Cardiac Glycosides

Cardiac glycosides are steroid-derived drugs—digoxin being the only one in routine modern use—that inhibit the sarcolemmal Na⁺/K⁺-ATPase to produce a positive inotropic and negative chronotropic/dromotropic effect. They occupy a uniquely high-yield niche in pharmacology because of a razor-thin therapeutic index, a classic mechanism, and a textbook antidote (digoxin-specific Fab). This note builds the topic from molecule to bedside.

Source, Chemistry & Classification

Cardiac glycosides are obtained from plants and one toad species. Each molecule has three structural parts:

• Aglycone (genin) — a steroid nucleus bearing an unsaturated lactone ring; this is the pharmacodynamically active portion.
• Lactone ring — confers cardiotonic activity. A 5-membered ring = cardenolides (digoxin, digitoxin); a 6-membered ring = bufadienolides (from toad).
• Sugar (glycone) residues — modify pharmacokinetics (water solubility, potency, duration), but have no intrinsic activity.

Glycoside	Source	Key feature
Digoxin	Digitalis lanata	Drug of choice; renal excretion; t½ ~36–40 h
Digitoxin	Digitalis purpurea	Hepatic metabolism; very long t½ (~7 days); rarely used
Ouabain (G-strophanthin)	Strophanthus gratus	Highly polar, IV only, research/historical
Bufalin/bufotoxin	Toad (Bufo) skin	Bufadienolide; aphrodisiac poisoning ("love stone")

High-yield: Digoxin is renally excreted (dose-reduce in renal failure); digitoxin is hepatically metabolised (safer in renal failure but obsolete).

Mechanism of Action

The unifying action is reversible inhibition of the membrane-bound Na⁺/K⁺-ATPase (the sodium pump) by binding to its extracellular α-subunit.

Stepwise cascade:

1. Digoxin binds and inhibits Na⁺/K⁺-ATPase → less Na⁺ pumped out → intracellular Na⁺ rises.
2. Raised intracellular Na⁺ reduces the gradient driving the Na⁺/Ca²⁺ exchanger (NCX) → less Ca²⁺ extruded.
3. Intracellular Ca²⁺ accumulates and is taken up into the sarcoplasmic reticulum (SERCA).
4. Greater Ca²⁺ release per action potential → enhanced actin–myosin cross-bridging → positive inotropy.

Mnemonic — "Digoxin Drives Sodium up, Calcium up, Contraction up."

Electrophysiological / autonomic effects:

• Vagomimetic (parasympathomimetic) action — increases vagal tone at the SA and AV nodes. This is the basis of the negative chronotropic (slowed heart rate) and negative dromotropic (slowed AV conduction) effects, exploited in atrial fibrillation.
• At toxic levels, increased sympathetic outflow and direct enhanced automaticity (from Ca²⁺ overload and delayed afterdepolarisations) cause arrhythmias.

High-yield: The therapeutic AV-nodal slowing is largely vagally (parasympathetically) mediated, whereas inotropy is the direct Na⁺/K⁺-ATPase effect.

Effect on the ECG and action potential

Effect	Mechanism	ECG/clinical correlate
↑ Contractility	Ca²⁺ overload	Improved cardiac output
↓ AV conduction	↑ Vagal tone	Prolonged PR interval
↓ Heart rate	↑ Vagal tone + ↓ sympathetic	Bradycardia
Shortened ventricular AP/refractoriness	K⁺ changes	Shortened QT, T-wave flattening/inversion
Repolarisation change	—	"Reverse-tick"/sagging ST depression ("Salvador Dalí moustache")

High-yield: The "reverse tick" (sagging) ST-segment depression is the digoxin effect (a sign of use, not toxicity). It does NOT predict toxicity.

Pharmacokinetics (Digoxin)

• Oral bioavailability ~60–80% (tablet); ~10% of patients harbour gut Eubacterium lentum that inactivates digoxin—antibiotics can raise levels.
• Volume of distribution is very large (~6–7 L/kg) — concentrates in skeletal muscle and myocardium; not removed by dialysis.
• Protein binding ~25% (low).
• Onset 1–2 h oral / 5–30 min IV; half-life ~36–40 h (longer in renal impairment).
• Excretion mainly unchanged in urine (renal). Loading dose ("digitalisation") may be used; maintenance dose adjusted to renal function.
• Therapeutic range: 0.5–0.9 ng/mL (modern target for heart failure; older texts say 0.8–2.0 ng/mL). Toxicity risk rises markedly above 2 ng/mL.

