G7ii: Classify antihypertensive agents by their MoA + Outline each mechanism briefly + Give an example of a drug from each class

Definition

Hypertension = pathological state of elevated blood pressure

Classified Antihypertensives

  1. Sympatholytics
  • Centrally acting
  • Ganglion blocking
  • Adrenoreceptor agents
  1. RAAS Inhibition
  • ACEI
  • ARB
  1. Vasodilators
  • Direct vasodilators
  • NO simulators
  • Calcium channel blockers
  1. Diuretics

1) Sympatholytics

  • Centrally acting α2 agonist → CLONIDINE
    • Symp n. innervation of heart & vessels are post ganglionic efferent which originate from symp ganglia
    • Preganglionic symp n. fibres which travel to these ganglia originate in medulla
    • α2 RECEPTORS located on PRE-GANGLIONIC NEURONS
    • Gi receptor
    • Associates with AC
    • ↓cAMP
    • Inhibits release of NA
    • ∴↓SYMP TONE & ↑VAGAL TONE
    • ∴↓BP
  • Ganglion blocker → TRIMETHAPHAN
    • Competitively inhibits nAChR on postganglionic neurons
    • ↓SYMP TONE & ↑VAGAL TONE
    • ∴↓BP
  • Adrenoreceptor agents
    • α-blocker → PRAZOSIN
      • α1 receptors on vascular smooth m.
      • Gq
      • ↑IP3
      • ↑Ca2+
      • VC
      • ∴α1 blockers → VD → ↓BP
      • α1 blockers dilate both arteries & veins 
  • β-blocker → ESMOLOL
      • Cardioselective β1 antagonist
      • Β1 receptor
      • GS
      • Activates AC
      • ↑cAMP
      • ↑Ca2+
      • ↑CHRONO, DROMO, INOTROPY
      • ∴Inhibition → ↓CO → ↓BP 
  • α & β blocker → LABETALOL
      • α1: competes with NA/Adr for binding to α1 receptor (Gq)
        • Smooth m. relaxation
        • ↓BP
      • β1: competes with NA/Adr for binding to β1 receptor (GS)
        • ↓cAMP → ↓Ca2+ → ↓chrono, dromo, inotropy
        • ↓BP
      • β2: intrinsic sympathomimetic activity
        • Activates β2 (G5) receptor of smooth m.
        • Relaxation → ↓BP

2) RAAS Inhibition

  • RAAS = enzyme cascade involved in the defence of ECF volume & maintenance of BP
Angiotensinogen
  • RENIN secretion is rate limiting step
  • AII is effector
  • ACE INHIBITOR → LISINOPRIL
Inhibits
    • ∴↓AII formation
  • AII RECEPTOR BLOCKERS
    • Antagonise AII activity at AT1 receptor
    • ∴both block effects of AII → ↓BP

AT1 Rec Location

Vasc smooth m.

AII Effect

VC

↑endothelin secretion

Inhibition

VD

VD

AT1 Rec Location

Adrenal cortex

AII Effect

↑aldosterone synthesis which ↑Na+ reabsorption @ DCT

Inhibition

↓Na+ retention

↓circulation volume

AT1 Rec Location

Kidney

AII Effect

VC efferent > afferent

↑Na+ reabsorption @ PT

Inhibition

↓NFP = ↓Na+ reabsorption & H2O loss

↓circulatory volume

↓circulatory volume

AT1 Rec Location

CNS

AII Effect

↑symp outflow

Thirst

↑ADH release

Inhibition

↓MAP

↓circulatory volume

↓H2O reabsorption

AT1 Rec Location

Heart vessels

AII Effect

Myocyte hypertrophy

Vasc + cardiac fibrosis

Inhibition

↓cardiac remodelling

NB: ACEI inhibits BK breakdown

  • ↑[BK] = VD
  • ARB do not have the ↑[BK] of ACEi
  • There are alternate routes for AII formation

3) Vasodilators

  • Direct vasodilators → HYDRALAZINE
    • ?mechanism
    • ↓Ca2+ entry into cells or ↓Ca2+ release from intracellular stores
    • ↓smooth m. contraction → VD → ↓BP
    • Predominate arteriolar VD
  • NO simulator → GTN
    • PRODRUG → denitrated to produce active NO
    • NO

↓

Diffuses into smooth m. cells

↓

Binds to & activates Guanylyl Cyclase:

GTP

↓

cGMP

  1. Inhibits Ca2+ entry into smooth m. cell
  2. Activates K+ channels → hyperpolarises cell (inactive)
  3. Stimulates “CGMP-dependent-protein-kinases” which activates MLC phosphatases → dephosphorylates MLC

↓

Smooth m. relaxation → VD → ↓BP

  • Calcium channel blockers → NIMODIPINE (Dihydropyridines)
    • Prevents Ca2+ entry into smooth m. cell
    • Relaxation smooth m. → VD → ↓BP

4) Diuretics

Class

OSMOTIC

Drug

MANNITOL

MoA

Small molecular weight substance

→ Freely filtered, not absorbed

→ Exerts osmotic force

→ Prevents H2O reabsorption

→ Mass H2O loss & some Na+ loss → ↓BP

Class

CA INHIBITOR

Drug

ACETAZOLAMIDE

MoA

Non-competitive inhibitor of CA enzyme on luminal side PCT

→ Less H+ liberation inside PCT cell → Na/H antiport cannot work → NaHCO3 loss in urine → modest diuresis

Class

LOOP

Drug

FRUSEMIDE

MoA

Inhibits Na/K/2Cl transporter on TAL → ↓NaCl reabsorption → H2O follows → ↓BP

Class

THIAZIDE

Drug

HYDROCHLOROTHIAZIDE

MoA

Inhibits Na/Cl transporter on luminal side of DCT cells

→ DCT impermeable to H2O

→ Produces hyperosmolar urine

→ ↓BP

Class

K SPARING

Drug

SPIRONOLACTONE

MoA

Competitive antagonist of aldosterone receptor → ↓Na/K/ATPase activity → ↓Na+ reabsorption → diuresis → ↓BP