Antihypertensive & Pulmonary Therapy

• Blood pressure reduction achieved via three primary physiologic targets
  • Decrease total peripheral resistance (TPR)
  • Decrease cardiac output (CO)
  • Reduce circulating blood volume
• Homeostatic counter-regulatory responses limit efficacy
  • Reflex tachycardia — triggered by baroreceptor unloading; increases myocardial oxygen demand
  • Edema and fluid retention — driven by renin–angiotensin–aldosterone system activation
• Clinical implication: combination therapy often required to offset compensatory mechanisms

• Vasodilator selectivity determines hemodynamic and side-effect profile
  • Arteriolar-predominant: CCBs, hydralazine, K⁺ channel openers → reduce afterload
  • Venular-predominant: nitrates → reduce preload
  • Mixed arteriolar/venular: nitroprusside, alpha-blockers → reduce both preload and afterload
• Orthostatic (postural) hypotension arises primarily from venular dilation → decreased venous return → reduced CO on standing

Thiazide Diuretics

• Mechanism: inhibit Na⁺/Cl⁻ cotransporter in distal convoluted tubule → ↓ sodium reabsorption → ↓ plasma volume → ↓ CO and TPR over time
• First-line for uncomplicated essential hypertension
• Preferred in elderly patients and those with isolated systolic hypertension
• Side-effect considerations: hypokalemia, hyperuricemia, glucose intolerance, hypercalcemia

ACE Inhibitors & ARBs

• ACEIs (captopril, lisinopril, others ending in "-pril")
  • Block conversion of angiotensin I → II
  • Reduce AT₁ receptor stimulation → vasodilation + ↓ aldosterone
  • Prevent bradykinin degradation → contributes to vasodilation but also causes side effects
• ARBs (losartan, others ending in "-sartan")
  • Selectively block AT₁ receptors
  • Same BP-lowering effect as ACEIs
  • Do not affect bradykinin metabolism → lower cough incidence
• Renin inhibitor: aliskiren
  • Blocks conversion of angiotensinogen → angiotensin I
  • Reduces formation of both angiotensin I and II
  • No bradykinin effect
• Common indications
  • Mild-to-moderate hypertension (all three classes)
  • Diabetic nephropathy — proteinuria reduction (ACEIs/ARBs)
  • Chronic heart failure with reduced ejection fraction (ACEIs/ARBs)
• Adverse effects shared by ACEIs
  • Dry, persistent cough (bradykinin-mediated) — most common reason for switching to ARB
  • Hyperkalemia — risk increases with renal impairment or K⁺-sparing diuretic co-administration
  • Acute kidney injury in bilateral renal artery stenosis
  • Angioedema — rare but potentially life-threatening
• Absolute contraindication: pregnancy (fetotoxic; risk of oligohydramnios and fetal renal agenesis)

Calcium-Channel Blockers

• Block L-type Ca²⁺ channels in cardiac myocytes and vascular smooth muscle
• Dihydropyridines ("-dipines", e.g., nifedipine)
  • Vascular-selective → potent arteriolar vasodilation → ↓ TPR
  • Reflex tachycardia common (baroreceptor-mediated)
  • Gingival hyperplasia with chronic use
• Non-dihydropyridines (verapamil, diltiazem)
  • Cardiac-selective → ↓ CO (negative chronotropy and inotropy)
  • Verapamil: constipation (common), AV nodal depression
  • Diltiazem: intermediate cardiac/vascular selectivity
• Clinical uses
  • Hypertension (all CCBs)
  • Stable angina (all CCBs)
  • Supraventricular tachyarrhythmias (verapamil, diltiazem)

Beta Blockers

• Not considered first-line for uncomplicated hypertension
• Strongly indicated in patients with coexisting conditions
  • Stable angina — reduce myocardial oxygen demand
  • Chronic heart failure with reduced EF — mortality benefit
  • Post-myocardial infarction — reduce sudden death
• Mechanism: competitive antagonism at β₁ (and β₂) adrenoceptors → ↓ HR, ↓ contractility, ↓ renin release
• Adverse effects
  • Cardiovascular depression — bradycardia, heart block, hypotension
  • Fatigue, exercise intolerance
  • Sexual dysfunction
  • Dyslipidemia — ↑ LDL, ↑ triglycerides
• Caution / contraindications
  • Asthma / COPD — non-selective β-blockers may precipitate bronchospasm
  • Vasospastic (Prinzmetal) angina — may worsen coronary vasospasm
  • Diabetes — mask hypoglycemic tachycardia; may impair glycemic recovery

Alpha-1 Blockers

• Drugs: prazosin, doxazosin, terazosin
• Mechanism: competitive blockade of α₁-adrenoceptors on vascular smooth muscle → arteriolar and venular dilation → ↓ TPR
• Reflex tachycardia may occur but less prominent than with direct vasodilators
• Dual use
  • Hypertension (often as add-on therapy)
  • Benign prostatic hyperplasia — relaxes prostatic and bladder neck smooth muscle → improved urinary flow
• Side-effect profile
  • First-dose syncope — marked orthostatic hypotension after initial dose (take at bedtime)
  • Orthostatic hypotension, dizziness
  • Urinary incontinence (especially in elderly women)
• Metabolic advantage: favorable lipid effects — ↑ HDL, ↓ LDL

