Mechanism of Action of Mineralocorticoids

1. The Receptor: Mineralocorticoid Receptor (MR)

• N-terminal transcriptional regulatory domain - regulates transactivation
• Central DNA-binding domain (DBD) - two zinc finger motifs that bind to specific DNA sequences
• C-terminal ligand/hormone-binding domain (LBD) - binds aldosterone

"In the absence of hormone, MR is distributed relatively evenly between nuclear and cytoplasmic compartments but, in the presence of hormone, it is highly concentrated in the nucleus." - Brenner and Rector's The Kidney

2. Genomic (Classical) Pathway - Step by Step

3. Key Target Genes and Downstream Effects

• Na+ reabsorption from the lumen via ENaC (apical membrane)
• Na+ pumped out of cell into blood via Na+/K+-ATPase (basolateral)
• K+ enters the cell via Na+/K+-ATPase, then exits into the lumen via ROMK
• The lumen becomes electrically negative, driving paracellular Cl- reabsorption

4. The Role of 11β-Hydroxysteroid Dehydrogenase Type 2 (11β-HSD2)

"Because the mineralocorticoid receptor also binds glucocorticoids with high affinity, an enzyme (11β-hydroxysteroid dehydrogenase) in renal tubular cells inactivates glucocorticoids, allowing selective renal responses to mineralocorticoids such as aldosterone." - Harrison's Principles of Internal Medicine 22E

5. Nongenomic Effects

• An alternate non-MR membrane receptor
• The classical MR producing rapid signaling in addition to its genomic role
• Nonspecific interactions with other signaling cascades

6. Extra-Renal Effects (Nonepithelial Tissues)

• Fibrosis and collagen deposition (via upregulation of Ang II receptor responsiveness)
• Vascular smooth muscle hypertrophy
• Sodium influx in vascular smooth muscle
• Inhibition of norepinephrine reuptake in myocardial and vascular cells

Summary Table

Mechanism of Action of Mineralocorticoids (Simple Steps)

• α-ENaC - opens Na⁺ channels on the luminal (urine-facing) side
• SGK1 - a kinase that stabilizes ENaC and boosts Na⁺/K⁺-ATPase activity
• Na⁺/K⁺-ATPase - pumps Na⁺ out into blood, K⁺ into cell

In one line: Aldosterone → enters cell → binds MR → MR enters nucleus → switches on ENaC + SGK1 + Na/K-ATPase genes → Na⁺ retained, K⁺ lost.

Hormonal Contraceptives - Drugs and Mechanism of Action

How They Work - The Core Mechanism

"Exogenously administered estrogen in contraceptives provides negative feedback that blunts release of FSH by the pituitary gland, and progestin inhibits LH secretion, thus preventing ovulation." - Lippincott Illustrated Reviews: Pharmacology

Categories of Hormonal Contraceptives

1. Combined Oral Contraceptives (COCs) - Estrogen + Progestin

• Monophasic - same dose of estrogen + progestin every day (21 active + 7 placebo)
• Biphasic/Triphasic - dose of progestin increases progressively (mimics natural cycle)
• Extended cycle - 84 active days + 7 placebo (only 4 periods/year)
• Continuous - active pills every day (no periods)

1. Estrogen suppresses FSH → no follicle growth
2. Progestin suppresses LH → no ovulation
3. Progestin thickens cervical mucus → blocks sperm
4. Endometrium becomes thin and atrophic → implantation unlikely
5. Tubal motility is altered → slows sperm/egg transport

2. Transdermal Patch

• Contains ethinyl estradiol + norelgestromin (or levonorgestrel)
• One patch/week for 3 weeks → no patch in week 4 → withdrawal bleed
• Same mechanism as COC
• Less effective in women >90 kg
• Higher total estrogen exposure → increased VTE risk vs. oral pills

3. Vaginal Ring (NuvaRing)

• Contains ethinyl estradiol + etonogestrel
• Inserted vaginally for 3 weeks, removed for 1 week
• Same COC mechanism - local absorption through vaginal mucosa
• Avoids first-pass metabolism

4. Progestin-Only Pills (Mini-Pill)

• Contains norethindrone (or drospirenone in newer formulations)
• Taken every single day without a break

