🔬 REPRODUCTIVE PHARMACOLOGY - 2nd Year MBBS

Based on KD Tripathi: Essentials of Medical Pharmacology

1. SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs)

What are SERMs?

┌─────────────────────────────────────────────────────────────────┐
│                    SERM TISSUE PROFILE                          │
├──────────────┬──────────────────┬──────────────────────────────┤
│    DRUG      │  AGONIST TISSUE  │     ANTAGONIST TISSUE        │
├──────────────┼──────────────────┼──────────────────────────────┤
│ Tamoxifen    │ Bone, uterus,    │ Breast                       │
│              │ liver (lipids)   │                              │
├──────────────┼──────────────────┼──────────────────────────────┤
│ Raloxifene   │ Bone, liver      │ Breast, UTERUS               │
│              │ (lipids)         │ (no uterine stimulation)     │
├──────────────┼──────────────────┼──────────────────────────────┤
│ Clomiphene   │ Peripheral       │ Hypothalamus/pituitary       │
│              │ (ovary, uterus)  │ (blocks -ve feedback)        │
├──────────────┼──────────────────┼──────────────────────────────┤
│ Toremifene   │ Bone             │ Breast                       │
├──────────────┼──────────────────┼──────────────────────────────┤
│ Ospemifene   │ Vagina           │ Breast, uterus               │
└──────────────┴──────────────────┴──────────────────────────────┘

Names & Therapeutic Uses

Mechanism of Action

Estrogen (E2) binds ER → ER dimerizes → binds ERE on DNA → gene transcription
                                                  ↑
          SERMs compete for ER binding — but conformational change differs
          → Tissue-specific co-activators/co-repressors determine AGONIST vs ANTAGONIST effect

Adverse Effects

• Hot flushes (most common)
• Increased risk of endometrial cancer (agonist on uterus)
• Thromboembolism (DVT, PE) - agonist on clotting factors in liver
• Cataracts, retinopathy
• Vaginal discharge/bleeding
• Hypercalcaemia (tumour flare initially)
• Hepatotoxicity

• Hot flushes
• DVT/PE (similar to tamoxifen)
• Leg cramps
• No endometrial stimulation (advantage over tamoxifen)

• Ovarian hyperstimulation syndrome (OHSS)
• Multiple pregnancy (~8%)
• Hot flushes
• Blurred vision, visual disturbances (at higher doses)
• Ovarian cyst formation
• Anti-estrogenic on cervical mucus and endometrium (reduces implantation)

2. PROGESTERONE

Preparations

• Natural: Progesterone (micronized - Utrogestan)
• Synthetic Progestins:
  • 19-nortestosterone derivatives: Norethindrone, Norgestrel, Levonorgestrel, Desogestrel, Gestodene, Norgestimate
  • 17α-hydroxyprogesterone derivatives: Medroxyprogesterone acetate (MPA), Hydroxyprogesterone caproate, Megestrol acetate

Pharmacological Actions

┌─────────────────────────────────────────────────────────┐
│            PROGESTERONE: ACTIONS BY TISSUE               │
├──────────────────┬──────────────────────────────────────┤
│ UTERUS           │ Secretory phase in endometrium        │
│                  │ ↓ Myometrial contractility (relaxes)  │
│                  │ Thickens cervical mucus (sperm barrier)│
├──────────────────┼──────────────────────────────────────┤
│ OVARY/PITUITARY  │ Inhibits LH surge → prevents ovulation│
├──────────────────┼──────────────────────────────────────┤
│ BREAST           │ Lobulo-alveolar development           │
├──────────────────┼──────────────────────────────────────┤
│ CNS              │ Sedation, ↑ basal body temperature    │
│                  │ (thermogenic - 0.5°C rise after OV)   │
├──────────────────┼──────────────────────────────────────┤
│ METABOLISM       │ ↑ Insulin levels, mild catabolic      │
└──────────────────┴──────────────────────────────────────┘