High-yield: Digoxin has a narrow therapeutic index; therapeutic drug monitoring is standard, with sampling ≥6–8 h after the dose (distribution phase must be complete or the level is falsely high).

Clinical Uses

1. Chronic heart failure with reduced ejection fraction (HFrEF): Digoxin improves symptoms and reduces hospitalisation (DIG trial) but does NOT reduce mortality. Reserved as add-on therapy when symptoms persist despite ACE inhibitor/ARB/ARNI, beta-blocker, MRA, and SGLT2 inhibitor. Most useful in HFrEF with concomitant AF.
2. Atrial fibrillation / flutter — rate control: Slows the ventricular response by AV-nodal blockade. Best in sedentary or hypotensive patients and those with coexisting HFrEF; poor at controlling rate during exertion (vagal effect is overridden by sympathetic drive).
3. (Historical) Paroxysmal SVT — superseded by adenosine and AV-nodal blockers.

High-yield: In AF, digoxin controls resting but not exertional ventricular rate; beta-blockers/non-dihydropyridine calcium channel blockers are preferred first-line for rate control.

High-yield: Digoxin improves morbidity (fewer hospitalisations) but is mortality-neutral in HFrEF — a favourite exam fact.

Drug Interactions (commonly tested)

Drug	Effect on digoxin	Mechanism
Quinidine	↑↑ Level (classic)	Displaces from tissue + ↓ renal/biliary clearance (P-glycoprotein)
Amiodarone, verapamil, dronedarone	↑ Level	↓ Clearance / P-gp inhibition
Diuretics (loop, thiazide)	↑ Toxicity	Hypokalaemia potentiates binding
Macrolides, tetracyclines	↑ Level	Kill gut flora that inactivate digoxin
Cholestyramine, antacids, kaolin	↓ Absorption	Binding in gut
Potassium	Antagonises toxicity	Competes at Na⁺/K⁺-ATPase site

High-yield: Hypokalaemia, hypomagnesaemia, and hypercalcaemia all PRECIPITATE digoxin toxicity. Hyperkalaemia is protective against arrhythmia (but acute severe hyperkalaemia in overdose is an ominous prognostic marker).

Digoxin Toxicity

Toxicity may be acute (overdose/suicidal) or chronic (drug interaction, renal decline, electrolyte disturbance—the more common scenario in elderly).

Clinical features

Approach: Symptoms → think GI → Visual → CNS → Cardiac.

• Gastrointestinal (earliest): anorexia, nausea, vomiting, abdominal pain, diarrhoea.
• Visual: blurred vision, xanthopsia (yellow vision), also greenish halos, scotomata, photophobia. Classically linked to Van Gogh's "yellow period" (apocryphal but examinable).
• CNS: confusion, fatigue, headache, delirium, disorientation (especially elderly).
• Cardiac (most dangerous): virtually any arrhythmia can occur. The combination of increased automaticity + AV block is characteristic.

High-yield: The arrhythmia said to be pathognomonic / virtually diagnostic of digoxin toxicity is paroxysmal atrial tachycardia (PAT/atrial tachycardia) WITH AV block ("PAT with block"). Also classic: bidirectional ventricular tachycardia.

Toxic arrhythmias	Toxic conduction blocks
Ventricular ectopics (commonest)	First-degree AV block
Bidirectional VT	High-grade AV block
Atrial tachycardia with block	Sinus bradycardia/arrest
Junctional tachycardia	—

Precipitating factors

Mnemonic — "HARD HIT" precipitates digoxin toxicity: Hypokalaemia, Alkalosis/Age (elderly), Renal failure, Drugs (quinidine/amiodarone/verapamil), Hypomagnesaemia, Hypercalcaemia, Ischaemia/hypoxia, Thyroid (hypothyroidism).

Laboratory markers

• Serum digoxin level (correlate with symptoms, not in isolation).
• Serum potassium — in acute overdose, hyperkalaemia is the single best predictor of mortality (reflects massive pump inhibition). A serum K⁺ >5.5 mEq/L in acute poisoning historically predicted high mortality if untreated.

Management of Toxicity

Flow: Stop digoxin → correct electrolytes (K⁺, Mg²⁺) → treat arrhythmia → digoxin-specific Fab for life-threatening cases.

