---

Antihypertensive Drugs — Pharmacology

Classification of Antihypertensive Drugs

---

1. Diuretics

• Thiazides are first-line for essential hypertension and isolated systolic hypertension
• Mineralocorticoid receptor antagonists (MRAs) are preferred in hyperaldosteronism and heart failure
• In elderly: use low antihypertensive doses (not maximum diuretic doses) to avoid hypokalemia, hyperglycemia, and hyperuricemia

---

2. ACE Inhibitors (ACEIs)

• Heart failure
• Diabetes mellitus (especially with proteinuria/microalbuminuria)
• Post-MI, coronary artery disease
• Renal dysfunction, end-stage renal disease with proteinuria
• Previous stroke (with diuretics)
• Left ventricular hypertrophy
• Peripheral artery disease

---

3. Angiotensin Receptor Blockers (ARBs)

---

4. Calcium Channel Blockers (CCBs)

• Isolated systolic hypertension
• Asymptomatic atherosclerosis
• Stable angina (with β-blockers)
• Atrial fibrillation rate control (non-DHPs)
• Elderly patients (safe and effective)
• Metabolic syndrome, diabetes mellitus

---

5. Beta-Blockers (β-Blockers)

• Post-MI, coronary artery disease
• Chronic heart failure (bisoprolol, carvedilol)
• Angina pectoris
• Aortic aneurysm
• Prevention of atrial fibrillation

• Obstructive airway disease (asthma/COPD) — can cause bronchospasm
• Considered less useful in the elderly unless chronic heart failure is present

---

6. Centrally Acting Agents (Alpha-2 Agonists)

• Methyldopa: drug of choice in pregnancy-related hypertension
• Clonidine: hypertensive urgency, opioid withdrawal

---

7. Direct Vasodilators

---

8. Alpha-1 Blockers

---

Drug Selection by Compelling Indication

---

First-Line Recommendation (JNC / ACC/AHA Guidelines)

1. ACE Inhibitors / ARBs
2. Calcium Channel Blockers
3. Thiazide Diuretics
4. Beta-Blockers (particularly with compelling indications)

Blood pressure lowering per se is the most important goal — differences in outcome between drug classes are minimal when BP is equally controlled. Drug choice is individualized based on comorbidities and tolerability.

---

---

Drugs Affecting Cardiovascular Tone

---

Physiological Basis of Cardiovascular Tone

Baroreceptors in the carotid sinus and aortic arch monitor BP and relay signals to the rostral ventrolateral medulla (RVLM) → modulate sympathetic output to the heart and vasculature.

---

Classification of Drugs Affecting Cardiovascular Tone

A. VASOCONSTRICTORS (Drugs that ↑ Tone / ↑ BP)

1. Adrenergic Agonists (Sympathomimetics)

---

2. Renin-Angiotensin System (Angiotensin II)

• Angiotensin II is a potent vasoconstrictor acting via AT₁ receptors → vascular smooth muscle contraction + aldosterone release
• Drugs that block this system reduce tone (see vasodilators below)

---

3. Vasopressin (ADH) / Terlipressin

• Acts on V₁ receptors on vascular smooth muscle → vasoconstriction
• Used in: vasodilatory shock (sepsis), GI varices hemorrhage (terlipressin)

---

4. Endothelin Receptor Agonists

• Endothelin-1 is the most potent endogenous vasoconstrictor; acts via ETA receptors

---

B. VASODILATORS (Drugs that ↓ Tone / ↓ BP)

1. Nitrates / Nitric Oxide Donors

---

2. ACE Inhibitors

• Examples: Enalapril, Lisinopril, Ramipril, Captopril
• Mechanism: Block conversion of Ang I → Ang II; also prevent degradation of bradykinin (a vasodilator)
• Effect: ↓ Vasoconstriction + ↑ vasodilation via bradykinin
• Bradykinin inhibition by ACE contributes significantly to the antihypertensive action

