Alpha blockers
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Alpha Blockers (Alpha-Adrenoceptor Antagonist Drugs)
Classification
Alpha blockers are classified by receptor selectivity and reversibility:
| Category | Drugs | Reversibility |
|---|---|---|
| Non-selective (α1 + α2) | Phentolamine, Phenoxybenzamine | Reversible / Irreversible |
| Selective α1 | Prazosin, Terazosin, Doxazosin | Reversible |
| Selective α1A (uro-selective) | Tamsulosin, Alfuzosin, Silodosin | Reversible |
Mechanism of Action
Alpha blockers occupy alpha-adrenoceptors and prevent their activation by catecholamines (norepinephrine, epinephrine).
- Reversible blockers (phentolamine, prazosin): dissociate from receptors; their block can be overcome by high agonist concentrations. Duration depends mainly on the drug's plasma half-life.
- Irreversible blockers (phenoxybenzamine): covalently bind by forming a reactive ethyleniminium intermediate. The block cannot be surmounted regardless of agonist concentration. Restoration of receptor responsiveness requires synthesis of new receptors, which may take several days -- important when a patient needs urgent surgery.
Katzung's Basic and Clinical Pharmacology, 16th Ed., p. 245-246
Cardiovascular Effects
Because arteriolar and venous tone are largely maintained by alpha receptors on vascular smooth muscle, alpha blockade causes:
- Decreased peripheral vascular resistance and blood pressure
- Venous dilation - splanchnic capacitance veins dilate, reducing venous return
- Orthostatic hypotension - blocking sympathetically-mediated vasoconstriction prevents the normal compensation for postural changes (gravitational pooling of blood)
- Reflex tachycardia - baroreflex activation; beta receptors are unopposed, compensatory heart rate increase
Epinephrine reversal: When both alpha and beta receptors exist in vasculature, alpha blockers unmask the beta2 vasodilator effect of epinephrine. A pressor dose of epinephrine can be converted to a depressor response -- this is "epinephrine reversal."
Katzung's Basic and Clinical Pharmacology, 16th Ed., p. 246
Individual Drugs
Non-Selective Alpha Blockers
Phenoxybenzamine
- Irreversible, non-selective alpha blocker
- Covalently binds alpha receptors
- Use: Pre-operative management of pheochromocytoma (blocks catecholamine surges)
- Administer for 1-2 weeks before surgical removal; prevents hypertensive crises
- Effects persist days (until new receptors are synthesized)
- ADRs: Orthostatic hypotension, reflex tachycardia, nasal congestion, inhibition of ejaculation
Phentolamine
- Reversible, non-selective alpha blocker
- Uses: Pheochromocytoma (acute hypertensive crises), prevention/treatment of dermal necrosis from norepinephrine extravasation, hypertensive emergencies
- Short-acting; given IV for acute use
- ADRs: Tachycardia, arrhythmias, GI stimulation (due to unopposed parasympathetics + alpha2 blockade enhancing NE release)
Selective α1 Blockers
Prazosin, Terazosin, Doxazosin
- Competitive (reversible) selective α1 blockers
- Relax both arterial and venous smooth muscle
- Unlike non-selective blockers, cause minimal reflex tachycardia (α2 receptors on presynaptic terminals remain intact, limiting norepinephrine release)
- Minimal change in cardiac output, renal blood flow, or GFR
Key pharmacological difference: Unlike phenoxybenzamine/phentolamine, these agents do NOT block presynaptic α2 receptors, so the feedback inhibition of NE release is preserved.
| Drug | Half-life | Duration | Notes |
|---|---|---|---|
| Prazosin | ~3 hrs | Short | Prototype; 3x daily dosing |
| Terazosin | ~12 hrs | Intermediate | Once daily |
| Doxazosin | ~22 hrs | Long | Longest acting; fecal excretion |
Therapeutic Uses:
- Hypertension - not first-line (inferior cardiovascular outcomes vs other antihypertensives, e.g., ALLHAT trial findings)
- Benign Prostatic Hyperplasia (BPH) - relax smooth muscle of bladder neck and prostate
- May produce modest improvement in lipid profiles and glucose metabolism
First-dose effect: The initial dose can produce an exaggerated orthostatic hypotensive response leading to syncope. Minimized by:
- Starting at 1/3 to 1/4 of normal dose
- Giving first dose at bedtime
Lippincott Illustrated Reviews: Pharmacology, p. 257-259
Uro-Selective α1A Blockers (for BPH)
| Drug | Key Feature |
|---|---|
| Tamsulosin | High α1A selectivity; minimal BP effect |
| Alfuzosin | Moderate selectivity |
| Silodosin | Highest α1A selectivity; most uro-selective |
These agents are more selective for α1A receptors in the prostate and bladder (than α1B in blood vessels), so they improve urinary flow with less pronounced hypotension.
Mechanism in BPH: Blockade of α1A receptors decreases tone in smooth muscle of the bladder neck and prostate, improving urine outflow and reducing symptoms.
