Vasopressors and inotropes with mechanism of action and use
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Vasopressors and Inotropes: Mechanism of Action and Clinical Use
Overview
Vasopressors increase systemic vascular resistance (SVR) to raise blood pressure. Inotropes increase myocardial contractility to improve cardiac output. Some agents do both (epinephrine, dopamine, norepinephrine), while others are more selective. All vasoactive agents should be used at the lowest effective dose for the shortest possible time, as they increase myocardial oxygen consumption and carry arrhythmia risk.
VASOPRESSORS
1. Norepinephrine (First-line Vasopressor)
| Property | Detail |
|---|---|
| Receptors | Predominantly α1-agonist; some β1-agonism; minimal β2 activity |
| Mechanism | Increases SVR via α1-mediated vasoconstriction; modest positive inotropy via β1 |
| Hemodynamic effects | ↑ MAP, ↑ SVR, maintained/slightly ↑ cardiac output, maintained heart rate |
| Dose | Start 2-5 mcg/min; titrate to MAP >65 mmHg (up to 30 mcg/min) |
| Primary use | First-line for septic shock; cardiogenic shock; neurogenic shock |
| Advantages | Fewer arrhythmias than dopamine; superior 28-day and in-hospital mortality vs dopamine in meta-analysis; increases GFR and urine output in sepsis |
| Avoid | Sole agent in hemorrhagic shock |
- ROSEN's Emergency Medicine, p. 2759; Washington Manual, p. 298
2. Dopamine (Dose-Dependent Effects)
| Property | Detail |
|---|---|
| Receptors | Dopaminergic (D1, D2), β1, α1 - dose-dependent activation |
| Mechanism | Low dose (<5 mcg/kg/min): dopaminergic receptor stimulation → renal/splanchnic vasodilation; Mid dose (5-10 mcg/kg/min): β1 stimulation → inotropy; High dose (>10 mcg/kg/min): α1 stimulation → vasoconstriction |
| Dose | 2-20 mcg/kg/min (dose-dependent effect profile) |
| Primary use | Limited role; may still be used in bradycardic hypotension |
| Disadvantages | Higher rate of arrhythmias than norepinephrine; higher mortality in cardiogenic shock; significant interpatient variability; no longer first-line for septic or cardiogenic shock |
- Washington Manual, p. 297; ROSEN's, p. 2759; Harrison's 22E, p. 2371
3. Phenylephrine (Pure α1-Agonist)
| Property | Detail |
|---|---|
| Receptors | Selective α1-agonist |
| Mechanism | Pure vasoconstriction - increases SVR without direct cardiac stimulation |
| Hemodynamic effects | ↑ MAP, ↑ SVR; reflex bradycardia; may decrease cardiac output |
| Dose | 2-300 mcg/min |
| Primary use | Hypotension with tachyarrhythmia (when β-stimulation is undesirable); adjunct in neurogenic shock (pure vasodilation); anesthesia-induced hypotension |
| Advantages | Does not impair cardiac or renal function; useful when tachycardia limits other agents |
| Disadvantages | Decreases cardiac output; not ideal for low-CO states |
- Washington Manual, p. 298; ROSEN's, p. 2760
4. Vasopressin (Adjunct Vasopressor)
| Property | Detail |
|---|---|
| Receptors | V1a receptors on vascular smooth muscle; V2 in renal tubules |
| Mechanism | V1a receptor activation → phospholipase C → IP3/DAG pathway → intracellular Ca²+ release → vascular smooth muscle contraction (vasoconstriction); non-catecholamine mechanism |
| Hemodynamic effects | ↑ SVR; does NOT increase pulmonary vascular resistance |
| Dose | 0.01-0.04 units/min (fixed dose, not titrated) |
| Primary use | Second-line adjunct to norepinephrine in refractory septic shock; useful in pulmonary hypertension or right ventricular dysfunction (does not raise PVR); obstructive shock secondary to PE |
| Key point | In septic shock, vasopressin levels fall profoundly after an initial surge - this is the rationale for exogenous replacement |
