Why does pregabalin (an anticonvulsant medication) cause hypotension, particularly in older adults with a history of cardiovascular disease?

Why Pregabalin Causes Hypotension

Pregabalin causes hypotension primarily through its blockade of voltage-gated L-type calcium channels (specifically the alpha-2-delta-1 subunit), which disrupts normal vascular tone regulation and cardiac conduction, leading to vasodilation and reduced cardiac output. 1, 2

Mechanism of Action

Pregabalin binds to the alpha-2-delta-1 subunit protein of voltage-gated calcium channels throughout the cardiovascular system. 2 This mechanism, while therapeutic for anxiety and neuropathic pain, has unintended cardiovascular consequences:

• Vascular effects: Calcium channel blockade in peripheral blood vessels impairs the normal vasoconstrictor response needed to maintain blood pressure during postural changes, resulting in orthostatic hypotension. 1

• Cardiac conduction effects: The distribution pattern of L-type calcium channels in myocardium varies between individuals, which explains why some patients develop severe cardiac effects including complete atrioventricular block, while others experience only mild hypotension. 1

• Dose-dependent relationship: The hypotensive effect increases with higher doses (150-600 mg/day), as demonstrated in clinical trials where dizziness—a common manifestation of hypotension—was one of the most frequently reported adverse events. 2

High-Risk Populations

Elderly patients with cardiovascular disease face substantially elevated risk because pregabalin's hypotensive effects are compounded by age-related impairment of baroreceptor responses and altered pharmacokinetics. 3

• Patients with chronic kidney disease accumulate pregabalin due to reduced renal clearance (mean elimination half-life 6.3 hours in normal function), leading to toxic levels that precipitate severe cardiovascular events including complete AV block. 1, 2

• The combination of pregabalin with other hypotension-inducing medications (alpha-blockers, diuretics, vasodilators, ACE inhibitors) creates synergistic effects that dramatically increase fall risk and syncope. 3, 4

Clinical Manifestations Beyond Simple Hypotension

Pregabalin's cardiovascular toxicity extends beyond isolated blood pressure reduction:

• Peripheral and central edema: Dose-dependent fluid retention occurs through unclear mechanisms, potentially related to calcium channel effects on capillary permeability, leading to weight gain and even heart failure in susceptible patients. 5, 6

• Cardiac arrhythmias: Case reports document complete atrioventricular block, Mobitz type II block, and atrial fibrillation associated with pregabalin use, with elderly patients showing increased risk (RR 2.79-2.91 for new-onset AF). 1, 7

• Syncope and falls: The combination of orthostatic hypotension, dizziness, somnolence, and cognitive impairment creates a particularly dangerous profile in older adults. 3, 1

Critical Clinical Pitfalls

Do not simply reduce the pregabalin dose when hypotension develops—complete discontinuation is the primary treatment strategy for medication-induced orthostatic hypotension. 4 Dose reduction fails to adequately address the underlying calcium channel blockade mechanism.

• Switching to gabapentin is not a safe alternative, as it shares the same calcium channel mechanism and produces similar peripheral edema and hypotensive effects. 5

• The New York Heart Association issued warnings about prescribing pregabalin to patients with NYHA class III-IV heart failure, though published evidence remains limited. 5

• Tolerance to dizziness and somnolence may develop within weeks, but this does not indicate resolution of the underlying cardiovascular risk. 2

Monitoring Requirements

Before initiating pregabalin in at-risk patients, measure blood pressure after 5 minutes of sitting/lying, then at 1 and 3 minutes after standing to establish baseline orthostatic response. 4 Pregabalin should be avoided in patients with standing systolic BP <110 mmHg. 4

• Renal function monitoring is essential, as creatinine clearance <50 mL/min significantly increases risk of cardiovascular toxicity through drug accumulation. 1

• Cardiac monitoring with ECG is warranted in elderly patients or those with pre-existing conduction abnormalities, given the risk of AV block. 1