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Estrogen Drugs - Complete Pharmacology

1. What Are Estrogens?

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2. Endogenous Estrogens

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3. Mechanisms of Action

Genomic (Nuclear Receptor) Pathway - Primary Mechanism

1. Receptor dimerization
2. Binding to Estrogen Response Elements (EREs) on DNA (consensus sequence: GGTCAnnnTGACC)
3. Recruitment of coactivators (SRC-1, SWI/SNF, p300, TRAP complex) → chromatin remodeling → gene transcription

Non-genomic (Rapid) Signaling

• Membrane-associated ERα and GPER (GPR30, a G protein-coupled receptor) mediate rapid effects
• Crosstalk with EGF/IGF-1 pathways via MAPK and PI3K-Akt → phosphorylation of ERα at serine 118 causes ligand-independent activation

Receptor Isoforms

• ERα: Predominant in uterus, vagina, ovaries, mammary gland, hypothalamus, vascular endothelium
• ERβ: Predominant in prostate, ovaries, lung, bone, brain
• Both can form homodimers or heterodimers; ERβ can inhibit ERα-mediated transcription when co-expressed

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4. Pharmacological Preparations & Routes

Key note: Ethinyl substitution at C17 (ethinyl estradiol) greatly increases oral potency by blocking first-pass hepatic metabolism - making it much more potent than conjugated estrogens orally. Transdermal route bypasses hepatic first-pass, minimizing effects on hepatic protein synthesis and lipids.

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5. Therapeutic Uses

A. Hormonal Contraception

B. Menopausal Hormone Therapy (MHT)

• Relieves hot flashes, urogenital atrophy, mood changes
• Prevents postmenopausal osteoporosis
• Women with intact uterus must have a progestin added (to prevent endometrial hyperplasia)
• Preferred: Lowest effective dose for shortest duration

C. Induction of Sexual Maturation

D. Osteoporosis Prevention

E. Genitourinary Syndrome of Menopause

F. Palliative Cancer Treatment

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6. Estrogen Agonists/Antagonists: SERMs and Antiestrogens

Selective Estrogen Receptor Modulators (SERMs)

Pure Antiestrogens

• Fulvestrant: 7α-alkylamide derivative of estradiol; pure ER antagonist in all tissues; causes receptor downregulation. Used for breast cancer after tamoxifen failure.

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7. Estrogen Synthesis Inhibitors (Aromatase Inhibitors)

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8. Physiological Effects of Estrogens

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9. Adverse Effects & Contraindications

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10. Summary: Drug Classes at a Glance

ESTROGEN DRUGS
├── Estrogen Agonists (Replacement/Contraception)
│   ├── 17β-Estradiol (natural, patches, gels, IM)
│   ├── Ethinyl estradiol (oral contraceptives)
│   └── Conjugated equine estrogens (CEE - Premarin)
│
├── SERMs (Selective Estrogen Receptor Modulators)
│   ├── Tamoxifen (breast CA treatment)
│   ├── Raloxifene (osteoporosis + breast CA prevention)
│   ├── Toremifene (breast CA)
│   └── Clomiphene (ovulation induction)
│
├── Pure Antiestrogens
│   └── Fulvestrant (breast CA after tamoxifen failure)
│
└── Estrogen Synthesis Inhibitors (Aromatase Inhibitors)
    ├── Exemestane (steroidal, irreversible)
    ├── Anastrozole (non-steroidal, reversible)
    └── Letrozole (non-steroidal, reversible)

---

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Estrogen Drugs - Complete Overview

1. Endogenous Estrogens (Natural)

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2. Mechanism of Action

Genomic Pathway (Primary)

1. Estrogen binds ERα or ERβ in the nucleus
2. Receptor dimerizes → binds Estrogen Response Elements (EREs) on DNA
3. Recruits coactivators (SRC-1, SWI/SNF, p300) → gene transcription

Non-Genomic (Rapid)

• Membrane-associated ER and GPER (GPR30) → fast signaling via MAPK, PI3K-Akt

Receptor Distribution

• ERα: Uterus, vagina, ovaries, breast, hypothalamus, vascular endothelium
• ERβ: Prostate, ovaries, lung, bone, brain

---

3. Pharmacological Preparations

Ethinyl estradiol has a C17 ethinyl group that blocks first-pass hepatic metabolism, making it far more potent orally than conjugated estrogens. Transdermal routes avoid first-pass and minimize hepatic effects (lipids, coagulation factors).

---

4. Therapeutic Uses

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5. SERMs - Selective Estrogen Receptor Modulators

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6. Pure Antiestrogens

---

7. Aromatase Inhibitors (Estrogen Synthesis Inhibitors)

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8. Physiological Effects

---

9. Adverse Effects & Contraindications

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10. Quick Summary Diagram

ESTROGEN DRUGS
├── Agonists (Replacement / Contraception)
│   ├── 17β-Estradiol (patches, gels, IM, vaginal)
│   ├── Ethinyl estradiol (oral contraceptives)
│   └── Conjugated equine estrogens - CEE (Premarin)
│
├── SERMs
│   ├── Tamoxifen → breast cancer Rx
│   ├── Raloxifene → osteoporosis + breast CA prevention
│   ├── Toremifene → breast cancer
│   └── Clomiphene → ovulation induction
│
├── Pure Antiestrogen
│   └── Fulvestrant → breast CA (post-tamoxifen)
│
└── Aromatase Inhibitors (stop estrogen synthesis)
    ├── Exemestane (irreversible)
    ├── Anastrozole (reversible)
    └── Letrozole (reversible)

