Estrogen Drugs - Complete Pharmacology

1. What Are Estrogens?

2. Endogenous Estrogens

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

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.

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

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.

7. Estrogen Synthesis Inhibitors (Aromatase Inhibitors)

8. Physiological Effects of Estrogens

9. Adverse Effects & Contraindications

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)

Estrogen Drugs - Complete Overview

1. Endogenous Estrogens (Natural)

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

5. SERMs - Selective Estrogen Receptor Modulators

6. Pure Antiestrogens

7. Aromatase Inhibitors (Estrogen Synthesis Inhibitors)

8. Physiological Effects

9. Adverse Effects & Contraindications

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

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)

2. Mechanism of Action

3. Synthetic Progestins (Drugs Used Clinically)

Progestins for Contraception

Progestins for Hormone Therapy (HT)

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

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.

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

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

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

10. Drug Interactions

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

Progesterone & Progestogens

Lippincott Illustrated Reviews: Pharmacology - Chapter 25

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)

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

3. Classification of Progestogen Drugs

A. Natural Progesterone

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

B. Synthetic Progestins - For Contraception

4. Therapeutic Uses

5. Pharmacokinetics

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

7. Adverse Effects

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

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

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

10. Drug Interactions with Progestin-Containing Contraceptives

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)

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)

Parkinsonism Pharmacology

Lippincott Illustrated Reviews: Pharmacology - Chapter 15

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

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

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)

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

CLASS 5: Adenosine A2A Receptor Antagonist

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

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

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

Parkinsonism Pharmacology

Lippincott Illustrated Reviews: Pharmacology - Chapter 15

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

3. Treatment Strategy

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

4. Drug Classes

🔵 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