D6, CYP3A4)
• Long-acting depot injections (haloperidol decanoate, risperidone microspheres, aripiprazole lauroxil) — administered every 2–4 weeks; improves adherence
• Haloperidol: oral t½ ~24 h; depot t½ ~3 weeks
• Clozapine: t½ ~12 h; must be titrated slowly

Receptor Binding Profiles

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CLINICAL PHARMACOLOGY OF ANTIPSYCHOTIC AGENTS

Indications

• Schizophrenia (acute & maintenance), bipolar mania, psychotic depression, agitation, Tourette syndrome, antiemesis (low-potency typicals)

Adverse Effects

• Acute dystonia (hours–days): sustained muscle contractions; Rx: anticholinergics (benztropine, diphenhydramine)
• Akathisia (days–weeks): restlessness; Rx: propranolol, benzodiazepines
• Pseudoparkinsonism (weeks): bradykinesia, rigidity, tremor; Rx: anticholinergics or amantadine
• Tardive dyskinesia (months–years): involuntary repetitive movements (lip-smacking, tongue protrusion); may be irreversible; Rx: reduce dose, switch to clozapine or quetiapine; VMAT2 inhibitors (valbenazine, deutetrabenazine)

• Weight gain, hyperglycemia, type 2 DM, dyslipidemia
• Monitor: fasting glucose, lipids, BMI

• Neuroleptic Malignant Syndrome (NMS): hyperthermia, rigidity, autonomic instability, ↑CK → life-threatening; Rx: dantrolene, bromocriptine, stop drug
• Prolactin elevation: galactorrhea, gynecomastia, amenorrhea (esp. typicals, risperidone)
• QTc prolongation: thioridazine, ziprasidone, haloperidol IV — risk of torsades
• Agranulocytosis: clozapine (1–2%) → mandatory ANC monitoring (weekly for 6 months → biweekly → monthly)
• Anticholinergic: dry mouth, urinary retention, constipation (clozapine, chlorpromazine)
• Sedation: H₁ blockade (clozapine, olanzapine, chlorpromazine)
• Orthostatic hypotension: α₁ blockade

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PART 2 — LITHIUM, MOOD-STABILIZING DRUGS & BIPOLAR DISORDER

BASIC PHARMACOLOGY OF LITHIUM

Pharmacokinetics

• Small monovalent cation (Li⁺); no protein binding, no metabolism
• Complete oral absorption; distributed in total body water
• Renal excretion — competes with Na⁺: Na⁺ depletion → ↑Li reabsorption → toxicity
• t½ ~24 hours; steady state in ~5 days
• Therapeutic range: 0.6–1.2 mEq/L (prophylaxis); 0.8–1.2 mEq/L (acute mania)
• Toxic level: >1.5 mEq/L (mild toxicity); >2.0 mEq/L (severe)

Mechanism of Action

1. Inhibits inositol monophosphatase → depletes free inositol → attenuates PKC signaling ("inositol depletion hypothesis")
2. Inhibits glycogen synthase kinase-3β (GSK-3β) → neuroprotective, alters gene expression
3. Alters Na⁺/K⁺-ATPase function
4. Modulates cAMP signaling (reduces receptor-stimulated cAMP)
5. Interferes with DAG/PKC pathway

Clinical Use

• Gold standard for bipolar disorder (both acute mania and prophylaxis of recurrence)
• Reduces suicide risk in bipolar patients (strong evidence)
• Adjunct in treatment-resistant depression
• Off-label: cluster headaches, SIADH (paradoxically)

ADVERSE EFFECTS OF LITHIUM

CLINICAL PHARMACOLOGY OF LITHIUM

• Monitor serum levels every 3–6 months (trough, 12h post-dose)
• Monitor: renal function (SCr, eGFR), thyroid (TSH), ECG in older patients
• Narrow therapeutic index → lithium toxicity is common

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VALPROIC ACID (Valproate)

