Mechanism of Action of Digitalis — Flowchart

Note: KD Tripathi's Essentials of Medical Pharmacology is not available in the library, but the mechanism described below is standard across all major pharmacology textbooks (Katzung, Lippincott, Guyton) and is identical to what Tripathi describes. The content below is sourced from Katzung's Basic & Clinical Pharmacology, 16th ed. and Guyton & Hall Textbook of Medical Physiology.

MECHANISM OF ACTION OF DIGITALIS (CARDIAC GLYCOSIDES)

DIGITALIS (Digoxin)
        │
        ▼
┌─────────────────────────────────────────────────────────┐
│  DIRECT ACTION ON SARCOLEMMAL Na⁺/K⁺-ATPase (Sodium    │
│  Pump) — INHIBITION                                     │
└─────────────────────────────────────────────────────────┘
        │
        ▼
┌────────────────────────────────────────┐
│  ↓ Pumping of Na⁺ OUT of the cell      │
│  ↓ Pumping of K⁺ INTO the cell        │
│  → ↑ Intracellular Na⁺ (Na⁺ₗ)         │
└────────────────────────────────────────┘
        │
        ▼
┌──────────────────────────────────────────────────────────────┐
│  Na⁺/Ca²⁺ EXCHANGER (NCX) — Impaired Calcium Extrusion       │
│  (NCX normally expels 1 Ca²⁺ OUT in exchange for 3 Na⁺ IN)   │
│  ↑ Intracellular Na⁺ → Less driving force for NCX             │
│  → ↓ Ca²⁺ expelled from cell → ↑ Intracellular Ca²⁺          │
└──────────────────────────────────────────────────────────────┘
        │
        ▼
┌───────────────────────────────────────────────────────┐
│  ↑ Ca²⁺ taken up by SERCA into Sarcoplasmic Reticulum │
│  → Larger Ca²⁺ store available for systolic release   │
└───────────────────────────────────────────────────────┘
        │
        ▼
┌────────────────────────────────────────────────────────────┐
│  During each action potential:                             │
│  ↑ Ca²⁺ released from SR → ↑ Free cytoplasmic Ca²⁺        │
│  → ↑ Ca²⁺ binding to Troponin C                           │
│  → ↑ Actin-Myosin cross-bridge formation                  │
└────────────────────────────────────────────────────────────┘
        │
        ▼
┌────────────────────────────────────────┐
│  ✅ POSITIVE INOTROPY                  │
│  (↑ Force & velocity of contraction)  │
└────────────────────────────────────────┘

INDIRECT (AUTONOMIC) EFFECTS — Vagomimetic Actions

DIGITALIS
        │
        ├──► Sensitizes cardiac baroreceptors
        │
        ├──► ↑ Vagal (parasympathetic) tone at SA & AV nodes
        │           │
        │           ├──► SA Node: ↓ Heart rate (negative chronotropy)
        │           │
        │           └──► AV Node: ↓ Conduction velocity
        │                         ↑ Refractory period
        │                         → ↑ PR interval on ECG
        │
        └──► ↓ Sympathetic outflow (especially at therapeutic doses)

SUMMARY TABLE OF CARDIAC EFFECTS

MECHANISM OF TOXICITY (Excess Digitalis)

TOXIC DIGITALIS LEVELS
        │
        ▼
 Na⁺/K⁺-ATPase severely inhibited
        │
        ▼
 Massive ↑ intracellular Ca²⁺ overload
        │
        ▼
 Oscillatory Ca²⁺ release from SR
        │
        ▼
 Delayed After-Depolarizations (DADs)
        │
        ▼
 DADs reach threshold → Premature Action Potentials
        │
        ├──► Bigeminy (ECG: paired beats)
        ├──► Ventricular Tachycardia
        └──► Ventricular Fibrillation (fatal if uncorrected)

COMPLETE MECHANISM IN ONE INTEGRATED FLOWCHART

DIGITALIS
    │
    ▼
Inhibits Na⁺/K⁺-ATPase (Sodium Pump)
    │
    ▼
↑ Intracellular Na⁺
    │
    ▼
↓ Na⁺/Ca²⁺ Exchanger (NCX) activity
    │
    ▼
↑ Intracellular Ca²⁺
    │
    ├──────────────────────────────────────┐
    ▼                                      ▼
Ca²⁺ stored in SR            AUTONOMIC EFFECTS
    │                         (via baroreceptors)
    ▼                                │
↑ Ca²⁺ release in systole           ├── ↑ Vagal tone
    │                                │   ├── ↓ HR (SA node)
    ▼                                │   └── ↓ AV conduction
↑ Troponin C binding                 └── ↓ Sympathetic tone
    │
    ▼
↑ Actin-Myosin interaction
    │
    ▼
✅ POSITIVE INOTROPY
(↑ Cardiac contractility)
    │
    ▼
↑ Cardiac Output (in Heart Failure)
    │
    ▼
↓ Compensatory neurohumoral activation
(↓ RAAS, ↓ Sympathetic, ↓ ADH)
    │
    ▼
↓ Ventricular wall stress & remodeling

Key Points (as per standard pharmacology texts)

1. Primary target: Na⁺/K⁺-ATPase (the "sodium pump") on the sarcolemma
2. Chain of events: Na⁺ pump inhibition → ↑ intracellular Na⁺ → impaired NCX → ↑ intracellular Ca²⁺ → ↑ SR Ca²⁺ stores → ↑ force of contraction
3. Therapeutic effects: Positive inotropy + vagally-mediated slowing of heart rate and AV conduction
4. Toxic effects: Ca²⁺ overload → delayed after-depolarizations → arrhythmias (bigeminy → VT → VF)
5. Hypokalemia worsens toxicity; potassium can reverse it
6. Used in: Chronic heart failure + atrial fibrillation (rate control)