Alpha-2 Agonists

• Drugs: clonidine, methyldopa (prodrug → active metabolite)
• Mechanism: stimulate central α₂-adrenoceptors → ↓ sympathetic outflow from CNS → ↓ TPR and ↓ HR
• Clinical applications
  • Mild-to-moderate hypertension (both agents)
  • Opiate withdrawal symptom management (clonidine)
  • Hypertension in pregnancy (methyldopa — established safety record)
• Adverse effects
  • Methyldopa — positive Coombs test (hemolytic anemia rare but monitor)
  • CNS depression — sedation, drowsiness (both)
  • Edema and fluid retention (both)
• Drug interaction: tricyclic antidepressants reduce the antihypertensive effect of α₂ agonists

Nitric Oxide–Mediated Agents

• Hydralazine
  • Arteriolar-selective vasodilator → ↓ TPR, minimal venodilation
  • Use: moderate-to-severe hypertension (often in combination)
  • Adverse effects
    • Drug-induced lupus-like syndrome — risk in slow acetylators; manifest as arthralgias, rash, serositis
    • Edema and reflex tachycardia — offset with concomitant beta-blocker and diuretic
• Nitroprusside
  • Mixed arteriolar and venular dilation (nitric oxide donor)
  • Use: hypertensive emergencies — IV administration with continuous titration
  • Major toxicity: cyanide accumulation — manifests as metabolic acidosis, altered mental status
  • Antidote for cyanide poisoning: hydroxocobalamin + sodium thiosulfate
    • Hydroxocobalamin binds cyanide → cyanocobalamin (excreted renally)
    • Sodium thiosulfate provides sulfur donor for rhodanese-mediated detoxification

Potassium Channel Openers

• Drugs: minoxidil, diazoxide
• Mechanism: open ATP-sensitive K⁺ channels in vascular smooth muscle → hyperpolarization → relaxation → arteriolar vasodilation
• Clinical uses
  • Minoxidil — severe, refractory hypertension; also topical formulation for androgenic alopecia
  • Diazoxide — insulinoma (inhibits insulin release from pancreatic β-cells)
• Adverse effects
  • Minoxidil — hypertrichosis (excessive hair growth), fluid retention, reflex tachycardia
  • Diazoxide — hyperglycemia (↓ insulin secretion), fluid retention, reflex tachycardia

Hypertension in Pregnancy

• Chronic (preexisting) hypertension — methyldopa or labetalol are preferred
• Preeclampsia (new-onset hypertension after 20 weeks) — labetalol or hydralazine are first-line agents
• Avoid ACEIs, ARBs, and renin inhibitors in all trimesters due to fetotoxicity

• Choice of antihypertensive should be tailored to coexisting conditions for added benefit

• General principle: select agent that treats both hypertension and the comorbidity whenever possible
• Combination therapy often required to achieve target BP (especially in CKD and diabetes)

Overview

• Primary pulmonary hypertension (PAH) = sustained elevation of pulmonary arterial pressure without identifiable secondary cause
• Pathophysiology involves endothelial dysfunction, vasoconstriction, and vascular remodeling
• Treatment targets pulmonary vasodilation and reduction of right ventricular afterload

Endothelin Receptor Antagonist — Bosentan

• Mechanism: competitive antagonist at endothelin type A (ET-A) receptors
  • Blocks ET-1–mediated vasoconstriction and smooth muscle proliferation
  • ET-B receptor blockade also contributes but is less central to therapeutic effect
• Oral administration — convenient for chronic outpatient use
• Adverse effects
  • Vasodilation-related: headache, flushing, hypotension
  • Hepatotoxicity — requires monthly liver function monitoring
• Contraindication: pregnancy (teratogenic risk)

Prostacyclin Analog — Epoprostenol

• Synthetic prostacyclin (PGI₂) — potent vasodilator and antiplatelet agent
• Administration: continuous intravenous infusion (requires central venous access and pump)
• Use: WHO functional class III–IV PAH; also used as bridge to transplantation
• Adverse effects: dose-related flushing, headache, jaw pain, diarrhea; hypotension; risk of catheter-related infection

Phosphodiesterase-5 Inhibitor — Sildenafil

• Mechanism: selective inhibition of PDE-5 → prevents cGMP degradation → ↑ cGMP in pulmonary vascular smooth muscle → vasodilation
• Result: reduced pulmonary vascular resistance and improved exercise capacity
• Also approved for erectile dysfunction at different dosing
• Adverse effects: headache, flushing, nasal congestion, visual disturbance (mild and transient)
• Caution: contraindicated with nitrates (risk of severe hypotension)