---

Progesterone & Progestogens - Lippincott Illustrated Reviews: Pharmacology

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1. Overview of Progestogens

• Progesterone - the naturally occurring hormone (secreted by corpus luteum)
• Progestins - synthetic compounds with progesterone-like activity (more stable, better oral bioavailability)

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2. Mechanism of Action

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3. Synthetic Progestins (Drugs Used Clinically)

Progestins for Contraception

Progestins for Hormone Therapy (HT)

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4. Therapeutic Uses

1. Contraception - oral, injectable, transdermal, implant, IUD
2. Menopausal hormone therapy (HT) - combined with estrogen to protect endometrium from unopposed estrogen-induced hyperplasia
3. Control of heavy menstrual bleeding (menorrhagia) - levonorgestrel IUD especially effective
4. Dysmenorrhea - reduce uterine contractions
5. Endometriosis - suppress endometrial growth
6. Infertility management - luteal phase support

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5. Pharmacokinetics

Synthetic progestins are less rapidly metabolized than natural progesterone, making them suitable for once-daily oral dosing.

---

6. Adverse Effects

Less androgenic progestins (norgestimate, drospirenone) are preferred in women with acne.

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7. Progesterone Antagonist - Mifepristone (RU-486)

• Pure progesterone receptor antagonist
• Terminates pregnancy by blocking progesterone needed to maintain the endometrium
• Usually combined with misoprostol (prostaglandin analog) to induce uterine contractions
• Brand: Mifeprex
• Adverse effects: abdominal pain, uterine bleeding, risk of incomplete termination

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8. Progesterone Agonist/Antagonist - Ulipristal

• A selective progesterone receptor modulator (acts as agonist/antagonist)
• Used as emergency contraception (up to 120 hours after unprotected intercourse)
• Brand: Ella
• Better tolerated than estrogen-progestin combination emergency contraceptives

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9. Contraceptive Mechanisms (Summary)

• Estrogen → negative feedback → blunts FSH release → prevents follicle development
• Progestin → inhibits LH surge → prevents ovulation; also thickens cervical mucus to prevent sperm penetration
• Withdrawal of progestin (pill-free week) → withdrawal bleeding

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10. Drug Interactions

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Progesterone - Lippincott Summary

Mechanism

• Binds nuclear progesterone receptors → activates gene transcription
• Promotes secretory endometrium for implantation
• Inhibits LH/FSH (negative feedback) → prevents ovulation in luteal phase
• Maintains pregnancy + reduces uterine contractions
• Fall in progesterone → triggers menstruation

Key Drugs (Progestins)

Adverse Effects

• Headache, depression, weight gain, libido changes
• Acne/hirsutism - 19-nortestosterone-derived progestins (norethindrone, levonorgestrel) have androgenic activity
• Hyperkalemia - drospirenone (spironolactone analog) - caution with ACE inhibitors

Pharmacokinetics

• Natural progesterone: rapid first-pass metabolism - NOT used for contraception
• Synthetic progestins: more stable, once-daily oral dosing
• Depo-Provera (IM): half-life ~40-50 days, lasts 3 months

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Progesterone & Progestogens

Lippincott Illustrated Reviews: Pharmacology - Chapter 25

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1. What Are Progestogens?

• Progesterone - the natural hormone secreted by the corpus luteum
• Progestins - synthetic analogs with progesterone-like activity (more stable, better oral bioavailability)

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2. Mechanism of Action

1. Diffuse across the cell membrane
2. Bind to specific nuclear progesterone receptors
3. Activated hormone-receptor complex binds nuclear chromatin
4. Initiates specific RNA synthesis → specific protein production → physiological effects

Physiological Actions of Progesterone

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3. Classification of Progestogen Drugs

A. Natural Progesterone

Micronized form has larger surface area for better absorption, but still undergoes significant first-pass metabolism.

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B. Synthetic Progestins - For Contraception

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4. Therapeutic Uses

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5. Pharmacokinetics

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6. Contraceptive Mechanism of Action (How Progestins Prevent Pregnancy)

• Estrogen → negative feedback → blunts FSH release from pituitary → prevents follicle development
• Progestin → inhibits LH surge → prevents ovulation
• Progestin also thickens cervical mucus → blocks sperm from reaching the egg
• Withdrawal of progestin (during the pill-free / patch-free week) → withdrawal bleeding (not true menstruation)

• Primary mechanism: thickening of cervical mucus + thinning of endometrium
• Ovulation may still occur

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7. Adverse Effects

Tip: For women with acne, prefer norgestimate or drospirenone - less androgenic than norethindrone or levonorgestrel.

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8. Progesterone Antagonist - Mifepristone (RU-486)

• Pure progesterone receptor antagonist
• Blocks the progesterone required to maintain the endometrium
• Results in termination of early pregnancy
• Almost always combined with misoprostol (a prostaglandin E1 analog) to:
  • Induce uterine contractions
  • Complete evacuation of uterine contents

• Abdominal/uterine cramping
• Uterine bleeding (expected)
• Risk of incomplete termination of pregnancy

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9. Progesterone Agonist/Antagonist - Ulipristal

• Selective progesterone receptor modulator (partial agonist/antagonist)
• Mechanism: delays or inhibits ovulation; may also affect endometrial receptivity
• Used as emergency contraception - effective up to 120 hours (5 days) after unprotected intercourse
• Better tolerated than levonorgestrel + estrogen combination regimens

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10. Drug Interactions with Progestin-Containing Contraceptives