| Disadvantages | No mortality benefit shown when added to norepinephrine alone; do not use as sole initial vasopressor |
- Goodman & Gilman's, p. 2380; Barash Clinical Anesthesia, p. 3118; ROSEN's, p. 1475
5. Epinephrine (Combined Vasopressor/Inotrope)
| Property | Detail |
|---|---|
| Receptors | Potent α1, β1, and β2 agonist |
| Mechanism | At low doses: predominantly β-effects (inotropy, chronotropy, bronchodilation); at higher doses: α-mediated vasoconstriction predominates |
| Hemodynamic effects | ↑ HR, ↑ contractility, ↑ SVR, ↑ CO, ↑ MAP |
| Dose | 5-20 mcg/min (vasopressor use) |
| Primary use | Anaphylaxis (drug of choice); cardiac arrest; refractory shock unresponsive to other agents; combined septic + cardiogenic shock |
| Disadvantages | ↑ myocardial O2 consumption; ↑ systemic lactate (aerobic glycolysis - transient); ↓ splanchnic blood flow; associated with increased risk of death in cardiogenic shock when used alone; more arrhythmias |
- ROSEN's, p. 1477; Harrison's 22E, p. 2371
INOTROPES
6. Dobutamine (Most Commonly Used Inotrope)
| Property | Detail |
|---|---|
| Receptors | Mixed α1, β1, and β2 agonist |
| Mechanism | β1 stimulation → ↑ cAMP → ↑ intracellular Ca²+ → positive inotropy and chronotropy; β2 stimulation → vasodilation → ↓ afterload; net effect: ↑ cardiac output, ↑ stroke volume, ↓ SVR |
| Hemodynamic effects | ↑ CO, ↑ stroke volume, ↓ SVR/afterload, modest ↑ HR; may ↓ BP due to vasodilation |
| Dose | 2-15 mcg/kg/min (up to 20 mcg/kg/min if on beta-blockers) |
| Primary use | Cardiogenic shock with adequate blood pressure; acute decompensated heart failure with low output; septic shock with evidence of decreased LV function |
| Important notes | Tachyphylaxis occurs >24-48 hours (receptor desensitization); beta-blockers competitively antagonize effects (higher doses needed); do not use as sole agent in hypotension (vasodilatory effect); renal dysfunction - prefer over milrinone |
| Adverse effects | Tachycardia, arrhythmias, myocardial ischemia, possible cardiomyocyte apoptosis |
- Braunwald's Heart Disease, p. 120; ROSEN's, p. 1718; Washington Manual, p. 297
7. Milrinone (Inodilator)
| Property | Detail |
|---|---|
| Class | Phosphodiesterase III (PDE-3) inhibitor |
| Mechanism | Inhibits PDE-3 → ↓ cAMP degradation → ↑ intracellular cAMP → ↑ protein kinase A activity → ↑ intracellular Ca²+ → positive inotropy; also causes systemic and pulmonary vasodilation (↓ afterload and preload) |
| Hemodynamic effects | ↑ CO, ↓ SVR, ↓ PVR, ↓ PCWP; less chronotropy than dobutamine |
| Dose | 0.10-0.25 mcg/kg/min (loading dose 25-75 mcg/kg over 10-20 min, often omitted); up to 0.75 mcg/kg/min |
| Primary use | Acute decompensated heart failure; cardiogenic shock (esp. when on beta-blockers - works downstream of β-receptor); right heart failure (reduces PVR); bridging to MCS/transplant |
| Advantages | Effective even with beta-blocker use (mechanism independent of β-receptor); reduces PVR - useful in pulmonary hypertension |
| Disadvantages | Renally excreted - dose-reduce or switch to dobutamine in renal failure; delayed pharmacodynamic offset (half-life ~2.5 hours, PD effects >6 hours - monitor 48 hours after stopping); significant hypotension and arrhythmias; OPTIME-CHF trial showed increased hypotension, atrial arrhythmias, and no mortality benefit |
- Braunwald's Heart Disease, p. 201; Washington Manual, p. 297; Harrison's 22E
8. Levosimendan (Calcium Sensitizer - Not Available in USA)
| Property | Detail |
|---|---|