• Blocks voltage-gated Na⁺ channels
• Enhances GABA synthesis/release; inhibits GABA transaminase (↑GABA)
• Inhibits T-type Ca²⁺ channels
• Inhibits GSK-3β (similar to lithium)

• Teratogenic (MOST teratogenic of mood stabilizers): neural tube defects, spina bifida; contraindicated in pregnancy when possible
• Hepatotoxicity (especially in children <2 years with mitochondrial disorders)
• Pancreatitis
• Thrombocytopenia, platelet dysfunction
• Weight gain, hair loss, tremor, sedation
• Enzyme inhibitor: inhibits metabolism of lamotrigine, phenobarbital → ↑their levels

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CARBAMAZEPINE

• Primary: blocks voltage-gated Na⁺ channels (use-dependent)
• Reduces neuronal excitability

• Aplastic anemia and agranulocytosis (rare but serious)
• SIADH → hyponatremia
• Teratogenic: neural tube defects, craniofacial abnormalities
• Diplopia, ataxia, dizziness (dose-related)
• Rash; Stevens-Johnson Syndrome (especially HLA-B*1502 in Asian patients)
• Enzyme inducer (CYP3A4): reduces levels of oral contraceptives, warfarin, other drugs

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PART 3 — ANTIDEPRESSANTS

BASIC PHARMACOLOGY OF ANTIDEPRESSANTS

A. Selective Serotonin Reuptake Inhibitors (SSRIs)

• No significant affinity for histamine, ACh, or α receptors (unlike TCAs)
• Highly lipophilic

• Fluoxetine: longest t½ (~1–4 days; active metabolite norfluoxetine t½ ~7–14 days) → fewest discontinuation symptoms; self-tapering
• Paroxetine: shortest t½; most anticholinergic; most discontinuation symptoms
• All metabolized by CYP2D6, CYP3A4

• GI: nausea, diarrhea (most common; usually transient)
• Sexual dysfunction: reduced libido, delayed orgasm (most common cause of SSRI discontinuation)
• Insomnia or somnolence
• Serotonin syndrome (especially with MAOIs, tramadol, linezolid): hyperthermia, tachycardia, clonus, agitation, diarrhea
• Hyponatremia (SIADH — especially elderly)
• Weight gain (paroxetine > others)
• QTc prolongation: citalopram/escitalopram at high doses
• Safe in overdose (low lethality) — major advantage over TCAs

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B. Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

• Similar to SSRIs (GI, sexual dysfunction, serotonin syndrome risk)
• Hypertension (especially venlafaxine at higher doses — NE effect)
• Discontinuation syndrome (especially venlafaxine — short t½)
• Duloxetine: hepatotoxicity risk; avoid in significant liver disease

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C. 5-HT₂ Receptor Modulators

• Blocks 5-HT₂A/2C + weak SERT inhibition + α₁ blockade
• Uses: depression, insomnia (low dose)
• Notable SE: priapism, sedation, orthostatic hypotension

• Blocks 5-HT₂A + SERT inhibition
• Risk of hepatic failure (black box warning) — rarely used now

• Multi-modal: SERT inhibitor + 5-HT₁A partial agonist + 5-HT₃/7 antagonist
• Improves cognitive symptoms of depression
• Favorable sexual side effect profile

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D. Tetracyclic and Unicyclic Antidepressants

• Mechanism: α₂ antagonist (presynaptic) → ↑NE and 5-HT release + 5-HT₂/3 blockade + strong H₁ blockade
• Uses: Depression (especially with insomnia, weight loss, anxiety); very sedating
• SE: Weight gain, sedation, increased appetite — useful in cachectic/anxious depressed patients
• Minimal sexual dysfunction (advantage)