• Does not always suppress ovulation (variable)
• Main effect: thickens cervical mucus making it hostile to sperm
• Thins endometrium
• Safe for breastfeeding mothers (no effect on milk production unlike estrogen)

5. Injectable Progestin (Depot)

• Medroxyprogesterone acetate (DMPA / Depo-Provera)
• IM or SC injection every 3 months
• Provides high, sustained progestin levels
• Suppresses ovulation reliably (unlike mini-pill)
• Common side effects: amenorrhea, weight gain, delayed return of fertility (up to 12 months), bone loss (avoid >2 years)

6. Subdermal Implant

• Etonogestrel implant (Nexplanon)
• Placed under skin of upper arm - lasts up to 3 years
• Most effective hormonal method (failure rate <0.05%)
• Mechanism: suppresses ovulation + thickens cervical mucus
• Not dependent on patient adherence - hence highest efficacy

7. Hormonal Intrauterine Device (IUD)

• Levonorgestrel-releasing IUD (Mirena, Kyleena) - lasts 3-7 years
• Mechanism: mainly local - thickens cervical mucus + thins endometrium
• Minimal systemic progestin absorption
• Also treats heavy menstrual bleeding
• Avoid in: PID, history of ectopic pregnancy

8. Emergency Contraception (Postcoital)

Comparison of Failure Rates (Typical Use)

Quick Summary Table

Hormonal Contraceptives - Drugs & Mechanism of Action

The Core Concept

High estrogen → pituitary stops releasing FSH → no follicle grows High progestin → pituitary stops releasing LH → no ovulation trigger

4 Ways They Prevent Pregnancy

All Drug Categories

A. Combined (Estrogen + Progestin)

• Oral pill (COC) - daily pill, 21 active + 7 placebo days
• Transdermal patch - weekly patch x3 weeks (ethinyl estradiol + norelgestromin)
• Vaginal ring - monthly ring (ethinyl estradiol + etonogestrel)

B. Progestin-Only

Progestin-only options are preferred when estrogen is contraindicated - e.g., breastfeeding, smokers over 35, history of VTE, migraines with aura.

C. Emergency Contraception

Key Points to Remember

One-liner: Estrogen kills FSH (no egg grows), progestin kills LH (no egg releases) and makes cervical mucus hostile to sperm. Together = highly effective contraception.

Osteoporosis Drugs and Mechanism of Action

Understanding the Target: Bone Remodeling

• Osteoclasts - break down (resorb) old bone
• Osteoblasts - build new bone

Osteoblasts produce RANKL → binds RANK on osteoclast precursors → osteoclasts mature and resorb bone OPG (osteoprotegerin) - a natural decoy produced by osteoblasts that blocks RANKL

Classification of Drugs

1. Bisphosphonates

• Bisphosphonates are pyrophosphate analogues - they bind tightly to hydroxyapatite (bone mineral) at sites of active remodeling
• Osteoclasts engulf the drug during bone resorption
• Inside the osteoclast: amino-bisphosphonates (alendronate, zoledronate) inhibit farnesyl pyrophosphate synthase in the mevalonate pathway → blocks prenylation of signaling proteins (Ras, Rho) → osteoclast cytoskeletal disruption and apoptosis
• Net result: fewer and less active osteoclasts → reduced bone resorption

• Must be taken on empty stomach with full glass of water, stay upright 30 min (oral forms) - prevents esophageal irritation
• "Drug holiday" recommended after 5 years (reduce risk of atypical femur fracture and jaw osteonecrosis)
• Not cleared by kidney - caution in CKD (except zoledronate with care)

2. Denosumab (RANKL Inhibitor)

• Fully humanized monoclonal antibody that mimics OPG (the natural RANKL decoy)
• Binds to RANKL with high affinity → prevents RANKL from binding RANK on osteoclast precursors
• Blocks osteoclast formation, maturation, and survival → reduces bone resorption
• At least as potent as bisphosphonates in inhibiting bone resorption