| Mechanism | Calcium-dependent binding to troponin C → myofilament calcium sensitization (systolic inotropy without ↑ Ca²+ load); + opens K-ATP channels in vascular smooth muscle → vasodilation; some PDE-3 inhibition |
| Hemodynamic effects | ↑ CO, ↓ SVR, ↓ PCWP; improved dyspnea |
| Dose | Infusion 0.05-0.2 mcg/kg/min; loading 12-24 mcg/kg optional |
| Primary use | Acute heart failure with reduced EF and hypoperfusion; available in >40 countries (not USA) |
| Key advantage | Does not increase myocardial O2 consumption proportionally; active metabolite with half-life >80 hours (effects persist days after stopping infusion) |
| Disadvantages | Hypotension (common); no benefit shown in sepsis-induced organ dysfunction or high-risk cardiac surgery |
- Braunwald's Heart Disease, p. 212
9. Digoxin (Cardiac Glycoside - Oral Inotrope)
| Property | Detail |
|---|---|
| Mechanism | Inhibits Na+/K+-ATPase pump → ↑ intracellular Na+ → ↓ Na+/Ca²+ exchanger activity → ↑ intracellular Ca²+ → increased inotropy; also: ↑ vagal tone → ↓ HR, ↓ AV conduction |
| Primary use | Chronic heart failure with reduced EF (modest benefit); rate control in atrial fibrillation; the only oral inotrope |
| Note | Narrow therapeutic index; risk of toxicity (nausea, arrhythmias); caution in renal impairment |
Summary Comparison Table
| Drug | Main Receptor/Mechanism | Effect on CO | Effect on SVR | Effect on HR | Primary Use |
|---|---|---|---|---|---|
| Norepinephrine | α1 >>> β1 | ↔/↑ | ↑↑ | ↔ | Septic shock (1st line) |
| Dopamine | D1→β1→α1 (dose-dependent) | ↑ | ↑ (high dose) | ↑ | Limited; bradycardic hypotension |
| Phenylephrine | α1 selective | ↓ | ↑↑ | ↓ (reflex) | Tachyarrhythmia + hypotension |
| Vasopressin | V1a (non-catecholamine) | ↔ | ↑↑ | ↔ | Adjunct in refractory septic shock |
| Epinephrine | α1 + β1 + β2 | ↑↑ | ↑↑ | ↑↑ | Anaphylaxis; cardiac arrest |
| Dobutamine | β1 >> β2 > α1 | ↑↑ | ↓ | ↑ | Cardiogenic shock (normotensive) |
| Milrinone | PDE-3 inhibitor (↑cAMP) | ↑↑ | ↓↓ | ↔ | HF on beta-blockers; ↑ PVR |
| Levosimendan | Ca²+ sensitizer + KATP | ↑↑ | ↓ | ↔/↑ | Acute HF (non-USA) |
| Digoxin | Na/K-ATPase inhibitor | ↑ (modest) | ↔ | ↓ | Chronic HF; AF rate control |
Clinical Selection Guide
| Shock Type | First Choice | Add-on |
|---|---|---|
| Septic shock | Norepinephrine | Vasopressin (adjunct); dobutamine if low EF |
| Cardiogenic shock | Norepinephrine (MAP support) + Dobutamine | Milrinone if on beta-blockers |
| Neurogenic shock | Norepinephrine | Phenylephrine if tachyarrhythmia |
| Anaphylaxis | Epinephrine | - |
| Acute HF (normotensive) | Dobutamine or Milrinone | - |
| Tachydysrhythmia + hypotension | Phenylephrine or Vasopressin | - |
| Right heart failure / ↑ PVR | Milrinone | Vasopressin (does not increase PVR) |
Key Clinical Pearls:
- All catecholamine vasopressors should be administered via central venous catheter ideally; if extravasation occurs, phentolamine (α-blocker) injected locally reverses ischemia
- Vasopressors are not primary therapy in hemorrhagic shock - blood products and bleeding control are
- Dobutamine has tachyphylaxis after 24-48 hours; milrinone's effects persist 48 hours after stopping
- In patients on chronic beta-blockers, milrinone or levosimendan are preferred since they act downstream of the β-receptor
- No vasopressor has been definitively shown to change outcome in large cardiogenic shock trials; norepinephrine is preferred based on fewer arrhythmias
Sources: Braunwald's Heart Disease; Harrison's Principles of Internal Medicine 22E; ROSEN's Emergency Medicine; Washington Manual of Medical Therapeutics; Goodman & Gilman's Pharmacological Basis of Therapeutics; Barash Clinical Anesthesia 9e
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