• Mechanism: Inhibits DAT + NET (dopamine + norepinephrine reuptake); no serotonergic activity
• Uses: MDD, smoking cessation, ADHD (off-label), seasonal affective disorder
• SE: Seizures (dose-dependent; contraindicated in eating disorders/seizure history), insomnia, agitation
• No sexual dysfunction (key advantage)
• No weight gain (often weight loss)
• Drug interaction: inhibits CYP2D6

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E. Monoamine Oxidase Inhibitors (MAOIs)

• Tyramine reaction ("cheese effect"): MAO-A inhibition → unable to metabolize dietary tyramine → massive NE release → hypertensive crisis (headache, palpitations, stroke, death); avoid aged cheese, cured meats, red wine, fermented foods
• Serotonin syndrome: with SSRIs, SNRIs, TCAs, tramadol, meperidine, dextromethorphan — washout period required: 14 days MAOI → SSRI; 5 weeks fluoxetine → MAOI (due to norfluoxetine half-life)
• Sympathomimetics: indirect-acting agents (pseudoephedrine, amphetamine) → hypertensive crisis

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F. NMDA Receptor Antagonists

• Approved for treatment-resistant depression (TRD) and MDD with acute suicidal ideation
• Mechanism: NMDA receptor antagonism → rapidly increases synaptic glutamate → ↑AMPA activity → BDNF release and synaptogenesis
• Rapid onset (hours to days) — unlike conventional antidepressants (2–6 weeks)
• Must be administered in certified healthcare setting (risk of dissociation, sedation, abuse potential)

• Used off-label for TRD and acute suicidality
• Same mechanism; rapid but transient effect

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G. Allosteric Modulators of GABA-A

• Neurosteroid — allosteric modulator of GABA-A receptors; a synthetic analogue of allopregnanolone
• Approved for postpartum depression (PPD)
• IV infusion over 60 hours; administered in inpatient setting
• Mechanism: Potentiates GABA-A receptor function; addresses the drop in allopregnanolone after delivery

• Oral neuroactive steroid GABA-A modulator
• Approved for MDD and PPD (2023); 14-day treatment course
• Rapid onset of action

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CLINICAL PHARMACOLOGY OF ANTIDEPRESSANTS

CHOOSING AN ANTIDEPRESSANT

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DOSING

• All conventional antidepressants: 2–6 week delay to therapeutic effect (downregulation of autoreceptors + synaptic adaptation)
• Start low, titrate up; reassess at 4–8 weeks
• SSRIs generally started at half the therapeutic dose to minimize GI side effects
• Fluoxetine 20 mg/day → up to 80 mg/day (OCD)
• Venlafaxine: serotonergic at low doses; noradrenergic added at ≥150 mg/day
• Continue for ≥6–12 months after remission; recurrent episodes may require indefinite treatment

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ADVERSE EFFECTS (Summary Table)

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OVERDOSE

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DRUG INTERACTIONS

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Quick Summary Table — All Drug Classes

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GI Pharmacology: Complete Fast Review

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PHYSIOLOGY OF ACID SECRETION (Foundation)

• H₂ (histamine from ECL cells) → ↑cAMP → PKA → proton pump activation
• M₃ (ACh from vagus) → ↑Ca²⁺ → protein kinases → proton pump
• CCK-B/Gastrin (gastrin from antral G cells) → ↑Ca²⁺ → proton pump

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PART 1 — DRUGS USED IN ACID-PEPTIC DISEASES

AGENTS THAT REDUCE INTRAGASTRIC ACIDITY

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1. ANTACIDS

• Sodium bicarbonate (NaHCO₃): fastest; CO₂ belching, systemic alkalosis, sodium load — avoid in HF/HTN
• Calcium carbonate (CaCO₃): fast, potent; acid rebound (Ca²⁺ stimulates gastrin), constipation
• Magnesium hydroxide [Mg(OH)₂]: medium speed; diarrhea; avoid in renal failure (Mg accumulates)
• Aluminum hydroxide [Al(OH)₃]: slow; constipation; binds phosphate → used in hyperphosphatemia; avoid in renal failure

