What is the mechanism of action of vasopressors?

Vasopressor Mechanisms of Action

Vasopressors work through distinct receptor-mediated pathways to increase blood pressure: catecholamines act via adrenergic receptors (α1, α2, β1, β2) causing vasoconstriction and increased cardiac contractility, vasopressin binds V1a receptors on vascular smooth muscle through a catecholamine-independent mechanism, and angiotensin II activates AG1/AG2 receptors to induce vasoconstriction. 1

Catecholamine Mechanisms

Adrenergic Receptor Activation

• Direct-acting catecholamines (norepinephrine, epinephrine, phenylephrine, dopamine) stimulate α and β receptors on vascular smooth muscle and cardiac tissue, producing vasoconstriction and increased inotropy 1
• α-adrenergic stimulation increases arterial resistance and may increase cardiac afterload through arterial vasoconstriction 1
• Norepinephrine induces both arterial and venous α-adrenergic stimulation, causing venoconstriction particularly in the splanchnic circulation, which increases pressure in capacitance vessels and actively shifts splanchnic blood volume to the systemic circulation 1
• β-adrenergic stimulation directly increases myocardial contractility and heart rate, while β2-receptor activation decreases venous resistance and increases venous return 1

Specific Agent Characteristics

• Norepinephrine and epinephrine are equipotent regarding effects on systemic blood pressure and systemic vascular resistance, though low-dose epinephrine may lower systemic blood pressure via vascular β2-adrenergic receptor activation 1
• Phenylephrine is a pure α1-adrenergic agonist with no β-adrenergic activity, causing vasoconstriction without direct inotropic effects, which may improve blood pressure but reduce blood flow through increased systemic vascular resistance 1, 2
• Dopamine at high doses (10-20 μg/kg/min) stimulates α-adrenergic receptors and increases mean arterial pressure primarily through increased cardiac output with minimal peripheral vasoconstriction 1

Vasopressin and Analogues Mechanisms

V1a Receptor Pathway

• Vasopressin causes vasoconstriction by binding to V1a receptors on vascular smooth muscle coupled to the Gq/11-phospholipase C-phosphatidyl-inositol-triphosphate pathway, resulting in release of intracellular calcium 3
• V1a-receptor activation produces catecholamine-independent vasoconstriction, which explains why vasopressin complements norepinephrine in septic shock when α-adrenergic receptors are down-regulated 1
• Vasopressin is released from the posterior pituitary in response to hypotension and hypernatremia, but vasopressin deficiency develops in early septic shock due to depletion of stores and inadequate synthesis from the hypothalamic-pituitary axis 1, 4

Additional Receptor Effects

• V2 receptors are coupled to adenyl cyclase and mediate antidiuretic effects at lower concentrations 3
• Vasopressin paradoxically induces nitric oxide synthesis, which may limit vasoconstriction while preserving renal perfusion but may also contribute to cardiac depression 1
• Highly selective V1a agonists (like selepressin) may have better effects than vasopressin by minimizing V2-mediated antidiuresis and reducing vascular leak 1

Angiotensin II Mechanism

• Angiotensin II activates AG1 and AG2 receptors to substantially increase systemic vascular resistance without alteration in cardiac output, subsequently increasing blood pressure 1, 5
• This mechanism is independent of both catecholamine and vasopressin pathways, providing an alternative target in refractory shock 6

Hemodynamic Consequences

Blood Pressure Effects

• All vasopressors increase mean arterial pressure through either increased systemic vascular resistance (pure vasoconstrictors), increased cardiac output (inoconstrictors), or both 7
• The pressor effect of vasopressin is proportional to infusion rate, reaches peak within 15 minutes, and fades within 20 minutes after stopping infusion 3
• Norepinephrine decreases preload dependency by increasing venous return via a shift of unstressed to stressed volume, with subsequent transient increase in cardiac output 1

Organ-Specific Effects

• Vasopressors may increase cardiac afterload if infusion rate is excessive or left ventricular function is impaired, requiring assessment of cardiac function and potential addition of inotropic agents 1
• Excessive vasoconstriction can compromise microcirculatory flow, particularly with pure α-agonists like phenylephrine, leading to organ ischemia 1, 2
• At therapeutic doses, vasopressin increases systemic vascular resistance and mean arterial blood pressure while tending to decrease heart rate and cardiac output 3

Clinical Pitfalls

• Receptor responses follow sigmoidal curves rather than linear relationships, resulting in pharmacological response to increasing doses followed by a plateau effect 1
• Prolonged catecholamine exposure causes α-adrenergic receptor down-regulation in septic shock, reducing responsiveness and necessitating alternative vasopressor mechanisms 1, 4
• Vasopressor adverse effects include excessive vasoconstriction causing organ ischemia/infarction, hyperglycemia, hyperlactatemia, tachycardia, and tachyarrhythmias 5, 6