---

Drugs Used to Treat Hypotension (Antihypotensive / Vasopressor Agents)

---

1. Receptor Pharmacology Overview

---

2. Major Drug Classes

A. Selective α₁ Agonists — Pure Vasopressors

Phenylephrine

• Mechanism: Selective α₁ agonist → arterial and venous vasoconstriction → ↑ peripheral resistance → ↑ BP
• Effect: Raises systolic and diastolic BP; reflexively slows heart rate (baroreceptor-mediated vagal reflex) — no direct cardiac stimulation
• Uses: Intraoperative hypotension, septic shock adjunct, nasal decongestant (topical)
• Key point: Cardiac output may actually decrease slightly due to the reflex bradycardia, but stroke volume increases due to improved venous return

Midodrine

• Mechanism: Selective α₁ agonist (prodrug converted to desglymidodrine)
• Uses: Orthostatic hypotension — particularly useful for chronic management; also used in patients with autonomic dysfunction (e.g., Parkinson's, diabetic autonomic neuropathy, post-surgical autonomic failure)
• Route: Oral (unique among vasopressors)
• Key point: Widely used to ameliorate orthostatic hypotension in patients with autonomic failure where the compensatory baroreflex is absent, so there is no reflex tachycardia

---

B. Mixed α/β Agonists — Combined Vasopressor + Inotrope

Epinephrine (Adrenaline)

• Mechanism: Activates α₁, β₁, and β₂ receptors
  • At low doses: β₂ dominates → vasodilation
  • At high doses: α₁ dominates → vasoconstriction → ↑ BP
  • β₁ → ↑ heart rate, ↑ contractility, ↑ cardiac output
• Cardiovascular effects:
  • ↑↑ Systolic BP
  • Variable diastolic (↑ at high doses, ↓ at low doses)
  • ↑ Pulse pressure
  • ↑ Cardiac output
• Uses:
  • Anaphylactic shock — drug of choice (reverses bronchospasm + hypotension)
  • Cardiac arrest resuscitation
  • Adjunct in septic shock
  • Combined with local anesthetics (vasoconstriction prolongs action, reduces systemic toxicity)
• Route: IV, IM, SC, topical

Norepinephrine (Noradrenaline)

• Mechanism: Potent α₁ + α₂ agonist; moderate β₁; minimal β₂
• Effect: Strong vasoconstriction → ↑↑ TPR; modest inotropic effect; reflexive bradycardia possible
• Uses: Septic shock (first-line vasopressor per surviving sepsis guidelines), cardiogenic shock
• Key distinction from epinephrine: Less β₂ activity → more pure vasoconstriction, less tachycardia

Dopamine

• Mechanism: Dose-dependent receptor activation:
  • Low dose (1–5 μg/kg/min): D₁ receptors → renal/mesenteric vasodilation (increases urine output)
  • Moderate dose (5–10 μg/kg/min): β₁ → ↑ contractility, ↑ HR, ↑ CO
  • High dose (>10 μg/kg/min): α₁ → vasoconstriction → ↑ BP
• Uses: Shock states (particularly cardiogenic), acute heart failure with hypotension
• Note: The "renal-dose" dopamine concept has largely fallen out of favor in clinical practice

Ephedrine

• Mechanism: Indirect-acting (releases endogenous norepinephrine) + direct α and β agonist
• Effect: ↑ BP, ↑ HR, ↑ cardiac output; CNS stimulant
• Uses: Hypotension during spinal/epidural anesthesia, nasal congestion (oral)
• Tachyphylaxis: Occurs with repeated doses as norepinephrine stores deplete

---

C. Selective β₁ Agonists — Inotropes (for Low CO Hypotension)

Dobutamine

• Mechanism: Selective β₁ agonist; mild β₂ and α₁ activity
• Effect: ↑ contractility, ↑ CO; mild vasodilation (β₂); does not significantly raise BP by vasoconstriction
• Uses: Cardiogenic shock, acute decompensated heart failure where low cardiac output drives hypotension
• Also used as: Pharmacologic cardiac stress test (reveals myocardial ischemia)