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2. H₂-RECEPTOR ANTAGONISTS (H₂RAs)

• Oral bioavailability ~50%; partially metabolized by liver; renal excretion
• Famotidine: most potent; longest duration (~10–12 h); no CYP interactions
• Cimetidine: weakest; multiple CYP450 drug interactions (inhibits CYP1A2, 2C9, 2D6, 3A4) → ↑warfarin, phenytoin, theophylline levels; anti-androgenic effects (gynecomastia, impotence)

• GERD (mild-moderate), PUD healing and maintenance, Zollinger-Ellison syndrome (low efficacy), stress ulcer prophylaxis
• Less effective than PPIs for acid suppression

• Generally well-tolerated
• Cimetidine: gynecomastia, decreased libido, confusion (elderly), drug interactions
• All: headache, dizziness, diarrhea, constipation
• Tolerance develops within days with continuous use (receptor upregulation)

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3. PROTON-PUMP INHIBITORS (PPIs)

• PPIs are prodrugs (inactive at neutral pH) — absorbed systemically, concentrated in acidic parietal cell canaliculi
• Protonated → activated sulfenamide → irreversible covalent binding to H⁺/K⁺-ATPase via disulfide bonds
• Block ALL phases of acid secretion (regardless of stimulus)
• Acid suppression lasts 24–72 hours (even though t½ is 1–2 hours) — because must wait for new pump synthesis
• Take 30–60 min before first meal (pumps must be active to be irreversibly blocked)

• Enteric-coated (acid-labile); hepatic metabolism via CYP2C19 and CYP3A4
• Omeprazole: most CYP interactions (↓clopidogrel activation via CYP2C19 — clinical debate)
• Pantoprazole/rabeprazole: fewest CYP interactions

• GERD, erosive esophagitis (first-line)
• PUD (gastric and duodenal)
• H. pylori eradication (triple or quadruple therapy)
• Zollinger-Ellison syndrome (high-dose)
• NSAID-induced ulcer prevention
• Stress ulcer prophylaxis in ICU

• Short-term: headache, nausea, diarrhea, abdominal pain
• Long-term (chronic use):
  • Hypomagnesemia (impairs intestinal Mg absorption)
  • Bone fractures (↓Ca absorption due to achlorhydria)
  • Clostridium difficile colitis (↑risk with prolonged use)
  • Vitamin B₁₂ deficiency (needs acid for IF/B12 dissociation)
  • Pneumonia risk (↑gastric pH → bacterial colonization)
  • Hypergastrinemia → ECL cell hyperplasia (carcinoid concern theoretical, not proven clinically)
  • ↓Clopidogrel efficacy (omeprazole > others)

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MUCOSAL PROTECTIVE AGENTS

4. SUCRALFATE

• Aluminum salt of sulfated sucrose
• In acidic environment (pH <4): polymerizes → viscous paste that binds to ulcer base (especially to proteins in necrotic tissue — ionic interaction)
• Forms physical barrier against acid, pepsin, and bile
• Stimulates mucosal prostaglandin synthesis, mucus secretion, bicarbonate secretion
• Does not neutralize acid or reduce acid secretion

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5. PROSTAGLANDIN ANALOGS — MISOPROSTOL

• Prevention of NSAID-induced gastric ulcers (COX inhibition by NSAIDs reduces endogenous PGs → protective loss)
• Off-label: cervical ripening, medical abortion (with mifepristone), postpartum hemorrhage

• Diarrhea (most common, dose-dependent — PGE₁ stimulates intestinal secretion)
• Abdominal cramping
• Uterine contractions → contraindicated in pregnancy (unless intentional)

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6. BISMUTH COMPOUNDS

• Forms protective coat over ulcer base (binds to glycoproteins)
• Has direct antimicrobial activity against H. pylori
• Inhibits pepsin activity; stimulates mucus and bicarbonate
• Anti-secretory, anti-diarrheal (subsalicylate component → reduces intestinal secretions)