Therapeutic Uses

1. Dysfunctional uterine bleeding (DUB) - norethindrone, MPA
2. Endometriosis - suppresses ectopic endometrium
3. Threatened/habitual abortion - hydroxyprogesterone caproate, micronized progesterone
4. Premenstrual syndrome (PMS) - progesterone supplementation
5. Oral contraceptives - component of combined pills or progestin-only pill
6. Hormone replacement therapy (HRT) - combined with estrogen
7. Endometrial cancer - megestrol acetate (high dose)
8. Luteal phase support - during ART/IVF
9. Preterm labour prevention - vaginal progesterone (17-OHPC)
10. Breast cancer - megestrol acetate

Adverse Effects

• Breakthrough bleeding (most common with low-dose)
• Weight gain, edema (fluid retention)
• Mood changes, depression (especially 19-nortestosterone derivatives)
• Acne, hirsutism (androgenic effects - with older progestins)
• Nausea
• Breast tenderness
• Headache
• Cholestasis (with 17α-substituted compounds)
• Slight increase in LDL, decrease HDL (with androgenic progestins)
• Thromboembolism (controversial, less than estrogen)

3. EMERGENCY CONTRACEPTION

Definition

Classification & Regimens

┌─────────────────────────────────────────────────────────────────────┐
│                EMERGENCY CONTRACEPTION REGIMENS                      │
├──────────────┬─────────────────────────┬────────────────────────────┤
│ METHOD       │ DRUG/DOSE               │ TIMING                     │
├──────────────┼─────────────────────────┼────────────────────────────┤
│ YUZPE        │ EE 100µg + LNG 0.5mg    │ 2 doses, 12 hr apart       │
│ (Combined)   │ (or: 2 OCP tabs x 2)    │ within 72 hrs              │
├──────────────┼─────────────────────────┼────────────────────────────┤
│ LNG-only     │ Levonorgestrel 1.5mg    │ Single dose within 72 hrs  │
│ (Pill 72,    │ OR 0.75mg x 2 doses,   │ (effective up to 120 hrs)  │
│  I-pill,     │ 12 hrs apart            │                            │
│  Norlevo)    │                         │                            │
├──────────────┼─────────────────────────┼────────────────────────────┤
│ Ulipristal   │ 30 mg single dose       │ Within 120 hrs (5 days)    │
│ acetate      │                         │ Superior efficacy to LNG   │
├──────────────┼─────────────────────────┼────────────────────────────┤
│ Mifepristone │ 10-25 mg single dose    │ Within 72 hrs              │
├──────────────┼─────────────────────────┼────────────────────────────┤
│ Cu-IUD       │ Copper T 380A           │ Within 5 days (120 hrs)    │
│              │ (most effective)         │ Most effective method      │
└──────────────┴─────────────────────────┴────────────────────────────┘
Effectiveness: Cu-IUD > Ulipristal > LNG 1.5mg > Yuzpe regimen

Mifepristone (RU-486)

Mifepristone
    ↓
Binds progesterone receptor (PR) with HIGH affinity (3x > progesterone)
    ↓
Competitive antagonist → no progesterone effect
    ↓
     ├→ Endometrial decidua breaks down → bleeding
     ├→ Cervical softening/dilatation
     ├→ Increased uterine sensitivity to prostaglandins
     └→ At hypothalamus: blocks -ve feedback → ↑LH, disrupts LH surge
         (anti-ovulatory effect in early cycle)

Also: Antiglucocorticoid activity (binds GR with high affinity)
      Antiandrogen activity (weak)

1. Medical termination of pregnancy (MTP) - with misoprostol:
   • Mifepristone 200mg → 24-48 hrs later → Misoprostol 800µg (vaginal/sublingual)
   • Up to 63 days (9 weeks) gestation (WHO protocol)
2. Emergency contraception - 10mg single dose within 72 hrs
3. Cervical ripening before surgical termination
4. Cushing's syndrome (high doses - 300mg/day) - antiglucocorticoid
5. Endometriosis, uterine fibroids (investigational)
6. Labour induction (third trimester)

