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Antihistamines - Complete Pharmacology

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1. Definition

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2. Classification

By Receptor Type

H1 Antagonists by Generation

• Loratadine, desloratadine
• Cetirizine, levocetirizine
• Fexofenadine
• Azelastine (also available as nasal spray/eye drops)
• Bilastine, rupatadine

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3. Pharmacodynamics (Mechanism of Action)

Chemistry and Receptor Binding

Effects on Physiological Systems

• H1 blockers inhibit histamine-induced bronchoconstriction and constriction of GI/uterine smooth muscle
• They block the rapid vasodilator effects mediated by H1 receptors on endothelial cells (via NO release)
• They also inhibit venous constriction in certain vascular beds

• H1 blockers strongly suppress histamine-induced edema, wheal formation, and increased capillary permeability

• Reduce the flare (axon reflex) and pruritus caused by histamine
• Cutaneous pruritus (itching) is the response most readily suppressed

• H1 receptors mediate wakefulness; blockade produces sedation, drowsiness
• At higher doses: ataxia, blurred vision, tinnitus, restlessness, paradoxical CNS excitation (especially in children)
• Antiemetic effect (especially promethazine, dimenhydrinate) via central vestibular/CTZ blockade

• Bind muscarinic receptors - causing dry mouth, urinary retention, constipation, blurred vision, tachycardia

• Some (especially terfenadine and astemizole - now withdrawn) can block cardiac hERG K⁺ channels → QT prolongation → risk of torsades de pointes

• Uniquely has potent antihistamine AND serotonin 5-HT2 receptor antagonist properties, used as an appetite stimulant

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4. Pharmacokinetics

First Generation H1 Antagonists

Second Generation H1 Antagonists

H2 Antagonists (Cimetidine, Famotidine, Ranitidine)

• Oral bioavailability 40-90%; cimetidine is a potent CYP450 inhibitor (important drug interaction)
• Primarily renally excreted; dose adjustment needed in renal impairment
• Duration of action 6-12 hours (famotidine longest)

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5. Indications (Clinical Uses)

H1 Antagonists

• Allergic rhinitis (seasonal and perennial) - first-line: 2nd generation preferred
• Urticaria (hives) and angioedema - acute and chronic
• Atopic dermatitis / eczema - adjunct for pruritus
• Allergic conjunctivitis - topical azelastine/olopatadine
• Anaphylaxis - adjunct to epinephrine (not first-line alone)
• Drug/food hypersensitivity reactions

• Motion sickness - dimenhydrinate, meclizine, cyclizine
• Nausea and vomiting (antiemetic) - promethazine
• Vertigo - meclizine
• Insomnia (OTC sleep aids) - diphenhydramine, doxylamine
• Preanesthetic medication / sedation - promethazine, hydroxyzine

• Appetite stimulation - cyproheptadine
• Pruritus in cholestasis or uremia
• Common cold (decongestant combinations)
• Transfusion reactions (prophylaxis)
• Prevention of contrast media reactions
• Urticaria pigmentosa (mastocytosis) - H1 + H2 combination

H2 Antagonists

• Peptic ulcer disease (duodenal and gastric)
• Gastroesophageal reflux disease (GERD)
• Zollinger-Ellison syndrome
• Stress ulcer prophylaxis in ICU
• In combination with H1 blockers for refractory urticaria and anaphylaxis

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6. Contraindications

Absolute/Relative Contraindications

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7. Adverse Effects

First-Generation H1 Antihistamines

• Sedation, drowsiness (most common) - impairs driving, operating machinery
• Dizziness, ataxia, incoordination
• Blurred vision, tinnitus
• Paradoxical excitation in children (restlessness, insomnia, tremors, convulsions)
• Confusion and delirium in elderly (particularly high anticholinergic burden)

• Dry mouth, throat, nasal passages
• Constipation
• Urinary retention
• Blurred vision (cycloplegia/mydriasis)
• Tachycardia
• Decreased GI motility

• QT prolongation (most notably with terfenadine and astemizole - both withdrawn from markets)
• Hypotension (especially IV promethazine)

• Nausea, vomiting, anorexia, epigastric distress
• Diarrhea or constipation

• Photosensitivity (especially phenothiazines like promethazine)
• Paradoxical hypersensitivity reactions
• Hemolytic anemia, agranulocytosis (rare)
• Teratogenicity concern in first trimester (category B generally, but caution advised)

Second-Generation H1 Antihistamines

• Mild headache, fatigue (cetirizine has slightly more sedation than others)
• Dry mouth (mild)
• Rare: QT prolongation (noted with high doses of some agents)
• Weight gain with long-term use (minor)

H2 Antagonists

• Cimetidine: multiple CYP450 drug interactions, gynecomastia, impotence, confusion in elderly (crosses BBB)
• Ranitidine: withdrawn in many countries due to NDMA impurity concerns
• Famotidine: generally well-tolerated; headache, dizziness, constipation
• Thrombocytopenia (rare, class effect)
• Elevated liver enzymes (rare)

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8. Side Effects (Summary by System)

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Key Clinical Pearls

1. 1st gen vs 2nd gen: First-generation agents sedate because they are lipophilic and penetrate the CNS; second-generation agents (fexofenadine, loratadine, desloratadine) are peripheral-selective and essentially non-sedating.
2. Inverse agonism: Antihistamines are inverse agonists, not neutral antagonists - they actively reduce receptor activity below baseline.
3. Tachyphylaxis: Tolerance to the antiallergic effects can develop with continued use, particularly notable with first-generation agents.
4. Elderly caution: First-generation antihistamines are on the Beers Criteria as potentially inappropriate medications in older adults due to anticholinergic CNS toxicity risk.
5. Allergy skin testing: Oral H1 antihistamines must be stopped 2-7 days before skin prick testing to avoid false-negative results.
6. Cyproheptadine is unique - it acts as both an H1 blocker and a 5-HT2 antagonist, making it useful for conditions like serotonin syndrome, carcinoid-related flushing, and appetite stimulation.