---

D. Non-Catecholamine Vasopressors

Vasopressin (ADH / Arginine Vasopressin)

• Mechanism: V₁ receptors on vascular smooth muscle → vasoconstriction (independent of adrenergic pathway)
• Uses: Vasodilatory shock (e.g., septic shock) — often added to norepinephrine; also used in vasoplegic syndrome post-cardiac surgery
• Key advantage: Effective when adrenergic receptors are downregulated in prolonged shock

Terlipressin

• Long-acting synthetic vasopressin analogue
• Used in hepatorenal syndrome and variceal bleeding-associated hypotension

---

3. Cardiovascular Response Comparison

---

4. Clinical Indications Summary

---

5. Adverse Effects

• All vasopressors: Tissue ischemia/necrosis at injection site (extravasation), excessive hypertension, reflex bradycardia
• Epinephrine: Tachyarrhythmias, anxiety, tremor, hyperglycemia
• Dopamine: Tachyarrhythmias, excessive vasoconstriction at high doses
• Midodrine: Supine hypertension (must not be taken before lying down), pilomotor reactions, urinary retention
• Vasopressin: Coronary vasoconstriction, skin necrosis, hyponatremia

---

---

Classification of Antihypotensive Drugs

---

I. Sympathomimetic (Adrenergic) Drugs

A. Direct-Acting (act directly on adrenoceptors)

1. Selective α₁ Agonists

• Phenylephrine
• Methoxamine
• Midodrine (oral; prodrug → desglymidodrine)

2. α + β Agonists (Non-selective)

• Epinephrine (α₁, α₂, β₁, β₂)
• Norepinephrine (α₁, α₂, β₁ >> β₂)
• Dopamine (dose-dependent: D₁, β₁, α₁)

3. Selective β₁ Agonists (Inotropes)

• Dobutamine (β₁ >> β₂, α₁)
• Isoproterenol (β₁ + β₂ — raises CO but can drop DBP)

---

B. Indirect-Acting (release endogenous norepinephrine)

• Ephedrine
• Pseudoephedrine
• Amphetamine

---

C. Mixed (Direct + Indirect)

• Ephedrine (often classified here)
• Metaraminol

---

II. Non-Adrenergic Vasopressors

A. Vasopressin & Analogues (V₁ receptor agonists)

• Vasopressin (ADH)
• Terlipressin (longer-acting; hepatorenal syndrome)
• Desmopressin

B. Angiotensin II

• Angiotensin II (Giapreza) — approved for vasodilatory shock; acts on AT₁ receptors → vasoconstriction

---

III. Mineralocorticoids (Volume Expansion)

• Fludrocortisone — increases sodium/water retention → ↑ blood volume
• Used in: orthostatic hypotension, adrenal insufficiency

---

IV. Corticosteroids (Adjunct in Refractory Shock)

• Hydrocortisone — restores vascular sensitivity to catecholamines in septic shock
• Mechanism: upregulates adrenoceptor expression, anti-inflammatory

---

V. Plasma Volume Expanders (Indirect Correction of Hypotension)

• Crystalloids — Normal saline, Ringer's lactate
• Colloids — Albumin, Hydroxyethyl starch, Dextran
• Blood products — Packed RBCs, FFP (hemorrhagic shock)

---

Summary Tree

Antihypotensive Drugs
│
├── Sympathomimetics
│   ├── Direct-acting
│   │   ├── α₁ selective → Phenylephrine, Midodrine
│   │   ├── α + β → Epinephrine, Norepinephrine, Dopamine
│   │   └── β₁ selective → Dobutamine
│   ├── Indirect-acting → Ephedrine, Pseudoephedrine
│   └── Mixed → Metaraminol
│
├── Non-Adrenergic Vasopressors
│   ├── Vasopressin analogues → Vasopressin, Terlipressin
│   └── Angiotensin II
│
├── Mineralocorticoids → Fludrocortisone
│
├── Corticosteroids (adjunct) → Hydrocortisone
│
└── Volume Expanders → Crystalloids, Colloids, Blood products

---