• Incomplete abortion (if not followed by misoprostol)
• Heavy bleeding, prolonged bleeding
• Cramping, abdominal pain
• Nausea, vomiting, diarrhea
• Infection/sepsis (rare but serious - Clostridium)
• Contraindicated in: ectopic pregnancy, IUD in situ, adrenal insufficiency, long-term corticosteroid therapy, coagulopathy

4. ORAL CONTRACEPTIVE PILLS (OCPs)

Classification

┌─────────────────────────────────────────────────────────────────┐
│                  OCP CLASSIFICATION                              │
├─────────────────────────────────────────────────────────────────┤
│  A. COMBINED OCPs (Estrogen + Progestin)                        │
│     1. Monophasic - constant dose throughout cycle              │
│        e.g. EE 30µg + LNG 150µg (Ovral-L, Nordette)            │
│             EE 35µg + Norethindrone 0.5-1mg                     │
│             EE 30µg + Desogestrel 150µg (Marvelon)              │
│             EE 30µg + Gestodene (Femodene)                      │
│     2. Biphasic - dose changes once                             │
│        e.g. EE 35µg + Norethindrone (7 tabs then 14 tabs)       │
│     3. Triphasic - dose changes at 2 points (mimics cycle)      │
│        e.g. Trinordiol, Triphasil                               │
│             EE 30-40µg + LNG 50-125µg (varying)                 │
│                                                                  │
│  B. PROGESTIN-ONLY PILLS (Mini-pill)                            │
│     - Norethindrone 0.35mg (Micronor, Nor-QD)                   │
│     - Levonorgestrel 30µg (Microval)                            │
│     - Desogestrel 75µg (Cerazette) - most popular               │
│                                                                  │
│  C. CENTCHROMAN (Ormeloxifene) - Non-steroidal, SERM            │
│     - 30mg twice weekly x 3 months, then once weekly            │
│     - Selective ERβ modulator                                    │
└─────────────────────────────────────────────────────────────────┘

Mechanism of Action (Combined OCP)

COMBINED OCP: TRIPLE MECHANISM
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
          PRIMARY (Main)                SECONDARY
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
1. INHIBITION OF OVULATION             2. CERVICAL MUCUS
   EE → ↓FSH → no follicle growth        Progestin → thick,
   Progestin → ↓LH surge → no OV         scanty, hostile
                                          to sperm
                                       3. ENDOMETRIUM
                                          Atrophic, unreceptive
                                          to implantation
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
Pearl Index of combined OCP = 0.1-0.3 (very effective)

• Primary: Cervical mucus thickening (does NOT reliably inhibit ovulation)
• Secondary: Endometrial atrophy
• Some cycles: ovulation still occurs

Dosage Schedule (Combined OCP)

STANDARD 28-DAY SCHEDULE:
Day 1-21: Active pills (Estrogen + Progestin)
Day 22-28: Placebo/iron pills (pill-free week)

Take first pill on Day 1 of menstruation (Day 1 start)
OR on first Sunday after menstruation starts (Sunday start)
OR Quick start (same day counselling)

BACK-UP CONTRACEPTION required for first 7 days if:
- Starting after Day 5 of cycle
- Missed pills
- Drug interactions (rifampicin, AEDs)

MISSED PILL RULES:
• Missed 1 pill (< 24 hrs late): Take immediately, continue
• Missed 1 pill (> 24 hrs late) or 2+ pills:
  Take last missed pill immediately, use backup x 7 days
• If missed in week 3: Skip placebo, start new pack

Adverse Effects of OCPs

• Nausea, vomiting (most common, dose-related)
• Breast tenderness/engorgement
• Thromboembolism (DVT, PE, stroke) - ↑clotting factors II, VII, IX, X
• Hypertension (via ↑angiotensinogen → ↑angiotensin)
• Headache, migraine
• Chloasma (melasma) - skin pigmentation
• Corneal changes (contact lens intolerance)
• Cholestasis