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• Goodman & Gilman's The Pharmacological Basis of Therapeutics, Chapter 43 (Histamine, Bradykinin, and Their Antagonists)
• Tietz Textbook of Laboratory Medicine, 7th Edition - Antihistamines section
• Kaplan and Sadock's Synopsis of Psychiatry - Histamine Antagonists section

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Oral Contraceptive Pills (OCPs) - Complete Pharmacology

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1. Definition

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2. Classification

A. By Hormonal Composition

1. Combined Oral Contraceptive Pills (COCPs)

• Biphasic: Norethindrone dose changes once
• Triphasic: Ethinyl estradiol and/or progestin dose changes twice (e.g., Ortho Tri-Cyclen, Trivora, Tri-Sprintec)

2. Progestin-Only Pills (POPs / "Mini-pill")

• Contain only a progestin; no estrogen
• Norethindrone 0.35 mg (traditional) or Drospirenone 4 mg (newer, Slynd)
• Taken continuously, every day at the same time (no pill-free interval)
• Must be taken within a strict 3-hour window daily
• Used when estrogen is contraindicated

B. By Progestin Generation

C. By Cycle Regimen

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3. Pharmacodynamics (Mechanism of Action)

Primary Mechanism - Ovulation Inhibition

• Estrogen suppresses FSH release → prevents follicular development and the FSH-dependent growth of the dominant follicle
• Progestin suppresses the midcycle LH surge → prevents ovulation
• Together they maintain a negative feedback on the hypothalamus and anterior pituitary, preventing GnRH pulsatility and thus LH/FSH secretion

• No follicular maturation
• No dominant follicle selection
• No LH surge
• No ovulation

Secondary Mechanisms (especially important for progestin-only pills)

1. Cervical mucus thickening - Progestin makes cervical mucus thick, viscous, and scanty (similar to post-ovulation mucus), which impedes sperm penetration
2. Endometrial changes - Glandular atrophy and stromal decidualization make the endometrium inhospitable to implantation
3. Tubal motility - Altered secretion and motility in fallopian tubes reduces likelihood of fertilization

For progestin-only pills, continuous progestin does NOT reliably inhibit ovulation in all women, so cervical mucus and endometrial effects become the primary mechanisms.

Pharmacodynamic Effects by Organ System

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4. Pharmacokinetics

Estrogen Component (Ethinyl Estradiol - EE)

Progestin Component

Drug Interactions Affecting Pharmacokinetics

1. Enzyme inducers (rifampin, phenytoin, carbamazepine, phenobarbital, St. John's Wort) - Increase hepatic CYP3A4 activity → accelerated estrogen/progestin metabolism → reduced efficacy → breakthrough bleeding and contraceptive failure
2. Antibiotics (ampicillin, tetracycline) - Disrupt gut flora → reduce enterohepatic recycling of EE → reduced efficacy
3. Fosamprenavir (antiretroviral) - Coadministration decreases contraceptive effectiveness
4. Drospirenone - Mild CYP3A4 substrate; can raise serum potassium (antimineralocorticoid activity) when combined with K⁺-sparing drugs

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5. Indications (Clinical Uses)

Primary Indication

• Contraception - Prevention of pregnancy (most common use worldwide)

Non-Contraceptive Indications

Cancer Prevention Benefits

• Reduces risk of endometrial cancer by ~50% (with 1 year of use; benefit persists 20 years after stopping)
• Reduces risk of epithelial ovarian cancer by 40-60% (related to duration; persists ≥20 years)
• Reduces risk of colorectal cancer by approximately 20%
• Does NOT increase risk of liver cancer, melanoma, or prolactin-secreting pituitary adenomas - Goldman-Cecil Medicine

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6. Contraindications

WHO Medical Eligibility Criteria Category 4 (Absolute Contraindications)

WHO Category 3 (Relative Contraindications - risks usually outweigh benefits)

• Age ≥35 + smoking <15 cigarettes/day
• Controlled hypertension (140-159/90-99 mmHg) | Multiple cardiovascular risk factors
• Gallbladder disease
• BMI ≥30 kg/m² (obesity)
• Postpartum 21-42 days (non-breastfeeding)
• Migraines without aura (current use, age ≥35)
• Enzyme-inducing drug therapy

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7. Adverse Effects

A. Cardiovascular (Most Clinically Significant)

• Venous thromboembolism (VTE) - 3-4x increased risk; due to estrogen-induced increased synthesis of clotting factors (II, VII, IX, X, fibrinogen) and decreased antithrombin III; risk highest with 3rd-generation progestins (desogestrel, gestodene) vs. 2nd-generation (levonorgestrel)
• Arterial thrombosis - Increased risk of MI and ischemic stroke, particularly in smokers, hypertensives, and migraine-with-aura patients
• Hypertension - Estrogen increases renin substrate (angiotensinogen) → elevated blood pressure in susceptible women
• QT prolongation - Minor risk with certain formulations

B. Metabolic Effects

• Carbohydrate metabolism - Reduced glucose tolerance; insulin resistance; diabetic patients require monitoring
• Lipid metabolism - Estrogen raises HDL and triglycerides; progestins (especially androgenic ones like levonorgestrel) lower HDL and raise LDL; 3rd/4th gen progestins have more favorable lipid profiles
• Weight gain - Typically 1-2 kg; mostly fluid retention from estrogen; androgenic progestins may cause greater weight gain