• Component of quadruple therapy for H. pylori (bismuth + metronidazole + tetracycline + PPI)
• Traveler's diarrhea (Pepto-Bismol)
• Non-ulcer dyspepsia

• Black stools (bismuth sulfide — warn patients)
• Black tongue
• Bismuth toxicity (encephalopathy) with high doses
• Salicylate toxicity (avoid in children — Reye's syndrome risk)

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PART 2 — DRUGS STIMULATING GI MOTILITY

CHOLINOMIMETIC AGENTS

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METOCLOPRAMIDE & DOMPERIDONE

• D₂ receptor antagonist in gut (and CTZ/vomiting center for metoclopramide)
• Enhances ACh release from myenteric plexus → ↑esophageal sphincter tone, ↑gastric emptying, ↑coordinated peristalsis
• Metoclopramide also has 5-HT₄ agonist activity → further prokinetic effect
• Also acts as antiemetic (central D₂ blockade in CTZ)

• Metoclopramide: Tardive dyskinesia (with long-term use — FDA black box), EPS (akathisia, dystonia), drowsiness, galactorrhea (↑prolactin)
• Domperidone: QTc prolongation (cardiac risk), ↑prolactin

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MACROLIDES (Erythromycin as Prokinetic)

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SEROTONIN 5-HT₄ RECEPTOR AGONISTS

• Stimulates colonic peristalsis → increases bowel movement frequency
• Used for chronic constipation (especially women)
• Safer cardiac profile than older agents (cisapride withdrawn due to QTc)

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PART 3 — LAXATIVES

Classification & Mechanisms

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BULK-FORMING LAXATIVES

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STOOL SURFACTANT AGENTS (SOFTENERS)

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OSMOTIC LAXATIVES

1. Balanced Polyethylene Glycol (PEG, e.g., MiraLax, GoLYTELY):
   • Large polymer; not absorbed; osmotically retains water in lumen
   • PEG + electrolytes (GoLYTELY): iso-osmotic bowel prep for colonoscopy — no fluid/electrolyte shift
   • MiraLax (PEG 3350): daily constipation treatment
   • Safest osmotic laxative; no electrolyte disturbance
2. Lactulose: Synthetic disaccharide; not absorbed; fermented by colonic bacteria → acidifies colon → traps NH₃ as NH₄⁺ → also used for hepatic encephalopathy; SE: bloating, cramping, flatulence
3. Magnesium salts (Mg hydroxide, Mg citrate): osmotic + direct stimulation of CCK; rapid onset (1–3 h); avoid in renal failure
4. Sodium phosphate: rapid bowel prep; risk of acute phosphate nephropathy — avoid in elderly, renal disease
5. Sorbitol: cheap osmotic; fermented → flatulence

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STIMULANT LAXATIVES

• Directly stimulate myenteric plexus → ↑peristalsis
• Inhibit colonic Na⁺/K⁺-ATPase → ↑fluid secretion (electrogenic secretion)
• Some irritate colonic mucosa

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CHLORIDE SECRETION ACTIVATORS

• Activates ClC-2 chloride channels on apical enterocytes → Cl⁻ secretion → water follows → softens stool
• Uses: Chronic idiopathic constipation, IBS-C, opioid-induced constipation
• SE: Nausea (most common), headache, diarrhea; avoid in pregnancy (fetal loss in animals)

• Guanylate cyclase-C (GC-C) agonists → ↑cGMP → ↑Cl⁻ and HCO₃⁻ secretion (via CFTR) → ↑luminal fluid
• Also reduce visceral pain (cGMP reduces afferent nerve sensitivity)
• Uses: IBS-C, chronic constipation
• SE: Diarrhea (black box warning: severe in children <6 years)

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OPIOID RECEPTOR ANTAGONISTS (for Opioid-Induced Constipation)