• Weight gain, fluid retention
• Acne, hirsutism (androgenic progestins)
• Depression, mood changes
• Decreased libido
• Breakthrough bleeding (especially low dose)
• Adverse lipid profile (↑LDL, ↓HDL - with androgenic progestins)

• Breast cancer: slight increase (returns to baseline after stopping)
• Cervical cancer: slight increase (HPV co-factor)
• Hepatocellular adenoma (rare)

A - Abdominal pain (hepatic vein thrombosis, gallbladder disease)
C - Chest pain, shortness of breath (PE, MI)
H - Headache severe (stroke, hypertension)
E - Eye problems: blurred vision, diplopia (retinal vein thrombosis)
S - Severe leg pain, swelling (DVT)

Non-Contraceptive Health Benefits

╔═══════════════════════════════════════════════════════════╗
║         NON-CONTRACEPTIVE BENEFITS OF OCPs                ║
╠════════════════════════════════════════════╦══════════════╣
║ BENEFIT                                    ║  MECHANISM   ║
╠════════════════════════════════════════════╬══════════════╣
║ ↓ Dysmenorrhoea                            ║ ↓PGs, atrophy║
║ ↓ Menorrhagia / DUB                        ║ Endometrial   ║
║                                            ║ atrophy      ║
║ ↓ Iron-deficiency anaemia                  ║ ↓ blood loss  ║
║ ↓ Risk of ovarian cancer (50%)             ║ ↓ ovulations  ║
║ ↓ Risk of endometrial cancer (50%)         ║ Atrophic endo ║
║ ↓ Premenstrual tension (PMT/PMS)           ║ Hormonal      ║
║ Treatment of endometriosis                 ║ Suppression   ║
║ ↓ Benign breast disease                    ║ ↓ cyst formation║
║ Acne treatment (EE + cyproterone)          ║ ↓ androgens   ║
║ Hirsutism treatment                        ║ ↓ androgens   ║
║ Regulation of irregular cycles             ║ Cycle control ║
║ ↓ Ectopic pregnancy risk                   ║ ↓ all pregnancy║
║ ↓ Pelvic inflammatory disease              ║ Thick mucus   ║
║ ↓ Rheumatoid arthritis risk                ║ Immunomodulation║
╚════════════════════════════════════════════╩══════════════╝

5. POSTCOITAL CONTRACEPTION - MANAGEMENT OUTLINE

Definition

Management Schedule

POSTCOITAL CONTRACEPTION: STEP-BY-STEP MANAGEMENT
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
STEP 1 - ASSESSMENT
  - Time since UPSI (≤72 hrs? ≤120 hrs?)
  - Contraindications to methods
  - Exclude existing pregnancy
  - Assess for STI risk

STEP 2 - METHOD SELECTION
  ┌──────────────────────────────────────────────────────┐
  │ UPSI within 72 hrs → LNG 1.5mg (I-pill) PREFERRED   │
  │                    → Ulipristal 30mg if 72-120 hrs   │
  │                    → Yuzpe if LNG unavailable         │
  │ UPSI within 120 hrs → Cu-IUD (most effective)        │
  │                     → Ulipristal 30mg                 │
  └──────────────────────────────────────────────────────┘

STEP 3 - ADMINISTRATION
  LNG 1.5mg: Single tablet ASAP (with food, if nausea)
  Yuzpe: 2 doses of 100µg EE + 0.5mg LNG, 12 hrs apart
  Cu-IUD: Insert within 120 hrs by trained provider

STEP 4 - FOLLOW UP
  - If no period in 3-4 weeks → pregnancy test
  - Counsel on regular contraception
  - STI screening if indicated

STEP 5 - COUNSELLING
  - Not 100% effective (LNG: 85% if within 72 hrs)
  - Not for regular use
  - Does NOT terminate established pregnancy
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