C. Hepatic Effects

• Cholestatic jaundice (especially in women with prior intrahepatic cholestasis of pregnancy)
• Elevated liver enzymes
• Benign hepatocellular adenoma (rare, dose-related with high-estrogen older formulations; current low-dose OCPs do not increase this risk)
• Reduced biliary cholesterol solubility → increased gallstone risk (gallbladder disease)
• Impaired drug metabolism due to enzyme inhibition

D. CNS and Psychiatric Effects

• Headache (most common complaint)
• Mood changes, depression, anxiety, decreased libido
• Nausea (especially in early cycles; take with food)
• Increased risk of ischemic stroke (especially with migraine + aura)
• Rarely: chorea, benign intracranial hypertension (with implants)

E. Menstrual / Gynecological Effects

• Breakthrough bleeding or spotting (especially in first 3 months)
• Amenorrhea (post-pill amenorrhea; ~2% persistent >1 year)
• Breast tenderness and enlargement
• Changes in vaginal discharge
• Decreased menstrual flow / oligomenorrhea (often desired)

F. Endocrine Effects

• Decreased libido (from raised SHBG binding free testosterone)
• Suppressed ovarian function
• Altered thyroid function tests (raised TBG → raised total T4, but free T4 normal)
• Altered cortisol-binding globulin levels

G. Possible Cancer Risk

• Breast cancer - Modest increase in risk of current or recent (within 5-10 years) users, particularly under age 35; risk returns to baseline after stopping
• Cervical cancer - Possible small increased risk with prolonged use (though this may relate to sexual behavior and HPV exposure)

H. Other

• Chloasma (facial hyperpigmentation/"mask of pregnancy") - estrogen + sun exposure
• Contact lens intolerance (corneal edema)
• Drug interactions: enzyme inducers reduce efficacy; antibiotics may reduce enterohepatic recycling

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8. Side Effects (Summary Table)

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9. Key Clinical Pearls

1. Missed pill rule: Take missed pill as soon as remembered; if 2+ pills missed in week 3, skip the hormone-free interval and start new pack immediately; use backup contraception for 7 days. - Goldman-Cecil
2. Return of fertility: 75% ovulate in first post-pill cycle, 97% by the third cycle. This is not permanent infertility.
3. Progestin-only for estrogen contraindications: Use POPs in breastfeeding mothers, smokers >35 years, women with hypertension, migraines, VTE history, or liver disease.
4. Drospirenone caution: Has antimineralocorticoid activity (like spironolactone) - can raise serum potassium. Monitor K⁺ when combined with ACE inhibitors, ARBs, NSAIDs, or potassium-sparing diuretics.
5. "ACHES" mnemonic for warning signs requiring immediate discontinuation:
   • A - Abdominal pain (severe) → thrombosis/liver adenoma
   • C - Chest pain or shortness of breath → pulmonary embolism/MI
   • H - Headache (severe) → stroke/hypertension
   • E - Eye changes (vision loss, diplopia) → vascular occlusion
   • S - Severe leg pain/swelling → DVT
6. No pelvic exam required before prescribing: If no contraindications, OCPs can be prescribed via telemedicine without a pelvic or breast exam. - Goldman-Cecil Medicine
7. Starting OCPs: Starting on day of visit ("quick start") is associated with better long-term adherence.

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• Katzung's Basic and Clinical Pharmacology, 16th Edition, Chapter 40 (Gonadal Hormones & Inhibitors)
• Goldman-Cecil Medicine, Chapter 220 (Hormonal Contraception)
• Goodman & Gilman's The Pharmacological Basis of Therapeutics (Estrogens, Progestins, and Hormonal Contraception)

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Uterotonic Drugs - Complete Pharmacology

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1. Definition

• Induction and augmentation of labor
• Prevention and treatment of postpartum hemorrhage (PPH)
• Management of incomplete or missed abortion
• Active management of the third stage of labor

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2. Classification

A. Oxytocin and Analogs

B. Ergot Alkaloids

C. Prostaglandins

D. Other Agents

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3. Pharmacodynamics (Mechanism of Action)

Physiological Background

1. Increase intracellular Ca²⁺ via G-protein-coupled receptor activation (oxytocin, ergot, PGF2α)
2. Stimulate specific receptors that activate phospholipase C (PLC) → IP₃ → Ca²⁺ release from sarcoplasmic reticulum

A. Oxytocin

• Binds specific oxytocin receptors (OXTR) on myometrial cells - G-protein-coupled receptors (Gq/11)
• Activates PLC → generates IP₃ and DAG → IP₃ releases Ca²⁺ from the sarcoplasmic reticulum + DAG activates protein kinase C
• Elevated intracellular Ca²⁺ → MLCK activation → myosin phosphorylation → uterine contraction
• Also enhances gap junction formation between myometrial cells (coordinating contractions)
• Oxytocin receptor density in the myometrium increases dramatically throughout pregnancy and reaches maximum at term - this explains why uterine sensitivity to oxytocin is highest at term
• At low doses: increases frequency and force of contractions with normal relaxation between them
• At high doses: sustained tetanic contractions, vasodilation → hypotension, reflex tachycardia
• Also stimulates milk ejection (let-down reflex) by contracting myoepithelial cells in the breast