---

3. Angiotensin Receptor Blockers (ARBs)

• Examples: Losartan, Valsartan, Candesartan
• Block AT₁ receptors → prevent Ang II-mediated vasoconstriction
• Unlike ACEIs, do NOT accumulate bradykinin → no cough

---

4. Calcium Channel Blockers (CCBs)

• Mechanism: Block L-type Ca²⁺ channels in vascular smooth muscle and/or cardiac myocytes
• Dihydropyridines (Amlodipine, Nifedipine): predominantly vascular → peripheral vasodilation
• Non-dihydropyridines (Verapamil, Diltiazem): cardiac + vascular → ↓ HR + ↓ contractility

---

5. Kinins (Pharmacological Context)

• Bradykinin and Kallidin → act on B₂ receptors → stimulate NO and PGI₂ release → vasodilation
• ACE inhibitors amplify kinin levels → contributes to vasodilatory antihypertensive effect
• B₂ receptor antagonists (e.g., Icatibant) → used in hereditary angioedema
• Kallikrein inhibitors (Ecallantide, Aprotinin, Lanadelumab) → reduce kinin synthesis

---

6. Natriuretic Peptides

• Nesiritide (recombinant BNP) — venodilation + natriuresis in acute heart failure
• Sacubitril (neprilysin inhibitor, combined with valsartan as LCZ696/Entresto) — prevents ANP/BNP breakdown → prolongs vasodilatory/natriuretic effects

---

7. Endothelin Receptor Antagonists

---

8. Phosphodiesterase Inhibitors

---

9. Alpha-1 Blockers

• Prazosin, Doxazosin, Terazosin
• Block α₁ adrenoceptors → prevent norepinephrine-mediated vasoconstriction
• Used in hypertension + BPH

---

10. Direct Vasodilators

• Hydralazine — arteriolar dilation (mechanism unclear, possibly NO-related); used in heart failure, pregnancy HTN
• Minoxidil — opens K⁺_ATP channels → hyperpolarization → vasodilation; severe/resistant HTN
• Diazoxide — opens K⁺_ATP channels; hypertensive emergencies

---

11. Prostacyclin Analogues

---

Summary Table

---

---

Cardiovascular Tone — Drugs in Pharmacology

• Arteriolar tone → Peripheral vascular resistance (PVR) → arterial blood pressure
• Venous tone → Venous capacitance → ventricular preload (right ventricular diastolic wall stress)

---

Molecular Basis of Vascular Smooth Muscle Tone

Contraction Pathway (↑ Tone)

Ca²⁺ enters via L-type channels → binds Calmodulin → forms Ca²⁺-Calmodulin complex → activates Myosin Light Chain Kinase (MLCK)* → phosphorylates Myosin-LC → interacts with Actin → CONTRACTION

Relaxation Pathway (↓ Tone)

Four major drug-targetable mechanisms:

---

Figure 1 — Vascular Smooth Muscle Contraction & Relaxation

---

Figure 2 — Nitric Oxide / Nitrate Mechanism in Vascular Smooth Muscle

---

Classification of Drugs by Effect on Cardiovascular Tone

---

A. DRUGS THAT INCREASE TONE (Vasopressors / Vasoconstrictors)

1. Adrenergic Agonists (Sympathomimetics)

---

2. Vasopressin (ADH) / Terlipressin

• Receptor: V₁ (vascular smooth muscle)
• Effect: Potent vasoconstriction → ↑ SVR
• Use: Vasodilatory (septic) shock; variceal hemorrhage (terlipressin)

3. Angiotensin II

• Acts via AT₁ receptors → vasoconstriction + aldosterone release
• Not used pharmacologically as a vasopressor per se, but underlies RAAS-mediated tone
• Pharmacological relevance: Blocked by ACEIs and ARBs (see below)