6. HORMONAL CONTRACEPTIVES - COMPLETE CLASSIFICATION

HORMONAL CONTRACEPTIVES
│
├── A. ORAL
│   ├── Combined OCP (Estrogen + Progestin)
│   │   ├── Monophasic (Ovral-L, Marvelon)
│   │   ├── Biphasic (Binovum)
│   │   └── Triphasic (Trinordiol, Triphasil)
│   ├── Progestin-Only Pill/Mini-pill (Norethindrone, Desogestrel)
│   └── Centchroman / Ormeloxifene (non-steroidal SERM)
│
├── B. INJECTABLE (PARENTERAL)
│   ├── Depot-MPA (DMPA / Depo-Provera) - 150mg IM every 3 months
│   ├── Norethisterone enanthate (NET-EN) - 200mg IM every 2 months
│   └── Combined monthly injectables (CIC)
│       └── Cyclofem: DMPA 25mg + E2 cypionate 5mg - monthly IM
│
├── C. SUBDERMAL IMPLANTS
│   ├── Implanon/Nexplanon - Etonogestrel 68mg rod - 3 years
│   └── Jadelle - 2 levonorgestrel rods - 5 years
│
├── D. INTRAUTERINE
│   ├── Levonorgestrel IUS (Mirena) - 52mg LNG - 5 years
│   └── Progestasert (no longer available)
│
├── E. TRANSDERMAL PATCH
│   └── Ortho Evra - EE 600µg + Norelgestromin 6mg - weekly x 3 weeks
│
├── F. VAGINAL RING
│   └── NuvaRing - EE 15µg + Etonogestrel 120µg/day - 3 weeks in
│
└── G. EMERGENCY (POST-COITAL)
    ├── LNG 1.5mg
    ├── Mifepristone 10mg
    └── Ulipristal 30mg

Mechanisms (Summary Table)

Adverse Effects (Hormonal Contraceptives - General)

• Menstrual irregularity (most common with progestin-only)
• Weight gain
• Mood changes, depression
• Headaches
• Breakthrough bleeding
• Acne, hirsutism (androgenic progestins)
• Thromboembolic events (combined methods)
• Hypertension (estrogen-containing methods)

Benefits

• Highly effective (>99% with perfect use)
• Reduces ovarian and endometrial cancer risk
• Manages endometriosis, DUB, dysmenorrhoea
• Treats acne, hirsutism (combined pills)

7. PARENTERAL CONTRACEPTIVES

Types

• Dose: 150mg deep IM injection
• Frequency: Every 3 months (12 weeks)
• First injection: within first 5 days of menstrual cycle

• Dose: 200mg deep IM
• Frequency: Every 2 months (first 2 doses), then every 3 months
• Oily preparation (castor oil)

• DMPA 25mg + Estradiol cypionate 5mg - monthly

Advantages

ADVANTAGES OF PARENTERAL CONTRACEPTIVES
├── No daily pill taking (improved compliance)
├── Long-acting (3 months for DMPA)
├── Very effective (Pearl Index: 0.1-0.3)
├── Reversible
├── Suitable for lactating women (DMPA - progestin-only)
├── No estrogen-related side effects (DMPA)
├── Decreased menstrual blood loss → prevents anaemia
├── Protective against PID, endometrial cancer
├── No interaction with gut absorption
├── Safe in epilepsy (except enzyme inducers may ↓ efficacy)
└── Privacy (no pills to carry)

Disadvantages

DISADVANTAGES OF PARENTERAL CONTRACEPTIVES
├── MENSTRUAL IRREGULARITY (most significant)
│   ├── Spotting, breakthrough bleeding (common initially)
│   └── AMENORRHOEA (50% by 1 year with DMPA)
├── DELAYED RETURN OF FERTILITY
│   └── Average 9-10 months after last DMPA injection
├── Cannot be rapidly reversed (unlike pills - can be stopped)
├── Requires visit to healthcare provider
├── Weight gain (average 2-3 kg/year)
├── BONE DENSITY LOSS with DMPA (reversible after stopping)
│   └── Not recommended > 2 years in adolescents
├── Mood changes, depression
├── No STI protection
├── Injection site discomfort/haematoma
└── Headaches, decreased libido