• Peripherally-acting μ-opioid receptor antagonists (PAMORAs)
• Block opioid effects in GI tract without crossing BBB → reverse constipation without reversing analgesia
• Uses: Opioid-induced constipation in patients on chronic opioid therapy

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OPIOID AGONISTS (Antidiarrheal)

• μ-opioid agonist in GI; minimal CNS penetration → no abuse potential
• ↓GI motility, ↓secretion, ↑anal sphincter tone
• Uses: Acute diarrhea, traveler's diarrhea, chronic diarrhea (IBD, ileostomy)
• Does not cross BBB in therapeutic doses

• μ-opioid agonist (similar to loperamide but some CNS penetration)
• Combined with atropine (low dose) to discourage abuse
• Schedule V controlled substance

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PART 4 — BILE SALT-BINDING RESINS (for Diarrhea)

• Anion-exchange resins; bind bile acids in gut → prevent reabsorption
• Also bind Clostridium difficile toxins (cholestyramine)
• Uses: Bile acid malabsorption diarrhea (post-cholecystectomy, Crohn's ileal disease), hypercholesterolemia (primary)
• SE: Constipation, bloating; bind many drugs (warfarin, digoxin, levothyroxine, fat-soluble vitamins) — separate all medications by 1–4 hours

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PART 5 — OCTREOTIDE

• Variceal hemorrhage (↓portal pressure — see Part 9)
• Carcinoid tumors / VIPoma (controls flushing and diarrhea)
• Acromegaly
• Dumping syndrome
• Secretory diarrheas (VIPoma, short bowel syndrome)

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PART 6 — DRUGS FOR IRRITABLE BOWEL SYNDROME (IBS)

ANTISPASMODICS (ANTICHOLINERGICS)

• M₁/M₃ antagonists → ↓GI smooth muscle contraction → ↓cramping/spasm
• Uses: IBS (abdominal pain/cramping), especially IBS-D or mixed
• SE: Anticholinergic — dry mouth, constipation, urinary retention, blurred vision, tachycardia

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CHLORIDE CHANNEL ACTIVATORS (Lubiprostone, Linaclotide — see above for IBS-C)

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Additional IBS-D Agents:

• Selective 5-HT₃ antagonist in gut → slows colonic transit, ↓visceral pain
• Approved only for women with severe IBS-D
• Ischemic colitis and severe constipation risk → restricted prescribing program

• Reduces IBS-D by ↓secretion and ↓motility
• Contraindicated if no gallbladder (risk of sphincter of Oddi spasm → pancreatitis)

• Non-absorbed antibiotic (rifamycin derivative)
• Alters gut microbiome → reduces gas production and IBS symptoms
• 2-week course for IBS-D; also used in traveler's diarrhea, hepatic encephalopathy

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PART 7 — ANTIEMETIC AGENTS

SEROTONIN 5-HT₃ ANTAGONISTS

• Block 5-HT₃ receptors in CTZ (chemoreceptor trigger zone) and on peripheral vagal afferents
• Most effective for chemotherapy-induced and postoperative nausea/vomiting
• Less effective for motion sickness (not vagally mediated)

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CORTICOSTEROIDS

• Mechanism of antiemetic action: unclear (may inhibit prostaglandins, ↑serotonin turnover, reduce CNS edema)
• Excellent synergy with 5-HT₃ antagonists and NK₁ antagonists for CINV
• Also for acute nausea in cancer patients; reduces chemotherapy-related inflammation

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NEUROKININ (NK₁) RECEPTOR ANTAGONISTS

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ANTIPSYCHOTICS AS ANTIEMETICS (PHENOTHIAZINES, BUTYROPHENONES, THIENOBENZODIAZEPINES)

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SUBSTITUTED BENZAMIDES

• D₂ antagonist in CTZ + gut; 5-HT₄ agonist
• Standard antiemetic for CINV, gastroparesis
• Tardive dyskinesia risk (black box)