4. Endothelin-1 (ET-1)

• Most potent endogenous vasoconstrictor
• Stimulated by: Angiotensin II, catecholamines, hypoxia, thrombin, oxidized LDL, shear stress
• Inhibited by: NO, ANP, prostacyclin, PGE₂

---

B. DRUGS THAT DECREASE TONE (Vasodilators)

1. Organic Nitrates / Nitric Oxide Donors

• Predominantly venodilation at lower doses → ↓ preload
• Arteriolar dilation at higher doses → ↓ afterload
• Arterioles and precapillary sphincters dilate least due to reflex compensation and variable NO release
• Tolerance develops with continuous nitrate use (nitrate-free interval required)
• Nitroprusside does not develop tolerance (unlike nitroglycerin)

---

2. Calcium Channel Blockers (CCBs)

---

3. ACE Inhibitors (ACEIs)

• Examples: Captopril, Enalapril, Lisinopril, Ramipril, Perindopril
• Mechanism:
  • Block ACE → ↓ Angiotensin II → ↓ vasoconstriction + ↓ aldosterone
  • Also block bradykinin degradation → ↑ bradykinin → ↑ NO + PGI₂ → vasodilation
• Uses: HTN, HF, post-MI, diabetic nephropathy
• Side effect: Dry cough (bradykinin accumulation), angioedema

---

4. Angiotensin Receptor Blockers (ARBs)

• Examples: Losartan, Valsartan, Candesartan, Telmisartan
• Mechanism: Block AT₁ → prevent Ang II vasoconstriction without bradykinin accumulation
• No cough (unlike ACEIs)

---

5. Beta-Blockers

• Examples: Metoprolol (β₁), Atenolol (β₁), Carvedilol (α₁ + β₁ + β₂), Labetalol (α₁ + β)
• Mechanism: ↓ HR, ↓ contractility, ↓ CO → ↓ BP; also ↓ renin release
• Carvedilol and labetalol additionally block α₁ → direct vasodilation
• Uses: HTN, angina, HF, post-MI, arrhythmias

---

6. Potassium Channel Openers

---

7. PDE Inhibitors

---

8. Alpha-1 Blockers

• Examples: Prazosin, Doxazosin, Terazosin
• Prevent norepinephrine binding → arteriolar and venous dilation
• Side effect: First-dose orthostatic hypotension

---

9. Centrally Acting Agents (α₂ Agonists)

---

10. Endothelin Receptor Antagonists

---

11. Prostacyclin Analogues

---

12. Hydralazine (Direct Vasodilator)

• Mechanism: Direct arteriolar dilation (possibly via NO release or K⁺ channel opening)
• Uses: Resistant HTN, HF (combined with nitrates), hypertension in pregnancy
• Side effect: Reflex tachycardia, lupus-like syndrome with long-term use

---

Neurohumoral Regulators of Vascular Tone — Summary (Braunwald's Heart Disease)

---

Master Summary Table

---

---

Drugs for Hypotension — Pharmacology

Key principle: Adequate volume resuscitation must be attempted first. Vasopressors are initiated when hypotension and tissue hypoperfusion persist despite fluids (target MAP ≥ 65 mmHg).

---

A. VASOPRESSORS (Acute / ICU Setting)

1. Norepinephrine (Noradrenaline) — FIRST-LINE for Septic Shock

• Receptors: α₁ > α₂ (dominant), β₁
• Mechanism: α₁ → potent vasoconstriction → ↑ SVR; β₁ → ↑ inotropy + chronotropy
• Dose: Initial 0.02–0.05 mcg/kg/min IV; titrate up to 1.0 mcg/kg/min
• Pharmacokinetics: Half-life 1–2 min; metabolised via MAO + COMT
• Uses: Septic shock (first choice), post-cardiac arrest, mixed shock
• Adverse effects: Peripheral ischaemia, tissue necrosis (extravasation), tachyarrhythmia, ↓ splanchnic flow at high doses
• Admin: Preferred via central venous catheter