B. Ergot Alkaloids (Methylergonovine / Ergometrine)

• Act as partial agonists at α-adrenergic receptors and serotonin (5-HT2) receptors in the myometrium
• Also have partial agonist/antagonist activity at dopamine receptors
• Produce sustained, prolonged tetanic contractions of the entire uterus, including the lower uterine segment - this pattern differs from oxytocin which produces rhythmic coordinated contractions
• α-adrenoceptor stimulation in blood vessels → vasoconstriction → important adverse cardiovascular effect
• The sustained tonic contraction compresses uterine blood vessels, producing hemostasis (mechanically stops bleeding)

C. Prostaglandins

• Binds FP receptors (G-protein-coupled) on myometrial cells → Gq/11 pathway → PLC → IP₃ → Ca²⁺ → contraction
• Produces strong, coordinated uterine contractions
• Also stimulates GI smooth muscle → nausea, vomiting, diarrhea
• Constricts pulmonary and bronchial smooth muscle → bronchoconstriction (important in asthma)

• Binds EP receptors (EP1, EP3 are contractile; EP2, EP4 are relaxant)
• Primarily acts via EP1/EP3 at term → uterine contraction
• Also directly remodels cervical collagen (increases proteoglycan content, alters collagen structure) → cervical ripening/softening independent of its contractile effect
• Metabolized ~95% on first pass through the lungs; plasma half-life 2.5-5 minutes

• Binds EP receptors on myometrium → uterine contractions
• Stable, acid-resistant, orally bioavailable (unlike natural PGE1)
• Also stimulates GI motility, relaxes bronchial smooth muscle (unlike PGF2α)
• Additionally causes cervical softening

Molecular Summary: All Uterotonic Pathways

Oxytocin → OXTR (Gq/11) → PLC → IP₃ → ↑Ca²⁺ → MLCK → contraction
Ergot → α-AR + 5-HT2 → ↑Ca²⁺ → sustained tetanic contraction
PGF2α → FP receptor (Gq/11) → PLC → IP₃ → ↑Ca²⁺ → contraction
PGE2/E1 → EP1/EP3 receptor → ↑Ca²⁺ → contraction + cervical ripening

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4. Pharmacokinetics

A. Oxytocin

B. Ergot Alkaloids (Methylergonovine)

C. Carboprost Tromethamine (15-methyl-PGF2α)

D. Dinoprostone (PGE2)

E. Misoprostol (PGE1 analog)

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5. Indications (Clinical Uses)

A. Oxytocin

1. Induction of labor - Primary drug of choice; IV infusion starting at 6 mIU/min, titrating upward
2. Augmentation of dysfunctional labor (hypotonic uterine inertia)
3. Active management of third stage of labor - 10 units IM or 5 units IV slow injection immediately after delivery to prevent PPH
4. Treatment of PPH due to uterine atony - First-line agent (20-40 units in 1L crystalloid, IV infusion)
5. Induction of abortion (high-dose regimens)
6. To promote milk let-down (nasal spray, rarely used now)

B. Ergot Alkaloids (Methylergonovine / Ergometrine)

1. Prevention and treatment of PPH - Second-line after oxytocin failure
2. Subinvolution of the uterus (prolonged postpartum uterine atony)
3. Incomplete/threatened abortion with hemorrhage
4. Active management of third stage of labor (as part of Syntometrine - combined with oxytocin)

C. Carboprost (15-methyl-PGF2α)

1. PPH refractory to oxytocin and ergot alkaloids - 0.25 mg IM, can repeat every 15-90 minutes; maximum 2 mg total
2. Second-trimester abortion (weeks 13-20)
3. Induction of labor at term (if oxytocin fails)

D. Dinoprostone (PGE2)

1. Cervical ripening before induction of labor (at or near term)
2. Induction of labor (when cervix is unfavorable)
3. Second-trimester abortion (20-mg suppository every 3-5 hours)
4. Missed abortion and benign hydatidiform mole evacuation
5. Intrauterine fetal death management

E. Misoprostol (PGE1 analog)

1. Prevention of PPH - 600 mcg PO or 800-1000 mcg PR at delivery (especially in low-resource settings where injectable uterotonics unavailable)
2. Treatment of PPH - 800-1000 mcg PR/SL
3. Medical abortion (with mifepristone) - up to 70 days gestation
4. Cervical ripening for labor induction
5. Second-trimester abortion
6. Missed or incomplete abortion
7. Gastric ulcer prevention (with NSAIDs - a separate indication exploiting its GI cytoprotective effects)

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6. Contraindications

A. Oxytocin

B. Ergot Alkaloids (Methylergonovine)

C. Carboprost (PGF2α analog)

D. Dinoprostone (PGE2) / Misoprostol

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7. Adverse Effects

A. Oxytocin

B. Ergot Alkaloids (Methylergonovine)

C. Carboprost (15-methyl-PGF2α)

D. Dinoprostone (PGE2)

E. Misoprostol

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8. Side Effects Summary Table

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9. Clinical Step-Up Protocol for PPH (Uterotonic Use in Practice)

STEP 1 (First-line): Oxytocin 20-40 units IV infusion
         ↓ (if inadequate response)
STEP 2 (Second-line): Methylergonovine 0.2 mg IM
         OR Carboprost 0.25 mg IM (repeat q15 min, max 2 mg)
         OR Misoprostol 800-1000 mcg PR
         ↓ (if still refractory)
STEP 3: Surgical intervention (B-Lynch suture, uterine artery ligation, hysterectomy)

• Barash's Clinical Anesthesia, 9th ed.; Roberts & Hedges' Clinical Procedures in Emergency Medicine

