L7.1 Drugs used to treat hypertension II

Question 1

Control of HR and contractility

Answer 1

• PNS only innervates SA & AV nodes → only controls HR & not contractility
• SNS +ve inotropic & chronotropic
  
  • inotropic = force; chronotropic = rate

Question 2

Mechanism of B1 R.

Answer 2

• b1 → Ga → cAMP → pKA → ↑Ca channels (Ca flux) → ↑contractility

Question 3

Examples of B1 antagonist

Answer 3

• Take days to develop effect
• Non-selective: Propanolol
• Selective: Atenolol (hydrophilic → crosses BBB)

Question 4

B1 antagonist SE

Answer 4

• Cold extremeties: (loss of b2 mediated cutaneous dilations)
• Fatigue: Loss of skeletal muscle dilation during ex
• Dreams/insomnia (by crossing BBB)
• Cardiac depression/bradycardia
• Bronchoconstriction (contraindicated in asthma)

Question 5

B1 antagonist contraindications

Answer 5

• Asthma
• AV/SA dysfunctional patients
• Heart failures
• Peripheral vascular diseases

Question 6

B1 withdrawal

Answer 6

• Causes rebound sympathetic hyperactivity → rebound hypertension
• Therefore b1 selective preferred

Question 7

Significance of TPR on BF

Answer 7

• TPR controls BF
• SNS controls TPR & basal tone on SM
  
  • Secretes NA → renin → ANGII → AT1 → also vasoconstricts

Question 8

a1 antagonists

Answer 8

• Prazosin
• Used in moderate/severe hypertension & in combination
• Marked SE

Question 9

a1 antagonist SE

Answer 9

• 1st dose hypotension (in ~50% of patients)
• Initial reflex tachycardia (baroreflex) & ↑Renin
• Orthostatic hypotension
• Nasal congestion & headaches

Question 10

Diuretics

Answer 10

• Thiazides
• Influences Na & H2O secretion
  
  • Normally 99% of Na reabs via NaCl co-transporter (NCC)
• Orally active – Chlorthalidene, Hydrochlorothiazide
• Recommended as primary therapy (enhances efficacy of anti-HT drugs & anti-HT by itself
  
  • Given in combination with other drug
• High oral bioavailability & long duration

Question 11

Mechanism of diuretics

Answer 11

• Inhibits NCC → Increase Na excretion → ↑H2O loss → ↓BV
• Works on DCT
  
  • Abs via apical membrane (via NCC transporter)
  • Thiazides inhibits NCC → ↑Na excretion

Question 12

Thiazides SE

Answer 12

• K loss (due to Na reabs)
  
  • Uric acid retention (gout) → thiazide competes for tubular secretion
  • ↑Na reabs in collecting duct (from NA not reabs at DCT) → leads to ↑K excretion
• Impaired glucose tolerance (activation of KATP inhibits insulin secretion)
• Allergic reaction

Question 13

Vagueness of the mechanism thiazides use to lower BP

Answer 13

• Mech which thiazide uses to ↓BP not clear
  
  • Overtime CO & BV returns to normal
  • Hypotensive effect maintained → from ↓TPR
    
    • Thiazides promote vasodilation (relates to KATP channels)

Question 14

ACEi

Answer 14

• ↓ANGII & ↑Bradykinin (prevents inactivation of bradykinin)

Question 15

Function of ANGII

Answer 15

• ↑Aldosterone (↑Na reabs)
• PCT (↑Na reabs)
• Renal efferent vasoconstriction (other arterioles affected too)
• ↑ADH → thirst (in hypothalamus)
• Important in cardiovascular remodelling → Morbid changes in structure

Question 16

Distribution of AT1&2 Receptors

Answer 16

• AT1 (widely distributed – SM, heart, kidney, brain), AT2 (role in vascular dev)

Question 17

What is renin secreted by and what stimulates teh secretion?

Answer 17

• Renin secreted by JG cells (lines afferent & efferent arterioles of glomerulus), stimulated by:
  
  • ↓BP
  • SNS
  • ↓[Na]

Question 18

Examples of ACEi (prils)

Answer 18

• Teprotide (low potency & poor oral abs)
• Captopril
  
  • Orally available (75% bioavailability)
  • ½ life = 2h
• Enalapril
  
  • Inactive prodrug → hepatic hydrolysis into enalprilat
  • 60% bioavailability
    
    • ½ life = 20h ↑Compliance with patients (allows once/day dosage)
      
      • ↓SE

Question 19

Effects of a long term ACEi

Answer 19

• Inhibits morbid effects of ANG II on cardiovascular structures (vascular hypertrophy)

Question 20

ACEi SE

Answer 20

• 1st dose hypotension
• Hyperkalaemia (problematic with K sparing diuretics/renal impairment)
• Acute renal failure (reversible)
• Dry cough (from ↑bradykinin)
• Altered taste/rash (reversible)

Question 21

Adv of ACEi

Answer 21

• CV reflexes less affected
• Safer in asthmatics
• Enhances efficacy of diuretics (blunts ↑aldosterone which opposes diuretic-induced natriuresis)
• Inhibit cardiovascular remodelling

Question 22

AT1 antagonist (sartans)

Answer 22

• Losartan
• Non-peptide, orally active
• Inhibits ANGII CV effects, but does not affect bradykinin metabolism
• Binding often insurmountable in vivo
  
  • Sustained R blockade (allows once a day treatment)

Question 23

AT1 SE

Answer 23

• Same as ACEi
• But no dry cough
  
  • Inhibits the effects of ANGII but does not affect bradykinin metabolism