---

2. Epinephrine (Adrenaline) — Second-line Septic Shock / First-line Anaphylaxis / Cardiac Arrest

• Receptors: α₁, α₂, β₁, β₂ (non-selective)
• Mechanism:
  • Low dose: β₂ predominates → vasodilation + bronchodilation
  • High dose: α₁ predominates → vasoconstriction + ↑ SVR
  • β₁ → ↑ HR, ↑ contractility, ↑ CO
• Dose:
  • Cardiac arrest: 1 mg IV/IO every 3–5 min
  • Anaphylaxis: 0.3–0.5 mg IM (auto-injector) or IV infusion
  • Septic shock: 0.05–2 mcg/kg/min IV; titrate
  • Bradycardia: 2–10 mcg/min IV
• Half-life: <5 min
• Uses: Anaphylaxis, cardiac arrest (VF/VT/asystole), adjunct in septic shock when NE insufficient, symptomatic bradycardia
• Adverse effects: Tachyarrhythmias, myocardial ischaemia, ↓ splanchnic blood flow, pulmonary hypertension, lactic acidosis
• Formulations:
  • 1:10,000 (0.1 mg/mL) — for IV bolus in cardiac arrest
  • 1:1000 (1 mg/mL) — for IM anaphylaxis / IV infusion diluted

---

3. Dopamine — No Longer First-Line; Selective Use Only

• Receptors: Dose-dependent
  • Low (2–5 mcg/kg/min): D₁ → renal/mesenteric vasodilation
  • Moderate (5–10 mcg/kg/min): β₁ → ↑ HR, ↑ CO
  • High (>10 mcg/kg/min): α₁ → vasoconstriction
• Dose: 2–20 mcg/kg/min IV; max 50 mcg/kg/min
• Half-life: ~2 min; metabolised by MAO (75%) and converted to NE (25%)
• Uses: Haemodynamic support in MI, trauma, heart failure — only when NE unsuitable (bradycardia + low risk of tachyarrhythmia)
• Why downgraded: Randomised trials show ↑ tachyarrhythmia vs norepinephrine; ↑ mortality in cardiogenic shock subgroup
• Adverse effects: Tachyarrhythmia, ectopic beats, nausea, tissue ischaemia

---

4. Phenylephrine — Pure α₁ Agonist

• Receptors: α₁ selective
• Mechanism: Pure vasoconstriction → ↑ SVR → ↑ MAP; no β activity → causes reflex bradycardia
• Dose: IV bolus 40–100 mcg over 20–30 s (peri-anaesthesia); or IV infusion
• Half-life: Alpha phase ~5 min; terminal phase 2–3 h
• Uses: Hypotension under anaesthesia, peri-intubation hypotension, SVT (raises BP to trigger vagal response)
• Not recommended in septic shock (less effective than NE; ↓ cardiac output)
• Adverse effects: Reflex bradycardia, low CO, renal/mesenteric/myocardial ischaemia, hypertension

---

5. Vasopressin (ADH) — Add-on in Septic Shock

• Receptor: V₁ (vascular smooth muscle) → direct vasoconstriction; V₂ (renal) → antidiuresis
• Mechanism: Non-adrenergic vasoconstriction; does not cause tachycardia or increase myocardial oxygen demand
• Dose: Up to 0.03 units/min IV (added to norepinephrine)
• Uses:
  • Adjunct to NE in septic shock to ↑ MAP or ↓ NE dose
  • Vasodilatory shock (vasopressin deficiency present)
  • NOT recommended as single initial vasopressor in sepsis
  • No longer part of the ACLS cardiac arrest algorithm
• Adverse effects: Splanchnic ischaemia, coronary vasoconstriction, skin necrosis, hyponatraemia