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11. Contraindications

• Active or history of thromboembolic disease
• Estrogen-dependent cancers (for combined products)
• Liver disease
• Pregnancy
• Undiagnosed abnormal vaginal bleeding
• Women >35 years who smoke - avoid estrogen-containing contraceptives (progestin-only preferred)

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Summary Diagram

PROGESTOGEN DRUGS (Lippincott Ch. 25)
│
├── NATURAL
│   └── Progesterone (Prometrium, vaginal gel)
│       - Short half-life, first-pass metabolism
│       - Used for HRT & luteal phase support
│
├── SYNTHETIC PROGESTINS
│   ├── 19-Nortestosterone derivatives (androgenic)
│   │   ├── Norethindrone / Norethindrone acetate
│   │   ├── Levonorgestrel (Plan B, Mirena IUD, Twirla)
│   │   ├── Etonogestrel (Nexplanon, NuvaRing)
│   │   └── Norelgestromin (Xulane patch)
│   │
│   ├── Less androgenic
│   │   ├── Norgestimate (Ortho Tri-Cyclen)
│   │   ├── Desogestrel
│   │   ├── Dienogest (Natazia)
│   │   └── Drospirenone (Yaz, Yasmin) ← anti-mineralocorticoid
│   │
│   └── Pregnane derivatives
│       └── Medroxyprogesterone (Provera, Depo-Provera)
│           - Depo: 3-month injection
│
├── PROGESTERONE ANTAGONIST
│   └── Mifepristone (Mifeprex / RU-486)
│       - Medical abortion (+ misoprostol)
│
└── PROGESTERONE AGONIST/ANTAGONIST
    └── Ulipristal (Ella)
        - Emergency contraception (up to 120 hrs)

---

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Parkinsonism Pharmacology

Lippincott Illustrated Reviews: Pharmacology - Chapter 15

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1. What is Parkinsonism?

• Tremors (resting tremor - "pill-rolling")
• Muscular rigidity
• Bradykinesia (slowness of movement)
• Postural and gait abnormalities

---

2. Pathophysiology

The Core Problem

Normal Circuit

• Substantia nigra → Neostriatum: dopaminergic neurons (inhibitory - suppresses ACh)
• Neostriatum → Substantia nigra: GABAergic neurons (inhibitory)
• This mutual inhibition maintains balanced motor control

In Parkinson Disease

• Substantia nigra cells die → dopamine ↓ in neostriatum
• Without dopamine's inhibition → ACh neurons become overactive
• Result: dopamine/ACh imbalance → loss of muscle movement control

Secondary (Drug-Induced) Parkinsonism

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3. Treatment Strategy

1. Increase dopaminergic activity (main approach) - using levodopa, dopamine agonists, MAO-B inhibitors, COMT inhibitors, amantadine
2. Decrease cholinergic activity - using anticholinergics

Current drugs only offer symptomatic relief - they do NOT arrest or reverse neuronal degeneration.

---

4. Drug Classes

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CLASS 1: Levodopa + Carbidopa (FIRST-LINE)

Why Levodopa, not Dopamine?

Why Add Carbidopa?

• Reduces levodopa dose by 4-5 fold
• Reduces nausea, vomiting, cardiac arrhythmias, hypotension (from peripheral dopamine)
• Does NOT cross BBB itself - only acts peripherally

Pharmacokinetics

• Absorbed rapidly from small intestine (best on empty stomach - food delays/reduces absorption)
• Short half-life: 1-2 hours → plasma fluctuations → motor fluctuations
• Motor fluctuations include "wearing off" (end-of-dose) and "on-off" phenomenon

Adverse Effects

Drug Interactions

• Pyridoxine (Vit B6): accelerates peripheral levodopa metabolism → reduces CNS availability (less relevant when carbidopa is co-administered)
• MAOIs (non-selective): risk of hypertensive crisis - contraindicated
• Antipsychotics: block dopamine receptors - antagonize levodopa
• High-protein diet: amino acids compete for intestinal absorption and BBB transport

Clinical Note

• Effective for ~3-5 years; then motor fluctuations develop as neurons continue to die
• In early disease: ~20% residual substantia nigra neurons still convert levodopa to dopamine adequately
• Withdrawal must be gradual (abrupt withdrawal → neuroleptic malignant-like syndrome)

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CLASS 2: Dopamine Agonists

Mechanism

Therapeutic Use

• Used as monotherapy in early PD or as adjuncts to levodopa in advanced PD
• Allow reduction of levodopa dose and smooth out motor fluctuations
• Apomorphine: used as rescue therapy for acute "off" episodes

Adverse Effects

• Nausea, vomiting, orthostatic hypotension (like levodopa, but often less severe)
• Hallucinations, confusion (more common than with levodopa, especially in elderly)
• Impulse control disorders: compulsive gambling, hypersexuality, binge eating (especially pramipexole, ropinirole)
• Somnolence (sudden "sleep attacks" while driving - important warning)
• Bromocriptine: ergot-derived - can cause fibrotic reactions (pleuropulmonary, retroperitoneal)

---

CLASS 3: MAO-B Inhibitors

Selectivity

• At recommended doses: selective for MAO-B only → safe, no tyramine interaction ("cheese effect")
• At high doses: lose selectivity → inhibit MAO-A → risk of hypertensive crisis with tyramine-containing foods

Use

• As adjuncts to levodopa to enhance and prolong its effect; allow levodopa dose reduction
• Selegiline may also have neuroprotective properties (debated)

