Orthostatic Hypotension: Amlodipine + Multiple Myeloma

What Is Orthostatic Hypotension?

• Drop in systolic BP ≥ 20 mmHg (or ≥ 30 mmHg in hypertensive patients) within 3 minutes of standing
• Drop in diastolic BP ≥ 10 mmHg within 3 minutes of standing
• Or a pulse rise of > 30 bpm within 3 minutes of standing

Cause 1: Amlodipine

• Peripheral vasodilation: Amlodipine blocks L-type calcium channels in vascular smooth muscle, causing arterial dilation and reduced systemic vascular resistance (SVR).
• When a person stands up, blood pools in the lower extremities. Normally, reflexive vasoconstriction and increased heart rate compensate. Amlodipine blunts this vasoconstriction, so BP drops.

Cause 2: Multiple Myeloma

A. AL Amyloidosis - Autonomic Neuropathy

• MM produces abnormal immunoglobulin light chains (kappa or lambda). These deposit as amyloid fibrils in tissues including peripheral and autonomic nerves.
• AL (amyloid light chain) amyloidosis causes a progressive sensorimotor polyneuropathy with autonomic involvement (Bradley and Daroff's Neurology in Clinical Practice).
• Autonomic neuropathy disrupts the baroreceptor reflex arc: the body cannot sense the BP drop on standing and cannot mount a compensatory increase in heart rate or vasoconstriction.
• This is a form of neurogenic orthostatic hypotension - characterized by a BP drop on standing without the expected rise in pulse.

B. Direct Peripheral Neuropathy

• Even without amyloidosis, MM can cause peripheral and autonomic polyneuropathy directly, through paraprotein deposition, immune-mediated damage, and also as a side effect of treatment (notably bortezomib causes significant peripheral neuropathy).

C. Hypovolemia / Anemia

• MM patients often have anemia (bone marrow infiltration) and may be relatively volume depleted. Both worsen the postural BP response.

Why the Combination Is Dangerous

Diagnosis of OH in This Patient

1. Orthostatic vitals (most important): Measure BP and HR supine (after 5 min rest), then at 1 and 3 minutes standing. The sit-to-stand test uses lower cutoffs (SBP drop ≥ 15 mmHg, DBP drop ≥ 7 mmHg) per recent data.
2. Note the pulse response: If HR does NOT rise appropriately (< 10-15 bpm increase) with a BP drop, this strongly suggests neurogenic/autonomic OH (MM-related) rather than purely drug-induced.
3. Serum protein electrophoresis (SPEP), urine free light chains - assess MM disease activity and AL amyloid burden.
4. Check for other contributors: hydration status, hemoglobin, renal function.

Management

Drug Review

• Consider reducing or stopping amlodipine if BP control allows, or switching to an agent with less vasodilatory OH risk (e.g., a beta-blocker if appropriate).
• Review all other OH-inducing medications: diuretics, alpha-blockers, opioids.

Non-pharmacological (first-line for all OH)

• Rise slowly: Sit at the edge of bed/chair for 30-60 seconds before standing.
• Physical countermaneuvers: Leg crossing, toe raises, squatting - activate muscle pump to push blood back to the heart.
• Increase fluid and salt intake (unless contraindicated by cardiac or renal disease).
• Compression stockings/abdominal binders to reduce venous pooling.
• Elevate head of bed (reduces nocturnal hypertension and morning OH).
• Avoid hot environments, large carbohydrate meals, alcohol.

Pharmacological (if non-pharm insufficient)

• Fludrocortisone: Increases plasma volume via sodium retention.
• Midodrine: Peripheral alpha-1 agonist - increases SVR on standing.
• Pyridostigmine: Cholinesterase inhibitor that improves ganglionic sympathetic transmission; useful in neurogenic OH as it works mainly when upright.
• Treat underlying MM - reducing paraprotein/amyloid burden may slow autonomic neuropathy progression.

Key Clinical Pearl

Other Causes of Vertigo in This Patient (Amlodipine + Multiple Myeloma)

Framework: Peripheral vs. Central Vertigo

Category 1: Multiple Myeloma - Direct Neurological Causes

1. Hyperviscosity Syndrome

• MM paraproteins (especially IgA, IgG3, and IgM types) markedly increase serum viscosity.
• Impaired cerebral blood flow causes: headache, fatigue, visual disturbances, ataxia, vertigo, somnolence, and in severe cases - coma (Harrison's Principles, 22nd Ed.).
• Key exam finding: fundoscopy may show retinal venous engorgement ("linked sausages"), hemorrhages, papilledema.
• Labs: serum viscosity > 4 cP is symptomatic; rouleaux formation on blood smear.
• This is an emergency - requires plasmapheresis.