---

6. Dobutamine — First-Line INOTROPE in Cardiogenic Shock

• Receptors: β₁ > β₂, minimal α
• Mechanism: ↑ Inotropy (β₁) + ↑ CO; β₂ → peripheral vasodilation (↓ afterload) — unlike NE
• Dose: 2–20 mcg/kg/min IV
• Uses: Cardiogenic shock, acute decompensated heart failure
• Can be combined with NE in mixed distributive + cardiogenic shock
• Adverse effects: Tachycardia, arrhythmias; long-term use deleterious in CHF (↑ catecholamine toxicity, receptor downregulation)

---

7. Milrinone — Inodilator (PDE-3 Inhibitor)

• Mechanism: Inhibits PDE-3 → ↑ cAMP → ↑ inotropy + ↑ chronotropy + ↓ SVR (vasodilation)
• Use: Acute decompensated HF; cardiogenic shock (especially when β-blocker cannot be stopped)
• Advantage: Works independent of β-receptors (useful when receptors are downregulated in chronic HF)
• Adverse effects: Hypotension (vasodilation), arrhythmias

---

B. DRUGS FOR ORTHOSTATIC / CHRONIC HYPOTENSION

Step-wise Pharmacotherapy

1. Fludrocortisone — First Step

• Class: Synthetic mineralocorticoid
• Mechanism: ↑ Renal Na⁺ and water reabsorption → ↑ intravascular volume → ↑ BP
• Dose: 0.1 mg/day (low dose)
• Onset: Requires ≥7 days for significant clinical effect
• Adverse effects: Supine hypertension, hypokalaemia, oedema

---

2. Midodrine — Selective α₁ Agonist (Oral)

• Class: Prodrug → converted peripherally to desglymidodrine (active α₁ agonist)
• Mechanism: Arteriolar + venous constriction → ↑ SVR + ↑ venous return → ↑ standing BP
• Dose: 5–10 mg three times daily
• Timing: Taken before getting out of bed, before lunch, and not within 3–4 hours of bedtime (avoid supine hypertension)
• Use: Symptomatic orthostatic hypotension, POTS (postural tachycardia syndrome)

---

3. Droxidopa — Norepinephrine Precursor

• Mechanism: Oral synthetic amino acid → decarboxylated to norepinephrine by AAAD in sympathetic postganglionic terminals and non-neuronal tissues → restores NE levels
• Dose: 100–600 mg three times daily
• Use: Neurogenic orthostatic hypotension (Parkinson's, MSA, pure autonomic failure)
• Same timing rule as midodrine (avoid supine hypertension)

---

4. Pyridostigmine

• Mechanism: Acetylcholinesterase inhibitor → ↑ cholinergic transmission in autonomic ganglia → ↑ sympathetic output on demand (only when standing) → less risk of supine hypertension
• Dose: 30–60 mg 2–3×/day
• Advantage: Does not worsen supine hypertension

---

5. Atomoxetine (NE Reuptake Inhibitor)

• Mechanism: Blocks NE reuptake → ↑ NE at neurovascular junction
• Dose: 10–18 mg twice daily
• Use: Orthostatic hypotension with preserved peripheral sympathetic function (e.g., MSA)

---

6. Octreotide (Somatostatin Analogue)

• Mechanism: Splanchnic vasoconstriction → reduces postprandial blood pooling
• Use: Postprandial hypotension
• Dose: 0.2–0.4 mcg/kg SC

---

7. Acarbose (α-glucosidase inhibitor)

• Mechanism: ↓ GI absorption of glucose → ↓ insulin-mediated vasodilation → ↓ postprandial BP drop
• Use: Postprandial hypotension (especially in diabetics)

---

8. Caffeine

• Mechanism: Adenosine receptor antagonist → inhibits adenosine-mediated vasodilation
• Use: Mild orthostatic hypotension, postprandial hypotension (morning coffee strategy)

---

Summary Table — Vasopressors & Inotropes

---

Summary Table — Orthostatic Hypotension Drugs

---