Adverse Effects

• Nausea, headache, confusion
• Insomnia (selegiline - from amphetamine metabolites - do not give after midday)
• Serotonin syndrome if combined with SSRIs, SNRIs, TCAs, meperidine - avoid concurrent use

---

CLASS 4: COMT Inhibitors

• Competes with levodopa for BBB transport
• Reduces CNS uptake of levodopa

Adverse Effects

• Dyskinesias (from increased levodopa effect - may need to reduce levodopa dose)
• Diarrhea, nausea
• Urine discoloration (orange-brown) - harmless
• Tolcapone only: hepatotoxicity (fatal cases reported) - monitor LFTs

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CLASS 5: Adenosine A2A Receptor Antagonist

• Adjunct to levodopa-carbidopa for "off" episodes
• Adverse effects: dyskinesia, dizziness, nausea, insomnia

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CLASS 6: Anticholinergics (for Tremor)

Use

• Most useful for controlling tremor and rigidity
• Less effective for bradykinesia and postural instability
• Useful for drug-induced (pseudoparkinsonism) caused by antipsychotics

Adverse Effects (Anticholinergic = "Dry" effects)

• Dry mouth, constipation, urinary retention
• Blurred vision (cycloplegia)
• Tachycardia
• Confusion, memory impairment (especially in elderly - use with caution)
• Contraindicated in glaucoma, BPH

---

CLASS 7: Amantadine

Mechanism (Multiple)

1. Increases presynaptic dopamine release
2. Inhibits dopamine reuptake
3. Weak NMDA glutamate receptor antagonist → reduces dyskinesias
4. Some anticholinergic activity

Use

• Mild early PD as monotherapy
• Adjunct to levodopa to smooth motor fluctuations
• Treatment of levodopa-induced dyskinesias (extended-release form - Gocovri)

Adverse Effects

• Livedo reticularis (mottled skin discoloration - characteristic side effect)
• Ankle edema
• Confusion, hallucinations
• Insomnia

---

5. PD Psychosis Management

• Pimavanserin - serotonin 5-HT2A inverse agonist (no dopamine blockade) → treats PD psychosis without worsening motor function
• Antipsychotics with very weak dopamine antagonism (e.g., quetiapine, clozapine) may also be used

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6. Complete Drug List (Lippincott Ch. 15)

PARKINSON DISEASE DRUGS
│
├── LEVODOPA COMBINATIONS (First-line)
│   ├── Levodopa + Carbidopa (Sinemet)
│   └── Levodopa + Carbidopa + Entacapone (Stalevo)
│
├── DOPAMINE AGONISTS
│   ├── Pramipexole (Mirapex) - D2/D3 agonist
│   ├── Ropinirole (Requip) - D2/D3 agonist
│   ├── Rotigotine (Neupro) - transdermal patch
│   ├── Bromocriptine (Parlodel) - ergot-derived
│   └── Apomorphine (Apokyn) - rescue SC injection
│
├── MAO-B INHIBITORS
│   ├── Selegiline/Deprenyl (Eldepryl) - → amphetamine metabolites
│   ├── Rasagiline (Azilect) - 5× more potent; no amphetamine
│   └── Safinamide (Xadago) - reversible; adjunct to levodopa
│
├── COMT INHIBITORS
│   ├── Entacapone (Comtan) - peripheral only; per-dose
│   ├── Opicapone (Ongentys) - peripheral only; once-daily
│   └── Tolcapone (Tasmar) - central + peripheral; hepatotoxic
│
├── ADENOSINE A2A ANTAGONIST
│   └── Istradefylline (Nourianz) - adjunct for "off" episodes
│
├── ANTICHOLINERGICS (for tremor/rigidity)
│   ├── Trihexyphenidyl
│   └── Benztropine (Cogentin)
│
└── AMANTADINE (Gocovri)
    - Multiple mechanisms: ↑ DA release, blocks reuptake, NMDA antagonist
    - Also treats levodopa-induced dyskinesias

---

7. Summary Table - Mechanisms at a Glance

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Parkinsonism Pharmacology

Lippincott Illustrated Reviews: Pharmacology - Chapter 15

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1. Definition & Features

• Tremor - resting "pill-rolling" tremor
• Rigidity - cogwheel or lead-pipe
• Bradykinesia - slowness of movement
• Postural instability - gait and balance abnormalities

---

2. Pathophysiology

Core Mechanism

Normal Circuit

In PD

• DA neurons die → DA ↓
• ACh neurons lose inhibition → ACh ↑ (relatively)
• DA/ACh imbalance → motor dysfunction

Secondary (Drug-Induced) Parkinsonism

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3. Treatment Strategy

All current drugs give symptomatic relief only - none arrest or reverse neuronal degeneration.

---

4. Drug Classes

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🔵 CLASS 1: Levodopa + Carbidopa — FIRST-LINE

Why Levodopa?

Why Add Carbidopa?