Lippincott Illustrated Reviews: Pharmacology, p. 257-258
Adverse Effects (Class-Wide)
| Effect | Mechanism |
|---|---|
| Orthostatic hypotension | Venous dilation, impaired sympathetic vasoconstriction on standing |
| Reflex tachycardia | Baroreflex response (more with non-selective blockers) |
| First-dose syncope | Exaggerated hypotension - especially with prazosin |
| Nasal congestion | Nasal mucosal vasodilation |
| Inhibition of ejaculation | Block of α1 receptors in vas deferens (phenoxybenzamine > others) |
| Floppy iris syndrome | Intraoperative - iris billows during eye surgery; particularly tamsulosin |
| Additive hypotension | With vasodilators, nitrates, PDE-5 inhibitors (e.g., sildenafil) |
| Dizziness, drowsiness, fatigue | CNS effects |
Lippincott Illustrated Reviews: Pharmacology, p. 259
Clinical Uses - Summary
| Indication | Drug of Choice | Notes |
|---|---|---|
| Pheochromocytoma (pre-op) | Phenoxybenzamine | Start weeks before surgery; irreversible block needed |
| Pheochromocytoma (acute crisis) | Phentolamine IV | Rapid-acting reversible |
| Hypertension | Doxazosin / Terazosin | Not first-line; used as add-on |
| BPH | Tamsulosin, Alfuzosin, Silodosin | First-line; uro-selective preferred |
| NE extravasation necrosis | Phentolamine (local) | Injected around the site |
| PTSD nightmares | Prazosin | Off-label, reduces nightmare frequency |
Key Exam Points
- Epinephrine reversal = classic alpha blocker pharmacology exam concept
- Phenoxybenzamine is the only irreversible alpha blocker
- First-dose syncope is specific to selective α1 blockers (prazosin > others); minimized by bedtime dosing at low starting dose
- Floppy iris syndrome is most associated with tamsulosin - patients must inform their ophthalmologist before cataract surgery
- Alpha blockers are NOT first-line for hypertension (inferior outcomes per ALLHAT trial)
- Doxazosin has the longest duration; fecal excretion (unlike others which are urinary)
- ALLHAT trial showed doxazosin inferior to chlorthalidone for cardiovascular outcomes in hypertension
Microscopic image of atherscolisid in pathology
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Atherosclerosis - Microscopic Pathology
1. Atherosclerotic Plaque - Histology (Coronary Artery Cross-Section)
What you see in this image (A, B, C):
-
(A) Low power - Masson trichrome stain:
- L = Lumen (narrowed due to eccentric plaque)
- F = Fibrous cap (blue stain = dense collagen)
- C = Central necrotic/lipid core (pale, acellular)
- Arrow = area of vessel wall that is unaffected (eccentric lesion - key feature)
- The plaque occupies one side of the vessel; the opposite wall is relatively normal
-
(B) Medium power - elastin stain (black):
- Internal and external elastic membranes are attenuated and disrupted under the plaque
- Media of artery is thinned at the site of maximal plaque (arrow)
- Yellow staining = collagen-rich fibrous cap
-
(C) High power - junction of fibrous cap and necrotic core:
- Scattered inflammatory cells (lymphocytes, macrophages)
- Calcification = basophilic deposits (arrowheads)
- Neovascularization = small new blood vessels within the plaque (small arrows)
- Empty spaces = cholesterol clefts (cholesterol crystals washed out during processing)
Robbins & Kumar Basic Pathology, p. 319
2. Plaque Rupture and Thrombosis (Histology)
- (A) Plaque rupture without superimposed thrombus - arrow points to site of cap disruption
- (B) Acute coronary thrombosis superimposed on a ruptured plaque - the thrombus (dark pink mass) completely occludes the lumen; arrow shows site of fibrous cap rupture - this is the morphology of fatal myocardial infarction
Robbins & Kumar Basic Pathology, p. 322
3. Atheromatous Plaque - Structural Diagram
This labeled diagram shows the microscopic components of a mature atherosclerotic plaque:
Fibrous cap contains:
- Smooth muscle cells (SMCs)
- Macrophages and foam cells
- Lymphocytes
- Collagen, elastin, proteoglycans
- Neovascularization
Necrotic center contains:
- Cell debris
- Cholesterol crystals
- Foam cells (lipid-laden macrophages)
- Calcium deposits
Shoulder area (most vulnerable to rupture): Densest concentration of macrophages and T cells; thin cap here is where plaque rupture most commonly occurs.
Robbins & Kumar Basic Pathology, p. 314
4. Pathogenesis - Inflammasome Activation and Foam Cell Formation
Key microscopic events shown:
- Monocytes adhere to damaged endothelium and differentiate into macrophages in the intima
- LDL enters the intima and is oxidized → taken up by macrophages via scavenger receptors
- Cholesterol crystals form within macrophages → activate the NLRP3 inflammasome
- This releases IL-1β and IL-18 → sustains chronic inflammation
- Lipid-laden macrophages = foam cells (the hallmark early lesion = fatty streak)
Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 469
5. Natural History of Atherosclerosis - Summary Diagram
The progression from normal to clinical disease:
| Stage | Microscopic Features | Clinical Phase |
|---|---|---|
| Normal artery | Intact endothelium, normal intima | Asymptomatic |
| Fatty streak | Subendothelial foam cells, lipid deposits | Preclinical |
| Fibrofatty plaque | SMC migration to intima, ECM synthesis, lipid core | Preclinical |
| Advanced/vulnerable plaque | Thin cap, large lipid core, foam cells, inflammation | Subclinical or angina |
| Acute plaque changes | Rupture, erosion, or hemorrhage into plaque | Acute MI, stroke, sudden death |
Key Microscopic Features to Remember
| Feature | Significance |
|---|---|
| Foam cells | Lipid-filled macrophages; hallmark of fatty streak |
| Fibrous cap | Dense collagen + SMCs covering the necrotic core |
| Cholesterol clefts | Empty needle-shaped spaces (cholesterol dissolved in processing) |
| Calcification | Dystrophic calcium deposits in advanced plaques |
| Neovascularization | New capillaries within plaque - may bleed and cause intraplaque hemorrhage |
| Shoulder region | Most inflammatory, thinnest cap - highest rupture risk |
| Eccentric lesion | Plaque involves only part of the vessel circumference (cross-section appears asymmetric) |
Robbins & Kumar Basic Pathology, p. 319-322
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