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10. Key Clinical Pearls

1. Never give oxytocin as an IV bolus - it causes acute severe hypotension. Always administer as a dilute IV infusion or slow IM injection.
2. Ergot alkaloids are absolutely contraindicated in hypertension (including preeclampsia). They can cause fatal hypertensive crises and coronary vasospasm.
3. Carboprost is contraindicated in asthma - it causes bronchoconstriction and can be fatal in asthmatic patients; misoprostol is the safer alternative in this population.
4. Misoprostol is the preferred uterotonic in low-resource settings due to its oral bioavailability, thermostability (no refrigeration needed), and low cost.
5. Uterine sensitivity to oxytocin increases throughout pregnancy due to progressive upregulation of oxytocin receptors; sensitivity is maximal at term.
6. Water intoxication from oxytocin: Large doses of oxytocin have intrinsic ADH-like antidiuretic activity. If given with large volumes of hypotonic IV fluids, it can cause dilutional hyponatremia, convulsions, and coma.
7. Carbetocin (long-acting oxytocin analog) is used as a single dose (100 mcg IV or 100 mcg IM) for PPH prevention at cesarean delivery - equivalent efficacy to an oxytocin infusion in a single injection.

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• Goodman & Gilman's The Pharmacological Basis of Therapeutics, Chapter 48 (Uterine Smooth Muscle Stimulants and Relaxants)
• Katzung's Basic and Clinical Pharmacology, 16th Edition, Chapters 17 & 40 (Prostaglandins and Reproductive Pharmacology)
• Roberts & Hedges' Clinical Procedures in Emergency Medicine, Chapter 56 (Management of Postpartum Hemorrhage)
• Barash, Cullen & Stoelting's Clinical Anesthesia, 9th Edition, Table 41-5 (Uterotonic Therapy)
• Schwartz's Principles of Surgery, 11th Edition (Obstetric Procedures)

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Anticonvulsant (Antiepileptic) Drugs - Complete Pharmacology

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1. Definition

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2. Classification

A. By Generation / Era of Introduction

First-Generation (Classical) Antiepileptic Drugs

Second-Generation (Newer) Antiepileptic Drugs

Third-Generation (Newest) Drugs

B. By Molecular Mechanism of Action

C. By Seizure Type Efficacy

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3. Pharmacodynamics (Mechanisms of Action)

The Core Problem: Abnormal Neuronal Hyperexcitability

A. Sodium Channel Blockers (Phenytoin, Carbamazepine, Lamotrigine, Valproate)

• Seizure firing requires rapid cycling of Na⁺ channels
• These drugs bind preferentially to the inactivated state of the Na⁺ channel and slow recovery from inactivation (use-dependent or frequency-dependent block)
• At low-frequency (normal) firing: minimal effect - channels recover quickly
• At high-frequency (seizure) firing: channels accumulate in the inactivated state → progressive reduction in available channels → burst firing is selectively suppressed
• Net effect: Normal neuronal firing is unaffected; pathological high-frequency seizure firing is blocked

B. T-Type Calcium Channel Block (Ethosuximide, Valproate)

• Ethosuximide: Selectively blocks T-type Ca²⁺ channels in thalamic neurons → interrupts the thalamocortical 3 Hz spike-wave oscillation that underlies absence seizures
• Valproate: Also blocks T-type Ca²⁺ channels (among multiple mechanisms)
• T-type channels normally mediate the "rebound burst" firing in thalamic pacemaker cells; their blockade prevents the low-threshold Ca²⁺ spike bursts that pace absence rhythms

C. GABA-A Receptor Enhancement (Benzodiazepines, Barbiturates)

• Bind to the benzodiazepine allosteric site on GABA-A receptors (between α and γ subunits)
• Increase the frequency of Cl⁻ channel opening in response to GABA (require GABA to be present)
• Enhance inhibitory tone → raise seizure threshold

• Bind to a different allosteric site on GABA-A receptors (barbiturate site on β subunit)
• Increase the duration of Cl⁻ channel opening in response to GABA
• At high (anesthetic) doses, can activate GABA-A receptors directly (without GABA)
• Also inhibit Na⁺ currents (secondary mechanism)

D. SV2A Synaptic Vesicle Protein (Levetiracetam, Brivaracetam)

• SV2A is a ubiquitous synaptic vesicle glycoprotein involved in vesicle trafficking and neurotransmitter exocytosis
• Levetiracetam and brivaracetam bind SV2A → modulate vesicle priming and presynaptic neurotransmitter release
• The precise link to anti-epileptic action is still being investigated, but they reduce excessive synchronous neuronal activity
• Unique mechanism with no cross-tolerance with other ASD mechanisms

E. α2δ Calcium Channel Subunit (Gabapentin, Pregabalin)

• These drugs are structurally related to GABA but do NOT directly act on GABA receptors
• They bind the α2δ-1 subunit of voltage-gated Ca²⁺ channels (P/Q-type, N-type), reducing Ca²⁺ influx → reduced neurotransmitter release from presynaptic terminals
• Do not affect GABA metabolism or GABA receptor function despite their structural mimicry

F. Valproate - Unique Multi-Target Agent

1. Blocks fast Na⁺ channel inactivation
2. Blocks T-type Ca²⁺ channels
3. Enhances GABA synthesis and reduces GABA degradation (indirectly potentiates GABAergic transmission)
4. Inhibits NMDA receptors (weak)
5. Blocks K⁺ channels
6. Histone deacetylase (HDAC) inhibition → epigenetic effects

G. AMPA Receptor Antagonism (Perampanel)

• AMPA receptors mediate fast excitatory transmission via glutamate
• Perampanel is a selective non-competitive antagonist at AMPA receptors → reduces excitatory neurotransmission → raises seizure threshold