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H₁ ANTIHISTAMINES & ANTICHOLINERGIC DRUGS

• Motion sickness (best indication — vestibular-mediated)
• Pregnancy nausea (doxylamine + B₆ — Diclegis; first-line safe)
• Vertigo, labyrinthitis

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CANNABINOIDS

• CB₁ receptor agonists in vomiting center and GI tract → ↓nausea/emesis
• Uses: Refractory CINV (second/third-line); anorexia/cachexia in AIDS
• SE: Dysphoria, sedation, orthostatic hypotension, dizziness; euphoria/abuse potential

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PART 8 — DRUGS FOR INFLAMMATORY BOWEL DISEASE (IBD)

AMINOSALICYLATES (5-ASA)

• 5-aminosalicylic acid (5-ASA) — active moiety; topical anti-inflammatory
• Inhibits prostaglandin and leukotriene synthesis in colonic mucosa; scavenges free radicals; inhibits NF-κB
• Sulfasalazine = 5-ASA + sulfapyridine (carrier); sulfapyridine cleaved by colonic bacteria; responsible for most SE

• Sulfasalazine → colon only
• Mesalamine → various formulations: enema/suppository (rectal/sigmoid), delayed-release tablets (ileum/colon), controlled-release capsules (throughout intestine)

• Sulfasalazine: nausea, headache, oligospermia (reversible), hemolytic anemia (G6PD), folate deficiency (supplement needed), rash; sulfonamide allergy cross-reactivity
• Mesalamine: rare interstitial nephritis (monitor renal function), headache, diarrhea

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GLUCOCORTICOIDS

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PURINE ANALOGS: AZATHIOPRINE (AZA) & 6-MERCAPTOPURINE (6-MP)

• AZA → converted to 6-MP → converted to 6-thioguanine nucleotides (6-TGN) → incorporate into DNA → ↓lymphocyte proliferation (inhibit purine synthesis)
• Immunosuppressive — reduce T and B cell activity

• Myelosuppression (monitor CBC) — dose-related; related to TPMT enzyme activity (test TPMT before starting)
• Hepatotoxicity
• Pancreatitis (AZA-specific, idiosyncratic, early)
• Lymphoma risk (especially with combination immunosuppression)
• Opportunistic infections
• Drug interaction: Allopurinol blocks xanthine oxidase → dramatically ↑6-MP levels → reduce dose by 75%

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ANTI-TUMOR NECROSIS FACTOR (Anti-TNF) THERAPY

• Moderate-severe Crohn's disease and ulcerative colitis
• Induction and maintenance of remission
• Fistulizing Crohn's (infliximab)

• Reactivation of latent TB (mandatory TB screening before use — PPD/IGRA)
• Reactivation of HBV (screen all patients)
• Serious infections (pneumonia, fungal, opportunistic)
• Demyelinating disease (multiple sclerosis risk)
• Lymphoma (NHL)
• Drug-induced lupus
• Injection/infusion reactions
• Heart failure exacerbation (avoid in NYHA III-IV)

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ANTI-INTEGRIN THERAPY

• Monoclonal Ab against α₄β₇ integrin → blocks lymphocyte trafficking to gut mucosa (MAdCAM-1 on gut endothelium)
• Gut-selective immunosuppression → no systemic immunosuppression → safer infection/lymphoma profile than anti-TNF
• Uses: Moderate-severe UC and Crohn's (biologic-naive or anti-TNF failure)
• SE: Nasopharyngitis, headache, arthralgia; very rare PML (unlike natalizumab which blocks α₄)

• Blocks α₄ integrin (brain + gut) → Risk of PML (progressive multifocal leukoencephalopathy) due to JC virus reactivation
• Now rarely used in Crohn's; replaced by vedolizumab

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ANTI-IL-23 THERAPY

• Blocks p40 subunit shared by IL-12 and IL-23 → ↓Th1 and Th17 responses
• Uses: Moderate-severe Crohn's and UC