Key PK Facts

• Absorbed from small intestine - best on empty stomach
• Half-life: 1-2 hours → plasma fluctuations → motor fluctuations
• Effective for 3-5 years, then declines as more neurons die
• Withdrawal must be gradual

Adverse Effects

Drug Interactions

• Non-selective MAOIs → hypertensive crisis (contraindicated)
• Pyridoxine (Vit B6) → accelerates peripheral metabolism (less relevant with carbidopa)
• Antipsychotics → block DA receptors, antagonize levodopa
• High-protein diet → amino acids compete for intestinal absorption and BBB transport

---

🟢 CLASS 2: Dopamine Agonists

• Nausea, hypotension
• Hallucinations/confusion (more than levodopa, especially elderly)
• Impulse control disorders - compulsive gambling, hypersexuality, binge eating (pramipexole/ropinirole)
• Sudden sleep attacks - risk while driving
• Bromocriptine: ergot fibrotic reactions (pulmonary, retroperitoneal)

---

🟡 CLASS 3: MAO-B Inhibitors

• Nausea, headache, confusion
• Selegiline: insomnia (amphetamine metabolites)
• Serotonin syndrome with SSRIs, SNRIs, TCAs, meperidine → avoid combination

---

🟠 CLASS 4: COMT Inhibitors

• Dyskinesias (↑ levodopa effect - may need dose reduction)
• Diarrhea
• Orange-brown urine discoloration (harmless)
• Tolcapone: fatal hepatotoxicity reported - reserved for refractory patients

---

🔴 CLASS 5: Adenosine A2A Receptor Antagonist

• Adjunct to levodopa-carbidopa for "off" episodes
• Adverse effects: dyskinesia, dizziness, nausea, insomnia

---

⚪ CLASS 6: Anticholinergics

• Anhydrosis (dry skin)
• Bladder retention (urinary retention)
• Constipation
• Dry mouth / blurred vision / Dysphoria
• Elevated heart rate (tachycardia)
• Confusion and memory impairment - especially dangerous in elderly

---

🟣 CLASS 7: Amantadine

1. ↑ Presynaptic dopamine release
2. Inhibits dopamine reuptake
3. NMDA glutamate receptor antagonist → reduces dyskinesias
4. Weak anticholinergic activity

• Mild early PD (monotherapy)
• Adjunct to levodopa
• Treatment of levodopa-induced dyskinesias (ER formulation - Gocovri)

• Livedo reticularis - mottled purplish skin discoloration (characteristic!)
• Ankle edema
• Confusion, hallucinations
• Insomnia

---

5. PD Psychosis - Special Consideration

---

6. Complete Summary Diagram

PARKINSONISM DRUGS (Lippincott Ch. 15)
│
├── LEVODOPA + CARBIDOPA ──── FIRST-LINE
│   ├── Sinemet (levodopa/carbidopa)
│   └── Stalevo (levodopa/carbidopa/entacapone)
│
├── DOPAMINE AGONISTS ──── D2/D3 direct stimulation
│   ├── Pramipexole (Mirapex) ← impulse control disorders
│   ├── Ropinirole (Requip) ← impulse control disorders
│   ├── Rotigotine (Neupro patch)
│   ├── Bromocriptine (Parlodel) ← ergot - fibrosis risk
│   └── Apomorphine (Apokyn) ← rescue SC injection
│
├── MAO-B INHIBITORS ──── ↓ dopamine breakdown
│   ├── Selegiline (Eldepryl) ← amphetamine metabolite → insomnia
│   ├── Rasagiline (Azilect) ← 5× potent, no amphetamine
│   └── Safinamide (Xadago) ← reversible; adjunct to LD/CD
│
├── COMT INHIBITORS ──── ↑ levodopa CNS availability
│   ├── Entacapone (Comtan) ← per-dose; peripheral only
│   ├── Opicapone (Ongentys) ← once-daily; peripheral only
│   └── Tolcapone (Tasmar) ← central+peripheral; hepatotoxic
│
├── A2A ANTAGONIST ──── indirect DA enhancement
│   └── Istradefylline (Nourianz)
│
├── ANTICHOLINERGICS ──── ↓ ACh excess; best for tremor
│   ├── Trihexyphenidyl
│   └── Benztropine (Cogentin)
│
└── AMANTADINE (Gocovri)
    └── ↑ DA release + ↓ reuptake + NMDA block
        → also treats levodopa-induced dyskinesias

---

7. Quick Comparison Table

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Sedative-Hypnotic Drugs

Katzung's Basic & Clinical Pharmacology, 16th Edition - Chapter 22

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1. Definition

• Sedative: Reduces anxiety and exerts a calming effect at low doses
• Hypnotic: Produces drowsiness and encourages sleep onset/maintenance at higher doses

Classification is based on clinical use, not chemical structure. Both effects can usually be achieved with the same drug - just at different doses.

---

2. Dose-Response Concept (Key Katzung Concept)

---

3. Chemical Classification

A. Benzodiazepines

• 1,4-benzodiazepine structure with a carboxamide group
• Substituent at position 7 (halogen or nitro group) required for sedative-hypnotic activity
• Triazolam and alprazolam have an additional triazole ring at the 1,2 position

B. Barbiturates

• Barbituric acid nucleus (not itself active)
• Activity depends on substituents at C5 position
• Steeper, more dangerous dose-response curve than benzodiazepines

C. Newer "Z-drugs" (Non-BZD GABA-A modulators)

• Zolpidem - imidazopyridine
• Zaleplon - pyrazolopyrimidine
• Eszopiclone - cyclopyrrolone (S-enantiomer of zopiclone)
• Structurally unrelated to BZDs but share similar mechanism

D. Melatonin Receptor Agonists

• Ramelteon, Tasimelteon - MT1/MT2 agonists

E. Orexin Receptor Antagonists

• Suvorexant, Lemborexant

F. Anxiolytic with different mechanism

• Buspirone - 5-HT1A partial agonist

---

4. Mechanism of Action

Benzodiazepines, Barbiturates, and Z-drugs - All act on GABA-A receptors

Key distinction: Barbiturates can open Cl⁻ channels directly at high doses (no GABA needed) → explains their higher lethality. Benzodiazepines cannot open channels without GABA → ceiling effect → safer.