• Can be used in renal failure (unlike bisphosphonates) - not renally cleared
• Do NOT stop abruptly - rebound bone resorption surge causes multiple vertebral fractures
• Watch for hypocalcemia, especially in vitamin D deficiency or CKD
• Slight increased risk of infection (RANKL is also expressed on immune cells)

3. SERMs - Selective Estrogen Receptor Modulators

• Acts as an estrogen receptor agonist in bone but antagonist in breast and uterus
• In bone: mimics estrogen → suppresses osteoclast activity → reduces bone resorption
• Estrogen normally suppresses RANKL production by osteoblasts - raloxifene replicates this effect in bone tissue only

• Does NOT increase risk of breast cancer or endometrial cancer (unlike estrogen)
• Reduces risk of vertebral fractures (but weaker hip fracture protection vs bisphosphonates)
• Increases VTE risk
• Used in postmenopausal women with osteoporosis who also have breast cancer risk

4. Calcitonin

• Binds calcitonin receptors on osteoclasts → directly inhibits osteoclast activity
• Reduces bone resorption
• Also has a central analgesic effect (useful in acute vertebral fracture pain)

• Weak antiresorptive effect - rarely first-line now
• Main current use: acute pain relief in vertebral compression fractures
• Tachyphylaxis develops with prolonged use (effectiveness decreases)
• Long-term use may be associated with slightly increased cancer risk - use limited to short courses

5. PTH Analogues (Anabolic Agents)

• Intermittent low-dose PTH (given as a daily injection) has a paradoxical anabolic effect on bone
• Acts on osteoblasts via PTH receptor → increases osteoblast proliferation and survival
• Also inhibits sclerostin secretion by osteocytes → further promotes osteoblast activity via Wnt/β-catenin pathway
• Stimulates both bone formation AND resorption, but net effect is formation > resorption at these doses
• Abaloparatide selectively binds the RG conformation of PTH receptor → more bone formation, less resorption than teriparatide → greater BMD gains

• Only agents that actually build new bone (others just slow loss)
• Reserved for severe osteoporosis or failure of antiresorptive therapy
• Limited to 2 years (black box warning for osteosarcoma risk in animal studies)
• Must be followed by antiresorptive (bisphosphonate or denosumab) to preserve gains

6. Romosozumab (Sclerostin Inhibitor) - Dual Action

• Monoclonal antibody that binds and neutralizes sclerostin
• Sclerostin is produced by osteocytes and blocks the Wnt receptor on osteoblasts → normally suppresses bone formation
• By blocking sclerostin → Wnt/β-catenin signaling is activated → osteoblast proliferation increases → bone formation goes up
• Simultaneously reduces bone resorption (mechanism not fully understood)
• Dual effect: anabolic + antiresorptive - unique among all osteoporosis drugs

• Causes rapid early rise in bone formation marker (P1NP) and sustained fall in resorption marker (CTX)
• Significant BMD gains within 12 months
• Limited to 1 year of treatment, then switch to antiresorptive
• Black box warning: contraindicated if MI or stroke within past year (cardiovascular safety signal in trials)

7. Estrogen / HRT

• Estrogen suppresses RANKL production by osteoblasts → less osteoclast activation → less bone resorption
• Also promotes osteoblast survival
• Protects bone throughout reproductive years - loss of estrogen at menopause is the main driver of postmenopausal osteoporosis

• Effective at preventing and treating osteoporosis
• No longer first-line due to increased risk of breast cancer, VTE, stroke, MI with long-term use
• Still considered in younger postmenopausal women (<60 years, <10 years since menopause) with vasomotor symptoms

Summary: Mechanism at a Glance

OSTEOCLAST SIDE (Antiresorptive)          OSTEOBLAST SIDE (Anabolic)
─────────────────────────────             ──────────────────────────
Bisphosphonates → osteoclast apoptosis    Teriparatide → ↑ osteoblast proliferation
Denosumab → blocks RANKL → no             Abaloparatide → same, more selective
             osteoclast formation          
Raloxifene → ER agonist in bone →         Romosozumab → blocks sclerostin →
             ↓ RANKL                                   ↑ Wnt → ↑ osteoblasts
Calcitonin → directly inhibits                         (ALSO reduces resorption)
              osteoclast activity
Estrogen → ↓ RANKL production