Adverse Effects of DMPA (Key for Exams)

8. UTERINE RELAXANTS (TOCOLYTICS)

Classification

UTERINE RELAXANTS (TOCOLYTICS)
│
├── 1. β₂-ADRENERGIC AGONISTS (β-mimetics) [MOST USED]
│   ├── Ritodrine (IV, oral) - prototype
│   ├── Terbutaline (SC, IV, oral) - most widely used now
│   ├── Salbutamol (Albuterol)
│   ├── Isoxsuprine (IV, oral) - older, less selective
│   └── Fenoterol, Nylidrin
│
├── 2. CALCIUM CHANNEL BLOCKERS
│   └── Nifedipine (oral) - increasingly preferred; 2nd line
│       (10mg sublingual or oral)
│
├── 3. MAGNESIUM SULFATE (MgSO₄)
│   ├── IV infusion
│   └── Mechanism: Mg²⁺ competes with Ca²⁺ at myometrium
│       (also: neuroprotection for preterm infant)
│
├── 4. OXYTOCIN RECEPTOR ANTAGONISTS
│   └── Atosiban (IV) - competitive OT antagonist
│       Approved in Europe; not FDA approved
│
├── 5. PROSTAGLANDIN SYNTHESIS INHIBITORS (NSAIDs)
│   └── Indomethacin (oral/rectal) - COX inhibitor
│       Risk: premature closure of ductus arteriosus
│       (use before 32 weeks only)
│
├── 6. NITRIC OXIDE DONORS
│   └── Glyceryl trinitrate (transdermal patch) - investigational
│
└── 7. PROGESTERONE
    └── Vaginal progesterone / 17-OHPC (weekly IM)
        - Prevents preterm labour in women with short cervix

Uses of Uterine Relaxants

1. Corticosteroid administration (betamethasone 12mg x 2 doses) - for lung maturity
2. Transfer to tertiary care centre

9. UTERINE STIMULANTS (OXYTOCICS / UTEROTONICS)

Classification

UTERINE STIMULANTS (OXYTOCICS)
│
├── 1. OXYTOCIN
│   ├── Synthetic oxytocin (Syntocinon) - IV infusion
│   └── Carbetocin (long-acting oxytocin analogue)
│
├── 2. ERGOT ALKALOIDS
│   ├── Ergometrine (Ergonovine) - IM/IV/oral
│   ├── Methylergometrine (Methergine) - IM/oral
│   └── Ergotamine (mainly for migraine; tonic uterine contraction)
│
├── 3. PROSTAGLANDINS
│   ├── PGE₁: Misoprostol (oral/vaginal/sublingual/rectal) - cheap, stable
│   ├── PGE₂: Dinoprostone (vaginal gel, pessary)
│   ├── PGF₂α: Carboprost (Hemabate) - 15-methyl PGF₂α - IM
│   └── PGE₁ analogue: Gemeprost (vaginal pessary)
│
└── 4. OTHERS
    ├── Dehydroepiandrosterone (DHEA) - ripens cervix
    └── Mifepristone (sensitizes uterus to PGs)

Pharmacological Actions

OXYTOCIN

OXYTOCIN - MOA AND ACTIONS
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
MOA: Binds OT receptor (Gq-coupled) on myometrium
     → ↑IP₃ + DAG → ↑intracellular Ca²⁺
     → Activates myosin light chain kinase (MLCK)
     → Uterine contraction

AT TERM: OT receptors ↑1000-fold → maximal sensitivity

DOSE-DEPENDENT EFFECTS:
Low dose  → RHYTHMIC contractions (like labour)
High dose → TONIC contraction (sustained)

Actions:
1. Uterus: Stimulates contraction (at term/near term)
2. Breast: Milk ejection (myoepithelial cell contraction)
3. CVS: Vasodilation (at high doses → hypotension)
        Slight ↑HR (reflex)
4. Antidiuretic effect (at very high doses) - similar to ADH
   → Can cause water retention, hyponatraemia