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4. Pharmacokinetics

Key Pharmacokinetic Properties of Major ASDs

Critical Drug Interactions Affecting Pharmacokinetics

• Phenytoin, carbamazepine, phenobarbital, primidone induce CYP1A2, CYP2C, CYP3A4
• Reduce plasma levels of: warfarin, oral contraceptives, other ASDs, cyclosporine, HIV drugs

• Valproate inhibits CYP2C9 and glucuronidation → increases levels of phenobarbital (~40%), lamotrigine (2-3x), phenytoin (variable)
• Felbamate inhibits CYP2C19

• Phenytoin: Nonlinear (zero-order) kinetics at therapeutic doses - extremely important clinically. A small dose increase can cause plasma levels to double, producing toxicity unexpectedly.
• Carbamazepine: Autoinduction - induces CYP3A4 (its own metabolism), so half-life shortens from ~30 hours to ~15 hours over the first 3-4 weeks of therapy. Dose often needs adjustment.
• Levetiracetam: No liver metabolism, no protein binding, no drug interactions - preferred when minimizing interactions is essential.

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5. Indications (Clinical Uses)

A. Epilepsy (Primary Indication)

B. Non-Epileptic (Other) Indications

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6. Contraindications

Drug-Specific Absolute Contraindications

General Contraindications (All or Most ASDs)

• Known hypersensitivity to the drug or its class
• Unmonitored pregnancy without risk/benefit counseling (most ASDs are teratogenic)
• Concurrent use with other CNS depressants (relative) - additive sedation
• Abrupt discontinuation - can precipitate status epilepticus

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7. Adverse Effects

A. Phenytoin

B. Carbamazepine

C. Valproate (Valproic Acid)

D. Phenobarbital

E. Ethosuximide

F. Lamotrigine

G. Levetiracetam

H. Gabapentin / Pregabalin

I. Topiramate

J. Benzodiazepines (Clonazepam, Diazepam, Lorazepam)

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8. Side Effects Summary Table

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9. Teratogenicity - Special Concern

1. Valproate - Highest (neural tube defects 1-2%, fetal valproate syndrome, autism)
2. Phenobarbital (~5.5% malformation rate)
3. Phenytoin (fetal hydantoin syndrome - digits, face, heart)
4. Carbamazepine (spina bifida, hypospadias)
5. Lamotrigine - More favorable profile; oral cleft (small risk)
6. Levetiracetam - Appears most favorable among newer drugs

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10. Key Clinical Pearls

1. Monotherapy first: Start with a single drug; ~50% of patients achieve seizure control with the first agent. Each additional drug adds only marginal benefit but significantly more adverse effects and interactions. - Adams & Victor's
2. Phenytoin's zero-order kinetics: At therapeutic doses, phenytoin metabolism is saturable. A small dose increase (e.g., 25 mg) can cause plasma levels to jump from 15 to 30 µg/mL - producing toxicity. Monitor levels and adjust in small increments.
3. Do not abruptly stop ASDs: Abrupt discontinuation of any ASD - particularly phenobarbital and benzodiazepines - can precipitate status epilepticus, a medical emergency.
4. Valproate + Lamotrigine interaction: Valproate is a potent inhibitor of lamotrigine glucuronidation. Co-administration approximately doubles/triples lamotrigine levels → must reduce lamotrigine dose and titrate slowly → Stevens-Johnson risk.
5. Carbamazepine autoinduction: Warn patients that carbamazepine may reduce its own levels (and oral contraceptive levels!) over the first month. Contraceptive failure is a real risk.
6. Genetic testing: Screen HLA-B*1502 (South/Southeast Asian patients) before starting carbamazepine - positive result predicts very high risk of fatal SJS/TEN.
7. "SAFE" drug for polypharmacy: Levetiracetam - renally excreted, no CYP interactions, no protein binding, no enzyme induction - is the safest choice for complex patients on multiple medications.
8. Enzyme-inducing ASDs (phenytoin, carbamazepine, phenobarbital) can cause contraceptive failure, reduce warfarin efficacy, and interfere with immunosuppressant levels - always review the full medication list.

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• Goodman & Gilman's The Pharmacological Basis of Therapeutics, Chapters 20-23 (Antiseizure Drugs)
• Adams and Victor's Principles of Neurology, 12th Edition, Chapter 15 (The Epilepsies and Convulsive Disorders)
• Katzung's Basic and Clinical Pharmacology, 16th Edition, Chapter 24 (Antiseizure Drugs)
• Morgan & Mikhail's Clinical Anesthesiology, 7th Edition (Antiepileptic Drug Table)

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Comprehensive Comparison of 5 Major Antiepileptic Drugs

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TABLE 1: Basic Identity & Mechanism

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TABLE 2: Pharmacokinetics

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TABLE 3: Seizure Type Indications

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TABLE 4: Contraindications

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TABLE 5: Adverse Effects Profile

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TABLE 6: Drug Interactions Summary

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TABLE 7: Special Populations

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TABLE 8: Key Clinical Pearls - "Unique Features"

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Quick-Reference Summary Card

PHENYTOIN     → Narrow spectrum | Na⁺ block | NONLINEAR kinetics | Gingival hyperplasia | IV cardiac risk | Strong inducer
CARBAMAZEPINE → Focal epilepsy #1 | Na⁺ block | AUTOINDUCTION | SIADH | SJS (Asian patients) | Strong inducer
VALPROATE     → BROADEST spectrum | Multi-target | Weight gain | Hair loss | HEPATOTOXIC | #1 TERATOGEN | Enzyme inhibitor
LAMOTRIGINE   → Broad spectrum | Na⁺ block | Titrate SLOWLY (rash→SJS) | Preferred in women | Levels depend on co-drugs
LEVETIRACETAM → Broad spectrum | SV2A | NO interactions | Renal clearance | Behavioral SE | Safest polypharmacy drug