2. Hypercalcemia

• Occurs in up to 30% of MM patients from osteoclast activation and bone destruction.
• Classic CNS symptoms: lethargy, weakness, depression, confusion - and importantly, dizziness/vertigo-like symptoms from direct neuronal dysfunction.
• Severe hypercalcemia (> 14 mg/dL) impairs brainstem and cerebellar function.
• Also worsens dehydration, compounding orthostatic hypotension.

3. AL Amyloid - Vestibular/Cochlear Nerve Infiltration

• Amyloid light chains deposit in peripheral cranial nerves, including the 8th cranial nerve (vestibulocochlear).
• This causes sensorineural hearing loss + vestibular dysfunction = peripheral vertigo with possible tinnitus.
• May be associated with carpal tunnel syndrome (another amyloid neuropathy sign).

4. Spinal Cord / Brainstem Compression

• MM causes lytic bone lesions, particularly in the vertebral column. Vertebral collapse or direct epidural tumor extension can compress the spinal cord or posterior fossa structures.
• Compression at the cervicomedullary junction or brainstem can produce central vertigo, nystagmus, ataxia, and balance problems.
• MM is the most common cause of spinal cord compression from an unrecognized primary tumor (Pye's Surgical Handicraft).
• Red flags requiring urgent MRI: back/neck pain + vertigo, new neurological signs, bowel/bladder dysfunction.

5. Leptomeningeal / Intracranial Plasmacytoma

• Rare but possible: plasma cell infiltration into the CNS or skull base can compress cranial nerves, including the vestibular system, or raise intracranial pressure.

Category 2: Amlodipine Drug-Related Causes

6. Amlodipine-Induced Dizziness (Non-orthostatic)

• Amlodipine lists dizziness as a direct adverse effect - partly from peripheral vasodilation reducing cerebral perfusion pressure even without a postural component.
• Can cause non-specific dizziness that is not purely positional.

7. Amlodipine + Drug Interactions

• If the MM patient is on dexamethasone (common in MM regimens), the combination with amlodipine can unpredictably alter BP and cause dizziness.
• Bortezomib (a first-line MM drug) causes peripheral neuropathy including autonomic neuropathy, amplifying orthostatic and non-orthostatic dizziness.
• Thalidomide/lenalidomide also cause peripheral and autonomic neuropathy.

Category 3: Comorbid / Incidental Causes (Must Not Miss)

8. BPPV (Benign Paroxysmal Positional Vertigo)

• Most common cause of vertigo in the general population.
• Brief episodes (< 1 minute) triggered by specific head movements (rolling over in bed, looking up).
• Distinguished from OH: triggered by head movement, not by standing up per se.
• MM patients may be at higher risk if they are bedbound (prolonged recumbency displaces otoliths).
• Diagnosed by Dix-Hallpike maneuver; treated by Epley maneuver.

9. Vertebrobasilar Insufficiency (VBI) / Posterior Circulation TIA or Stroke

• MM patients have a hypercoagulable state (M-protein interferes with clotting factors, and treatment drugs like thalidomide/lenalidomide increase thrombotic risk).
• TIA or ischemic stroke in the posterior circulation (cerebellum, brainstem) causes central vertigo.
• Associated with dysarthria, diplopia, facial numbness, ataxia, sudden severe headache.
• Must rule out with MRI brain (DWI sequence) if any CNS signs present.

10. Anemia

• ~80% of MM patients have normocytic normochromic anemia from marrow replacement and erythropoietin deficiency (Harrison's Principles, 22nd Ed.).
• Severe anemia (Hb < 8 g/dL) reduces oxygen delivery to the brain, especially on standing, contributing to lightheadedness and near-syncope.

Diagnostic Priority Framework for This Patient

Vertigo on sitting-to-standing
        |
        ├── Positional (head movement triggers) → BPPV (Dix-Hallpike)
        |
        ├── Postural (standing triggers, resolves sitting) → Orthostatic BP measurement
        |       → Drug review (amlodipine), hydration, anemia
        |
        ├── Persistent / non-positional + CNS signs → URGENT MRI brain
        |       → VBI/stroke, brainstem compression, plasmacytoma
        |
        ├── Headache + visual changes + fatigue → Serum viscosity
        |       → Hyperviscosity syndrome (emergency)
        |
        └── Confusion + polyuria + constipation → Serum calcium
                → Hypercalcemia (common MM emergency)

Key Investigations to Order