GABA-A Subunit Pharmacology (Katzung Box)

Benzodiazepine Potentiation - Electrophysiology

• BZDs increase the frequency of Cl⁻ channel opening events
• They do NOT substitute for GABA - they enhance GABA's effect allosterically
• They potentiate GABAergic inhibition at all levels of the neuraxis: spinal cord, hypothalamus, hippocampus, substantia nigra, cerebellar cortex, cerebral cortex

---

5. Pharmacokinetics

Benzodiazepines - Classified by Duration of Action

Barbiturates - Classified by Duration

Z-drugs - Pharmacokinetics

---

6. Pharmacological Effects

A. Anxiolysis (Sedation)

• Reduce anxiety and exert calming effect at low doses
• Cause anterograde amnesia in dose-dependent fashion
• Behavioral disinhibition (euphoria, impaired judgment) - especially at higher doses
• May cause paradoxical excitement (especially in elderly)

B. Hypnosis - Effects on Sleep Architecture

C. Anesthesia

• High doses of barbiturates → stage III general anesthesia
• Thiopental - IV induction agent; ultra-short acting
• Benzodiazepines (midazolam, diazepam) used for premedication and conscious sedation

D. Anticonvulsant

• Most BZDs and barbiturates elevate seizure threshold
• Diazepam/lorazepam IV: first-line for status epilepticus
• Phenobarbital: chronic seizure management
• Clonazepam: absence seizures, myoclonic seizures

E. Muscle Relaxation

• BZDs (via α2/α3 subunits) → central muscle relaxation
• Diazepam: used for skeletal muscle spasm

F. Respiratory Depression

• Dose-dependent depression of respiratory centers in medulla
• Barbiturates > Benzodiazepines (BZDs only significant when combined with other CNS depressants or in very high doses)
• Greatest risk in COPD patients

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7. Clinical Uses

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8. Adverse Effects

CNS Effects

Tolerance & Dependence

• Tolerance develops to sedative and hypnotic effects with repeated use (1-2 weeks)
• Physical dependence: withdrawal syndrome = anxiety, insomnia, tremors, convulsions
• Abrupt discontinuation of short-acting BZDs → rebound insomnia and anxiety
• Dependence liability: Barbiturates > Benzodiazepines > Z-drugs

Respiratory Depression

• Particularly dangerous in COPD, obstructive sleep apnea
• Barbiturates: severe respiratory depression even at modest overdose
• BZDs: respiratory depression mainly with IV use or in combination with opioids/alcohol

Teratogenicity

Barbiturate-Specific

• Hepatic enzyme induction (CYP inducers) → accelerate metabolism of many other drugs (oral contraceptives, warfarin, steroids)
• Porphyria: barbiturates enhance porphyrin synthesis → absolutely contraindicated in acute intermittent porphyria, variegate porphyria, hereditary coproporphyria

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9. Drug Interactions

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10. Overdose

Flumazenil (BZD Antidote)

• Competitive BZ receptor antagonist
• Also reverses eszopiclone, zaleplon, and zolpidem
• Limitations: Short duration (re-sedation common), unpredictable reversal of respiratory depression, may precipitate withdrawal in BZD-dependent patients
• Use remains controversial; requires careful monitoring

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11. Tolerance, Dependence, Withdrawal

Withdrawal Syndrome (Severity depends on dose, duration, and drug half-life)

• Short-acting BZDs (triazolam, alprazolam): rapid and intense withdrawal
• Long-acting BZDs (diazepam): delayed onset, more gradual withdrawal

• Substitute long-acting BZD (e.g., diazepam, chlordiazepoxide) → taper gradually
• Phenobarbital can also be used for BZD or ethanol withdrawal

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12. Special Agents

Buspirone (Katzung Box)

• Mechanism: Partial agonist at 5-HT1A receptors (NOT a GABA modulator)
• Onset: Slow (2-4 weeks) - not useful for acute anxiety
• No sedation, no dependence, no withdrawal, no potentiation of CNS depressants
• Use: Generalized anxiety disorder (GAD) - not panic disorder or sleep
• FDA category B in pregnancy - safest anxiolytic

Ramelteon & Tasimelteon

• Mechanism: MT1/MT2 melatonin receptor agonists in suprachiasmatic nucleus
• No effect on GABAergic neurotransmission
• No dependence, no rebound insomnia, no significant withdrawal
• Ramelteon: metabolized by CYP1A2 and CYP2C9
• Tasimelteon: metabolized by CYP1A2 and CYP3A4
• Use: Ramelteon = difficulty falling asleep; Tasimelteon = non-24-hour sleep-wake disorder (especially blind patients)

Suvorexant & Lemborexant

• Mechanism: Block orexin (hypocretin) receptors (OX1R + OX2R) → reduce wakefulness-promoting signals
• Use: Insomnia - decrease time to sleep onset AND increase total sleep time
• Suvorexant: decreases REM sleep
• Risk of sleep paralysis, complex sleep behaviors, suicidal ideation at high doses

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13. Complete Drug Summary Table