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Antipsychotic Drugs - Complete Pharmacology

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1. Definition

• Neuroleptic - coined by Deniker, referring to the tendency to cause neurological (extrapyramidal) side effects; now considered misleading since newer drugs treat psychosis without causing these effects
• Major tranquilizer - referred to the sedative "ataraxia" (calmness) effect; also misleading since tranquilization is a side effect, not the primary therapeutic action
• Antipsychotic - the preferred modern term, focusing on the primary therapeutic effect

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2. Classification

A. By Generation (Most Clinically Used System)

First-Generation Antipsychotics (FGAs) - "Typical" / "Conventional"

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Second-Generation Antipsychotics (SGAs) - "Atypical"

B. By Receptor Mechanism

C. Long-Acting Injectable (Depot) Formulations

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3. Pharmacodynamics (Mechanisms of Action)

The Dopamine Hypothesis of Schizophrenia

Four Key Dopamine Pathways and Antipsychotic Effects

Why Are SGAs "Atypical"? - The 5-HT2A/D2 Ratio Hypothesis

• Dopamine release is disinhibited in the nigrostriatum → reduces EPS
• Dopamine release is disinhibited in the prefrontal cortex → may improve negative symptoms and cognition

Aripiprazole - Unique Partial Agonist Mechanism

Additional Receptor Actions (All Antipsychotics)

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4. Pharmacokinetics

General Properties

Individual Drug Pharmacokinetics

Key PK Principles

1. Clozapine and smoking: Cigarette smoking strongly induces CYP1A2 (clozapine's main metabolic enzyme). Smokers need higher doses. When hospitalized patients stop smoking, clozapine levels can surge by 50%, causing toxicity.
2. Depot formulations have pharmacokinetics fundamentally different from oral forms. The ester is slowly hydrolyzed from the injection site, providing steady-state levels with once-every-2-to-4-week dosing. This dramatically improves adherence.
3. Most antipsychotics are CYP2D6 substrates. Poor metabolizers (7-10% of Caucasians) will have significantly higher plasma levels with standard doses.
4. Food effects matter: Ziprasidone must be taken with food (doubles bioavailability); lurasidone must also be taken with food; quetiapine's absorption is not significantly affected.

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5. Indications (Clinical Uses)

Psychiatric Indications

Non-Psychiatric Indications

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6. Contraindications

Absolute Contraindications

Black Box Warnings

Relative Contraindications

• Pregnancy (most are Category C; some fetal risks)
• Breast-feeding (most cross into breast milk)
• Severe hepatic impairment (most are hepatically metabolized)
• History of NMS with any antipsychotic
• Concurrent MAOI use (chlorpromazine)
• Narrow-angle glaucoma (anticholinergic drugs)
• Prostatic hypertrophy (anticholinergic drugs)

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7. Adverse Effects

A. Extrapyramidal Side Effects (EPS) - Nigrostriatal D2 Blockade

1. Acute Dystonia

• Onset: Hours to days after starting or dose increase
• Sustained involuntary muscle contractions - torticollis, oculogyric crisis, opisthotonus, laryngospasm
• More common in young males, high-potency FGAs
• Treatment: Anticholinergics (benztropine, biperiden) IM/IV; diphenhydramine

2. Akathisia

• Onset: Days to weeks
• Intense subjective restlessness; inability to sit still; constant movement
• Often mistaken for anxiety or worsening psychosis (dangerous diagnostic error)
• Treatment: Reduce dose; propranolol; benzodiazepines; switch to lower-EPS drug

3. Drug-Induced Parkinsonism (Pseudo-Parkinsonism)

• Onset: Weeks to months
• Bradykinesia, rigidity, tremor, mask-like facies, shuffling gait
• Caused by D2 blockade in the nigrostriatal pathway
• Treatment: Anticholinergics (benztropine, trihexyphenidyl); amantadine; reduce dose

4. Tardive Dyskinesia (TD)

• Onset: After months to years of therapy (hence "tardive" = late)
• Involuntary rhythmic movements: lip-smacking, tongue-rolling, chewing, facial grimacing, choreoathetoid limb movements
• Proposed mechanism: Chronic D2 blockade → receptor upregulation → dopamine hypersensitivity in nigrostriatum
• May be irreversible even after drug discontinuation
• Incidence: ~5%/year with FGAs; ~0.5-1%/year with SGAs
• Treatment: Valbenazine (VMAT2 inhibitor - FDA approved), deutetrabenazine; switch to clozapine or quetiapine (lowest TD risk); do not use anticholinergics (worsen TD)

B. Neuroleptic Malignant Syndrome (NMS)

• Caused by: D2 blockade in nigrostriatum (rigidity) and hypothalamus (hyperthermia)
• Labs: Elevated CK (rhabdomyolysis), leukocytosis, elevated LFTs, myoglobinuria
• Mortality: 5-20% if untreated
• Treatment: Immediate drug discontinuation; supportive care; dantrolene (direct muscle relaxant); bromocriptine (dopamine agonist); cooling; hydration