1. Discontinue digoxin and any precipitating drugs.
2. Correct hypokalaemia and hypomagnesaemia (magnesium also directly suppresses digoxin-induced arrhythmias). In acute overdose with hyperkalaemia, do NOT give calcium (theoretical "stone heart" from added Ca²⁺ load).
3. Bradyarrhythmias / AV block: atropine; temporary pacing if refractory.
4. Ventricular arrhythmias: lidocaine or phenytoin (phenytoin also improves AV conduction—useful when block coexists). Avoid quinidine/procainamide.
5. Definitive antidote — Digoxin-specific antibody fragments (Digoxin Immune Fab; DigiFab/Digibind):
   • Ovine (sheep) IgG Fab fragments that bind free digoxin → the digoxin–Fab complex is renally excreted.
   • Indications: life-threatening ventricular arrhythmias, K⁺ >5 mEq/L in acute toxicity, haemodynamically significant bradyarrhythmias unresponsive to atropine, ingestion of >10 mg (adult)/>4 mg (child), serum digoxin >10–15 ng/mL, or end-organ dysfunction from any glycoside.
   • Onset within ~30 min; reverses hyperkalaemia and arrhythmias dramatically.

High-yield: Digoxin-specific Fab is the definitive antidote. After Fab administration, measured total serum digoxin levels become uninterpretable (assay detects bound drug). Watch for rebound hypokalaemia as the pump reactivates.

High-yield: Dialysis is useless for digoxin (huge V_d, tissue-bound). This is a frequent distractor.

Contraindications & Cautions

• Wolff-Parkinson-White (WPW) with AF — digoxin (and other AV-nodal blockers) can accelerate conduction down the accessory pathway → VF. Absolute contraindication.
• Hypertrophic obstructive cardiomyopathy (HOCM) — positive inotropy worsens outflow obstruction.
• Second/third-degree AV block without pacemaker.
• Caution: renal impairment, electrolyte disturbance, elderly, hypothyroidism.

Key Differentials & Comparisons

Digoxin ECG "effect" vs "toxicity":

Feature	Digoxin effect (therapeutic)	Digoxin toxicity
ST segment	Sagging "reverse-tick" depression	—
T wave	Flattened/inverted	—
QT	Shortened	—
PR	Mildly prolonged	Marked AV block
Rhythm	Normal sinus/controlled AF	PAT with block, bidirectional VT, ectopics

Other positive inotropes (for contrast in HF): sympathomimetics (dobutamine, dopamine), PDE-3 inhibitors (milrinone, inamrinone), calcium sensitisers (levosimendan). Unlike these, digoxin also slows the heart rate and is orally bioavailable for chronic use.

Recently asked / exam angle

• Mechanism: "Digoxin increases intracellular calcium by inhibiting Na⁺/K⁺-ATPase and reducing Na⁺/Ca²⁺ exchange" — single most repeated stem.
• Antidote: Digoxin-specific Fab fragments — recurring one-liner.
• Pathognomonic arrhythmia: PAT with block / bidirectional VT — image-based and text MCQs.
• Electrolyte: Hypokalaemia precipitates toxicity; acute-overdose hyperkalaemia predicts mortality; calcium and digoxin are dangerous together.
• Therapeutic monitoring: sample 6–8 h post-dose; modern HF target 0.5–0.9 ng/mL.
• DIG trial: reduces hospitalisation, mortality-neutral.
• Contraindication: WPW with AF; HOCM.
• Visual symptom: xanthopsia (yellow vision) — Van Gogh association.
• Drug interaction: quinidine doubles digoxin levels (classic AIIMS/NEET pairing).
• Dialysis non-removability because of large volume of distribution.

Rapid revision

1. Digoxin inhibits Na⁺/K⁺-ATPase → ↑ intracellular Na⁺ → ↓ NCX → ↑ intracellular Ca²⁺ → positive inotropy.
2. AV-nodal slowing in AF is mainly vagally (parasympathetically) mediated.
3. Therapeutic HF level 0.5–0.9 ng/mL; toxicity rises above 2 ng/mL.
4. Digoxin is renally excreted; digitoxin is hepatically metabolised.
5. In HFrEF: fewer hospitalisations, no mortality benefit (DIG trial).
6. In AF: controls resting but not exertional ventricular rate.
7. Hypokalaemia, hypomagnesaemia, hypercalcaemia precipitate toxicity; K⁺ is protective.
8. Pathognomonic toxic rhythms: PAT with block and bidirectional VT.
9. Earliest toxicity symptoms are GI (nausea, anorexia, vomiting); classic visual sign is xanthopsia.
10. Antidote = digoxin-specific Fab fragments; indicated for K⁺ >5 mEq/L in acute toxicity and life-threatening arrhythmias.
11. Dialysis does not remove digoxin (large volume of distribution, tissue-bound).
12. Quinidine, amiodarone, verapamil raise digoxin levels; WPW with AF and HOCM are contraindications.