SEDATIVE-HYPNOTICS (Katzung Ch. 22)
│
├── BENZODIAZEPINES (GABA-A → ↑ Cl⁻ channel frequency)
│   ├── Long-acting: Diazepam, Chlordiazepoxide, Flurazepam
│   ├── Intermediate: Lorazepam*, Oxazepam*, Temazepam*
│   ├── Short-acting: Triazolam, Alprazolam, Midazolam
│   └── (*No active metabolites → safe in elderly/liver disease)
│
├── BARBITURATES (GABA-A → ↑ Cl⁻ channel duration)
│   ├── Ultra-short IV: Thiopental, Methohexital (anesthesia)
│   ├── Short: Secobarbital, Pentobarbital (insomnia)
│   └── Long: Phenobarbital (epilepsy), t½ 60-100h
│
├── Z-DRUGS (GABA-A α1 selective)
│   ├── Zolpidem - t½ 1.5-2.5h
│   ├── Zaleplon - t½ ~1h (ultra-short; mid-night use)
│   └── Eszopiclone - t½ 5-7h (long-term approved)
│
├── MELATONIN RECEPTOR AGONISTS (MT1/MT2)
│   ├── Ramelteon - sleep onset; CYP1A2 substrate
│   └── Tasimelteon - non-24h sleep-wake disorder
│
├── OREXIN ANTAGONISTS
│   ├── Suvorexant - insomnia (onset + maintenance)
│   └── Lemborexant - insomnia
│
└── BUSPIRONE (5-HT1A partial agonist)
    └── GAD only; slow onset; no dependence

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14. Benzodiazepines vs Barbiturates - Key Comparison

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Drugs for Epilepsy

Lippincott Illustrated Reviews: Pharmacology - Chapter 19

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1. Overview

• ~10% of the population has at least one seizure in their lifetime
• Epilepsy = 4th most common neurologic disorder (after migraine, stroke, Alzheimer)
• Epilepsy results from sudden, excessive, synchronous discharge of cerebral neurons
• ~75% of patients can be controlled with a single medication
• Medications are the most widely used treatment

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2. Classification of Seizures

A. Focal Seizures

• Involve one hemisphere only
• May occur with or without loss of consciousness/awareness
• May progress to bilateral generalized tonic-clonic seizures
• Begin with motor or non-motor activity

B. Generalized Seizures (both hemispheres)

C. Unknown

• Epileptic spasms (e.g., infantile spasms)

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3. Mechanisms of Antiseizure Drugs

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4. Individual Drug Profiles

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A. Phenytoin (Dilantin) / Fosphenytoin (Cerebyx)

• Oral, IV (fosphenytoin is a prodrug, given IV/IM → converted to phenytoin)
• Zero-order (saturable) kinetics at therapeutic doses → small dose increases cause disproportionately large rises in plasma levels → toxicity risk
• Highly protein-bound (90%); CYP2C9 substrate
• Strong CYP inducer (CYP2C9, CYP3A4) → reduces many drug levels

• Dose-related: Nystagmus, diplopia, ataxia, sedation, cognitive impairment (at increasing levels)
• Chronic: Gingival hyperplasia (characteristic), hirsutism, coarsening of facial features, peripheral neuropathy, folate deficiency, osteomalacia
• IV: Cardiovascular collapse with rapid IV administration; "Purple glove syndrome" with extravasation
• Teratogenic: Fetal hydantoin syndrome (cleft palate, cardiac defects)
• Hypersensitivity: Stevens-Johnson syndrome (rare)

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B. Carbamazepine (Tegretol)

• Oral; auto-induction of its own metabolism (CYP3A4 inducer) → doses must be increased over first few weeks
• Active metabolite: carbamazepine-10,11-epoxide

• Diplopia, dizziness, ataxia, nausea (common; dose-related)
• Hyponatremia (SIADH-like effect) - monitor sodium
• Bone marrow suppression (agranulocytosis, aplastic anemia - rare but serious)
• Steven-Johnson syndrome - associated with HLA-B*1502 allele (Asian populations - screen before use)
• Teratogenic (neural tube defects, craniofacial defects)
• Strong CYP inducer → reduces levels of many drugs including OCP, warfarin

Contraindicated in absence seizures (may worsen them)

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C. Oxcarbazepine (Trileptal) / Eslicarbazepine (Aptiom)

• No auto-induction
• No active epoxide metabolite
• Less bone marrow toxicity

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D. Valproic Acid / Divalproex (Depakote)

1. Blocks voltage-gated Na⁺ channels
2. Blocks T-type Ca²⁺ channels
3. Increases brain GABA levels (increases synthesis, decreases degradation)

• Absence seizures
• Tonic-clonic seizures
• Myoclonic seizures
• Focal seizures
• Also: bipolar disorder, migraine prophylaxis

• Oral; highly protein-bound
• Hepatic metabolism; CYP inhibitor (raises levels of phenytoin, phenobarbital, lamotrigine)

• Nausea, vomiting, weight gain, alopecia (dose-related)
• Hepatotoxicity - especially in children <2 years on polypharmacy; monitor LFTs
• Pancreatitis (rare but serious)
• Thrombocytopenia, inhibition of platelet aggregation
• Teratogenicity - most teratogenic antiepileptic drug: neural tube defects (spina bifida), cognitive impairment in offspring
• Avoid in pregnancy if possible; supplement with folic acid

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E. Lamotrigine (Lamictal)

• Oral; metabolized by UDP-glucuronosyltransferase (UGT)
• Valproate doubles lamotrigine levels (inhibits UGT) → must reduce lamotrigine dose
• Enzyme-inducing drugs (carbamazepine, phenytoin) halve lamotrigine levels

• Skin rash - common; can progress to Stevens-Johnson syndrome (especially with rapid titration or combination with valproate)
• Dizziness, diplopia, ataxia, headache
• Relatively safer in pregnancy compared to valproate

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F. Levetiracetam (Keppra) / Brivaracetam (Briviact)