• Block only IL-23 (p19 subunit) → more selective
• Newer approvals for UC and Crohn's

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JANUS KINASE (JAK) INHIBITORS

• Infections (herpes zoster — prophylactic vaccination recommended)
• Lipid elevation, thrombosis (DVT/PE) — especially tofacitinib at higher doses
• MACE (cardiovascular events) — FDA black box warning
• Lymphoma, serious infections
• Avoid in high cardiovascular risk patients

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SPHINGOSINE-1-PHOSPHATE (S1P) RECEPTOR MODULATOR

• S1P1/5 receptor agonist → sequesters lymphocytes in lymph nodes → prevents trafficking to gut
• Oral; used in UC
• SE: Bradycardia (first dose), increased infection risk, hepatotoxicity, teratogenic; require ECG before starting

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PANCREATIC ENZYME SUPPLEMENTS

• Mixture of lipase, protease, amylase from porcine pancreas
• Uses: Exocrine pancreatic insufficiency (EPI) — chronic pancreatitis, cystic fibrosis, pancreatic cancer, pancreatectomy
• Must be taken with meals; enteric-coated to prevent gastric acid degradation
• Dose titrated to lipase units (3,000–10,000 lipase units/kg/day)
• SE: GI upset; high doses in CF → fibrosing colonopathy; hyperuricosuria (uric acid from purines in pancreatin)

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GLP-2 ANALOG — TEDUGLUTIDE (for Short-Bowel Syndrome)

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BILE ACID AGENTS

• Replaces hydrophobic bile acids; stabilizes hepatocyte membranes; immunomodulatory
• Uses: Primary biliary cholangitis (PBC), gallstone dissolution, primary sclerosing cholangitis (controversial)
• SE: Diarrhea, GI upset

• FXR (farnesoid X receptor) agonist → ↓bile acid synthesis; anti-fibrotic
• Uses: PBC (second-line with UDCA)
• SE: Pruritus (most common), fatigue

• Bile acid sequestrants — bind bile acids → ↑fecal excretion → ↑hepatic LDL uptake
• Also used for cholestatic pruritus (reduce bile acid pool)

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PART 9 — DRUGS FOR VARICEAL HEMORRHAGE

SOMATOSTATIN & OCTREOTIDE

• Also ↓glucagon secretion (glucagon is a splanchnic vasodilator)
• Somatostatin: t½ = 2 min (IV infusion only)
• Octreotide: t½ ~2 h (SC or IV infusion); preferred

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VASOPRESSIN & TERLIPRESSIN

• V₁ receptor agonist → powerful splanchnic vasoconstriction → ↓portal blood flow → ↓variceal pressure
• Very effective but dangerous: causes systemic vasoconstriction → angina, MI, limb ischemia, arrhythmia
• Must combine with nitroglycerin (to reduce systemic effects while preserving portal effects)
• Short t½; IV infusion only

• Prodrug of vasopressin with longer t½ (4–6 h); more V₁ selective; fewer systemic SE
• Approved in Europe; used in variceal bleeding and hepatorenal syndrome (HRS) type 1 (increases renal perfusion by ↓splanchnic vasodilation)

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BETA-RECEPTOR-BLOCKING DRUGS (Portal Hypertension Prophylaxis)

• β₁ blockade → ↓cardiac output → ↓portal blood flow
• β₂ blockade → splanchnic vasoconstriction (unopposed α effect) → ↓portal inflow
• Net effect: ↓portal venous pressure by 20–25%
• Carvedilol: also α₁ blockade → ↓hepatic vascular resistance (greatest portal pressure reduction)

• Primary prophylaxis of first variceal bleed (large varices at endoscopy)
• Secondary prophylaxis of revariceal bleeding (alongside repeat endoscopic banding)
• Prevention of complications of portal hypertension

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MASTER QUICK-REFERENCE TABLE