C. Metabolic Syndrome (SGAs > FGAs)

• Weight gain - H1 and 5-HT2C blockade → appetite stimulation; olanzapine and clozapine cause most weight gain (up to 10 kg in first year)
• Diabetes mellitus type 2 - Direct antagonism of insulin signaling; weight gain
• Dyslipidemia - Elevated triglycerides, lowered HDL
• Hypertension - Weight-related
• Risk hierarchy (most to least): Clozapine ≈ Olanzapine > Quetiapine > Risperidone > Asenapine > Aripiprazole ≈ Ziprasidone ≈ Lurasidone

D. Cardiovascular Effects

• QT prolongation - Most antipsychotics; ziprasidone and thioridazine carry highest risk; can lead to torsades de pointes and sudden cardiac death
• Orthostatic hypotension - α1-adrenergic blockade; especially low-potency FGAs (chlorpromazine), clozapine, quetiapine
• Myocarditis / Cardiomyopathy - Clozapine specifically (first 4-8 weeks); monitor troponin and ECHO
• Tachycardia - Anticholinergic + α1-blockade; especially clozapine

E. Endocrine / Hormonal Effects

• Hyperprolactinemia - Tuberoinfundibular D2 blockade; most prominent with risperidone, haloperidol, paliperidone
• Consequences: Galactorrhea, amenorrhea, gynecomastia, sexual dysfunction (reduced libido, erectile dysfunction, anorgasmia), decreased bone density
• SGAs with minimal prolactin elevation: Aripiprazole, quetiapine, clozapine (can actually lower prolactin due to partial agonism/loose D2 binding)

F. Hematological Effects

• Agranulocytosis - Most serious with clozapine (~1% incidence; drops to 0.38% with monitoring); also reported rarely with other antipsychotics
• Leukopenia, neutropenia (clozapine)
• Clozapine requires mandatory ANC monitoring (weekly for 6 months, then biweekly for 6 months, then monthly)
• Eosinophilia - May accompany clozapine-induced myocarditis

G. Anticholinergic Effects (Low-Potency FGAs, Clozapine, Olanzapine)

• Dry mouth, urinary retention, constipation, paralytic ileus (severe in clozapine)
• Blurred vision (cycloplegia)
• Tachycardia
• Cognitive impairment - Particularly dangerous in elderly (worsens dementia)
• Hyperthermia (decreased sweating)

H. CNS Effects

• Sedation - H1 blockade; most pronounced with clozapine, olanzapine, quetiapine
• Lowered seizure threshold - Clozapine (dose-dependent; highest seizure risk; ~5% at doses >600 mg/day); chlorpromazine also
• Cognitive blunting
• Depression (particularly with FGAs in some patients)
• Suicidal ideation warning

I. Ophthalmologic Effects

• Thioridazine: Pigmentary retinopathy (irreversible; dose-related; limits long-term use)
• Chlorpromazine: Corneal and lens deposits (long-term, high dose)
• Quetiapine: Cataracts (initial concern from animal studies; less clear in humans)

J. Hypersensitivity / Skin Reactions

• Photosensitivity (particularly chlorpromazine) - Skin turns blue-grey in sun-exposed areas with prolonged use
• DRESS syndrome (rare)
• Contact dermatitis (nursing staff handling phenothiazines)
• Obstructive jaundice - Cholestatic hepatitis with phenothiazines (rare, early in therapy)

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8. Side Effects Summary Table

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9. Monitoring Parameters

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10. Key Clinical Pearls

1. D2 occupancy sweet spot: Antipsychotic efficacy requires 60-80% D2 receptor occupancy. Going above 80% dramatically increases EPS risk without additional benefit.
2. Clozapine is the only proven treatment for treatment-resistant schizophrenia (defined as failure of 2 adequate antipsychotic trials). It also reduces suicidality in schizophrenia (only drug with this indication). Despite its risks, it is underutilized.
3. Elderly dementia patients: ALL antipsychotics carry an FDA Black Box Warning for increased mortality (roughly 1.6-1.7x higher) in elderly patients with dementia-related psychosis - primarily from cardiovascular events and infections. Use with great caution and only when benefits clearly outweigh risks.
4. Never treat akathisia with increased antipsychotic dose: The restlessness of akathisia is frequently mistaken for worsening psychosis and may trigger dose escalation, which worsens the condition. The correct approach is dose reduction, propranolol, or benzodiazepines.
5. Clozapine + smoking: Cigarette smoking induces CYP1A2. When a clozapine patient is hospitalized (where smoking is prohibited), their clozapine levels can rise by 50% within days, causing toxicity. Always reduce the dose when a smoker is hospitalized.
6. AIMS test (Abnormal Involuntary Movement Scale): Should be performed at baseline and every 6-12 months to detect tardive dyskinesia early. If TD detected, consider switching to clozapine or quetiapine (lowest TD risk), and consider valbenazine.
7. Avoid FGAs in Parkinson disease: High-potency D2 blockers severely worsen parkinsonism. Use pimavanserin (no D2 blockade) or quetiapine/clozapine for psychosis in Parkinson patients.
8. The "atypical" distinction is blurring: Some SGAs (risperidone at high doses) cause as much EPS as FGAs, while some FGAs at low doses have few EPS. The distinction is more a spectrum than two discrete categories.

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• Kaplan & Sadock's Comprehensive Textbook of Psychiatry, Chapter 33 (Dopamine Receptor Antagonists and Atypical Antipsychotics)
• Rosen's Emergency Medicine: Concepts and Clinical Practice (Antipsychotic pharmacology and toxicology)
• Katzung's Basic & Clinical Pharmacology, 16th Edition, Chapter 29 (Antipsychotic Agents)
• Adams & Victor's Principles of Neurology, 12th Edition (Schizophrenia and Drug Treatment)
• Stahl's Essential Psychopharmacology (Neuroscientific Basis and Practical Applications)