CLINICAL USES:
├── Induction of labour
├── Augmentation of labour (uterine inertia)
├── Prevention + treatment of PPH (3rd stage management)
├── Medical MTP (with mifepristone)
└── Milk ejection (intranasal)
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

ERGOT ALKALOIDS

ERGOMETRINE / METHYLERGOMETRINE - ACTIONS
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
MOA: Partial agonist at α-adrenergic, 5-HT, dopamine receptors
     + Direct stimulation of uterine smooth muscle

UTERINE EFFECT:
Unlike oxytocin → produces TONIC (sustained) contraction
Not rhythmic, sustained contraction → NOT for induction of labour
→ Used for PPH (squeezes bleeding vessels)

DOSE DEPENDENT:
Low dose  → Rhythmic contractions (like OT)
High dose → Tonic contraction + tetanic (continuous)

CVS: Vasoconstriction (α-agonist)
     → ↑BP, peripheral vasoconstriction
     → Contraindicated in hypertension, pre-eclampsia

CLINICAL USES:
├── PPH (postpartum haemorrhage) - MAIN USE
│   IM immediately after delivery of placenta
├── Subinvolution of uterus
└── Combined with oxytocin: Syntometrine (Ergometrine 0.5mg + OT 5U IM)

ADVERSE EFFECTS:
├── Nausea, vomiting
├── Hypertension, headache (vasoconstriction)
├── Ergotism (prolonged use): gangrene, hallucinations, seizures
├── Coronary vasospasm → MI (rare)
└── CONTRAINDICATED in: hypertension, pre-eclampsia, eclampsia,
    CAD, obliterative vascular disease, induction of labour
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

PROSTAGLANDINS AS UTERINE STIMULANTS

PROSTAGLANDINS - UTERINE ACTIONS AND USES
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
Both PGE₂ and PGF₂α stimulate myometrial contractions
throughout pregnancy (unlike oxytocin - only at term)

MISOPROSTOL (PGE₁ analogue)
├── Cheap, heat-stable, oral/sublingual/vaginal
├── Uses:
│   ├── MTP (with mifepristone) - 800µg vaginal/sublingual
│   ├── Cervical ripening before induction
│   ├── PPH treatment (600µg sublingual/rectal)
│   ├── Treatment of missed abortion, incomplete abortion
│   └── Gastric ulcers (cytoprotective)
├── ADR: Diarrhoea, fever, chills, nausea (systemic PG effect)

DINOPROSTONE (PGE₂)
├── Vaginal gel (Prepidil 0.5mg) or pessary (Cervidil 10mg)
├── Uses: Cervical ripening, induction of labour
├── ADR: GI side effects, fever, uterine hyperstimulation

CARBOPROST (15-methyl PGF₂α)
├── IM injection 250µg every 15-90 min (max 8 doses)
├── Uses: PPH unresponsive to oxytocin/ergometrine
├── CONTRAINDICATED in asthma
├── ADR: Bronchospasm, diarrhoea, fever, flushing
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

Comparative Table: Uterotonic Uses

┌───────────────┬────────────┬───────────────┬──────────────┐
│ USE           │  OXYTOCIN  │   ERGOMETRINE │     PGs      │
├───────────────┼────────────┼───────────────┼──────────────┤
│ Induction of  │    ✓✓✓     │      ✗        │     ✓ (PGE₂) │
│ labour        │ (drug of   │ (tonic; not   │              │
│               │  choice)   │ safe for FOB) │              │
├───────────────┼────────────┼───────────────┼──────────────┤
│ Augmentation  │    ✓✓✓     │      ✗        │     ✗        │
│ of labour     │            │               │              │
├───────────────┼────────────┼───────────────┼──────────────┤
│ PPH           │    ✓✓✓     │     ✓✓✓       │ ✓ (Carboprost│
│ prevention/Rx │ (1st line) │  (2nd line)   │ if others    │
│               │            │               │  fail)       │
├───────────────┼────────────┼───────────────┼──────────────┤
│ MTP           │    ✓       │      ✗        │    ✓✓✓       │
│ (abortion)    │            │               │ (Misoprostol)│
├───────────────┼────────────┼───────────────┼──────────────┤
│ Cervical      │    ✗       │      ✗        │     ✓✓       │
│ ripening      │            │               │ (Misoprostol,│
│               │            │               │  Dinoprostone│
└───────────────┴────────────┴───────────────┴──────────────┘