• Oral/IV; not significantly protein-bound; primarily renal excretion (dose-adjust in renal impairment)
• Minimal drug interactions (not a CYP inducer or inhibitor) → important advantage

• Behavioral/psychiatric - irritability, aggression, depression, psychosis (notable side effect)
• Somnolence, dizziness
• Relatively safe in pregnancy

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G. Phenobarbital / Primidone (Mysoline)

• Primidone is metabolized to phenobarbital and phenylethylmalonamide (PEMA) - both active

• Sedation, cognitive impairment, depression
• Tolerance and dependence develop
• Strong CYP inducer → many drug interactions
• Teratogenic (craniofacial defects, cardiac malformations)
• Avoid in pregnancy; avoid in acute porphyria

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H. Benzodiazepines

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I. Ethosuximide (Zarontin)

If patient has both absence AND tonic-clonic seizures → use valproate (broad spectrum)

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J. Gabapentin (Neurontin) / Pregabalin (Lyrica)

• Oral; not metabolized - excreted unchanged in urine; no drug interactions (no CYP)
• Non-linear absorption (saturable transporter) for gabapentin; dose-dependent

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K. Topiramate (Topamax)

1. Blocks Na⁺ channels
2. Enhances GABA activity
3. Blocks AMPA/kainate glutamate receptors
4. Inhibits carbonic anhydrase

• Cognitive impairment - word-finding difficulties ("Dope-a-max")
• Kidney stones (carbonic anhydrase inhibition → ↑ urinary pH, ↓ citrate)
• Weight loss (useful adverse effect)
• Metabolic acidosis
• Teratogenic (cleft palate)

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L. Lacosamide (Vimpat)

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M. Vigabatrin (Sabril)

• Visual field defects (permanent, irreversible) - monitor visual fields every 3 months
• Sedation, weight gain

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N. Tiagabine (Gabitril)

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O. Felbamate (Felbatol)

• Aplastic anemia (~1:4000)
• Hepatic failure
• Only used when benefits outweigh serious risks

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P. Zonisamide (Zonegran)

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Q. Perampanel (Fycompa)

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R. Cenobamate (Xcopri)

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S. Cannabidiol (Epidiolex)

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T. Fenfluramine (Fintepla)

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5. Status Epilepticus - Emergency Treatment

1. Immediate: IV benzodiazepine (lorazepam or diazepam) - fast-acting
2. Next: IV phenytoin/fosphenytoin, divalproex, or levetiracetam - longer acting
3. Refractory: IV phenobarbital, propofol, or midazolam infusion

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6. Drug Selection by Seizure Type

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7. Pregnancy Considerations

• Avoid if possible: Divalproex (valproate) - highest teratogenicity risk (neural tube defects, cognitive impairment)
• Avoid: Barbiturates (phenobarbital)
• Relatively safer: Levetiracetam, lamotrigine, oxcarbazepine
• All women of childbearing potential on antiepileptics should take folic acid supplements
• Drug interactions with oral contraceptives: CYP inducers (carbamazepine, phenytoin, phenobarbital) reduce OCP efficacy → use backup contraception

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8. Drug Interactions Overview

• Carbamazepine, phenytoin, phenobarbital, primidone → ↓ OCP, warfarin, other antiepileptics

• Valproate → ↑ lamotrigine, phenobarbital, phenytoin
• Felbamate → inhibits CYP2C19, induces CYP3A4

• Levetiracetam, gabapentin, pregabalin (not significantly metabolized by CYP)

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9. Complete Drug Summary

ANTIEPILEPTIC DRUGS (Lippincott Ch. 19)
│
├── Na⁺ CHANNEL BLOCKERS
│   ├── Phenytoin / Fosphenytoin - zero-order kinetics; gingival hyperplasia
│   ├── Carbamazepine - auto-induction; hyponatremia; SJS risk
│   ├── Oxcarbazepine / Eslicarbazepine - like CBZ, less toxicity
│   ├── Lamotrigine - broad spectrum; SJS risk; ↑ by valproate
│   ├── Lacosamide - enhances slow inactivation; IV available
│   ├── Cenobamate - Na⁺ block + GABA modulation
│   └── Valproate* - also T-Ca²⁺ block + GABA ↑
│
├── GABA ENHANCERS
│   ├── Phenobarbital / Primidone - CYP inducers; sedating
│   ├── Benzodiazepines (Diazepam, Lorazepam, Clonazepam, Clobazam)
│   ├── Vigabatrin - GABA transaminase inhibitor; visual field loss
│   ├── Tiagabine - GABA reuptake blocker
│   └── Gabapentin / Pregabalin - α2δ Ca²⁺ subunit; no drug interactions
│
├── T-TYPE Ca²⁺ CHANNEL BLOCKER
│   └── Ethosuximide - ONLY absence seizures; DOC for pure absence
│
├── GLUTAMATE BLOCKERS
│   ├── Perampanel - AMPA antagonist; psychiatric side effects
│   └── Topiramate - AMPA + Na⁺ + CA inhibitor; cognitive impairment
│
├── SV2A BINDERS
│   ├── Levetiracetam - minimal drug interactions; behavioral side effects
│   └── Brivaracetam - similar to levetiracetam
│
├── SPECIAL/ORPHAN DRUGS
│   ├── Felbamate - Lennox-Gastaut; aplastic anemia risk
│   ├── Rufinamide - Lennox-Gastaut
│   ├── Cannabidiol - Dravet, Lennox-Gastaut
│   ├── Fenfluramine - Dravet syndrome
│   ├── Stiripentol - Dravet syndrome
│   └── Zonisamide - focal; kidney stones

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