Adverse Effects of Uterine Stimulants

QUICK REVISION FLOWCHART: PPH MANAGEMENT WITH UTEROTONICS

PPH (Blood loss > 500 mL vaginal delivery / >1000mL CS)
         ↓
   STEP 1: OXYTOCIN 10U IM (or IV infusion 20-40U/L)
         ↓ Not responding?
   STEP 2: ERGOMETRINE 0.5mg IM
         (CI if hypertension → skip, use carboprost)
         ↓ Not responding?
   STEP 3: CARBOPROST 250µg IM q 15-90 min (max 8 doses)
         (CI if asthma)
   STEP 4: MISOPROSTOL 800-1000µg sublingual/rectal
         ↓ Pharmacological failure
   SURGICAL OPTIONS (B-Lynch suture, arterial ligation, hysterectomy)

QUICK REVISION FLOWCHART: EMERGENCY CONTRACEPTION

UNPROTECTED SEXUAL INTERCOURSE
          ↓
How many hours since UPSI?
   ≤ 72 hours          72-120 hours          > 120 hours
       ↓                     ↓                     ↓
   LNG 1.5mg            Ulipristal           Cu-IUD
   (I-pill)              30mg (Ella)         (if ≤120 hrs)
   single dose          single dose           or pregnancy
   OR Cu-IUD            OR Cu-IUD             test/follow-up
   (most effective)     (most effective)

KEY MNEMONICS FOR EXAMS

• A - Arterial/venous thrombosis history
• B - Breast cancer
• C - CAD, Cerebrovascular disease
• D - Diabetes with vascular complications
• E - Estrogen-dependent tumours
• F - Focal migraine (with aura)
• G - Gallbladder disease
• H - Hypertension (severe), Hepatic impairment

• Berek & Novak's Gynecology (Mifepristone/emergency contraception data confirmed)
• Katzung's Basic and Clinical Pharmacology 16e (Progestins section confirmed)This is a complete, exam-ready pharmacology reference. Here's a summary of what's covered:

What's Included (All 9 Topics):

1. SERMs - Tissue-specific profiles (tamoxifen, raloxifene, clomiphene, etc.), mechanisms, therapeutic uses, adverse effects with comparison table
2. Progesterone - Classification of progestins, pharmacological actions by tissue (with diagram), all therapeutic uses, complete adverse effect profile
3. Emergency Contraception - All regimens tabulated (Yuzpe, LNG, Ulipristal, Mifepristone, Cu-IUD) with timing; Mifepristone MOA flowchart, uses, adverse effects
4. OCPs - Full classification (monophasic/biphasic/triphasic/mini-pill/centchroman), triple mechanism of action, ACHES warning signs mnemonic, dosage schedule with missed pill rules, non-contraceptive benefits table
5. Postcoital Contraception - Step-by-step management flowchart with decision tree
6. Hormonal Contraceptives - Complete classification tree (oral/injectable/implant/IUS/patch/ring/emergency), mechanism comparison table
7. Parenteral Contraceptives - DMPA/NET-EN/Cyclofem details, advantages/disadvantages bulleted lists, adverse effects table
8. Uterine Relaxants - Full classification (β-agonists, CCBs, MgSO4, oxytocin antagonists, NSAIDs, NO donors, progesterone), uses for each
9. Uterine Stimulants - Oxytocin/Ergot/PGs with MOA diagrams, PPH management flowchart, comparative uses table