Drugs Cardiac Failure

Question 1

What is the role of Ca ions in VSMC contraction?

Answer 1

Activation of GPCR = IP3 signalling = Ca-calmodulin

Question 2

What is the role of Ca ion in cardiomyocyte cell contraction?

Answer 2

VG Ca channel = ryanodine receptor CICR = Ca-troponin

Question 3

How does cardiac failure lead to low EF?

Answer 3

Large dilated LV so blood not effectively cleared in systole = increase chamber size = not pumping dynamically = reduced EF

Question 4

What causes ventricular hypertrophy in CF?

Answer 4

More cardiomyocytes trying to compensate for increased afterload = reduced chamber volume = reduced CO

Question 5

How is CF subcategorised?

Answer 5

• Systolic = weak contraction, reduced EF

- Diastolic = compromised relaxation, preserved EF

Question 6

Describe the RAA system

Answer 6

• Flow + pressure sensing cells in juxtaglomerular apparatus transduce any reduction in BP + trigger cascade
• Activation of angiotensin (II) = aldosterone mediated Na reabsorption from urine = H2O retention

Question 7

What does the activation of angiotensin cause?

Answer 7

• Thirst
• Vasoconstriction
• Ventricular hypertrophy + remodelling
• Aldosterone secretion (Na uptake)
• GFR maintenance
• ADH secretion from posterior pituitary

Question 8

How do ACE inhibitors work?

Answer 8

• Occupy active site of ACE that would normally be taken by angiotensin I
• 1st line therapy for managing CF associated with systolic dysfunction
• Black patients insensitive
• Frequent ADR = dry persistent cough (they prevent breakdown of bradykinin in lungs)

Question 9

How do ARB drugs work?

Answer 9

• e.g. Candesartan
  = angiotensin II receptor blockers = selective for ATIR so AII then has to bind to AT2R instead
• Active AT2R cause opposing effects to ATIR

Question 10

How do B blockers work?

Answer 10

• B1 adrenoreceptor antagonists
• Negative chronotrope + inotrope that reduces CO
• Unless patient acutely decompensating (which needs + inotropes), better to try stop failing heart

Question 11

When is digoxin used and how does it work?

Answer 11

• Positive inotrope used for congestive HF
• Useful for elderly sedentary patients
• Blocks Na/K ATPase = traps Na inside cell = cardiomyoctes flip NCX to import more Ca
• Can also be used as anti-arrythmic for AF or atrial flutter
• Can cross BBB + inhibit regulatory neurons in brainstem cardiocentre = increased vagal stimulation AVN = increased refactoriness = negative chronotrope

Question 12

How do diuretics work?

Answer 12

Increased concentration Na in urine = prevents osmosis of water from urine > blood = increased urine volume

Question 13

What are loop acting diuretics?

Answer 13

• e.g. Furosemide
• Inhibits Na/K/Cl symporter in thick ascending
• Indicated for CF with associated oedema
• Can cause hypokalaemia

Question 14

What are thiazide diuretics?

Answer 14

• e.g. Bendroflumethiazide
• Inhibits Na/Cl symporter in distal convoluted tubules
• Can cause hypokalaemia

Question 15

What are K sparing diuretics?

Answer 15

• Spironolactone
• Out-competes aldosterone = prevents Na reabsorption from urine
• Can cause hyperkalaemia + gynaecomastia
• Principal cells of CT - Na reabsorption due to ENAC = on apical membrane > traffics Na from urine > principal cells > Na/K/ATPase on basolateral side moves Na into blood

Question 16

How is K controlled by the kidneys?

Answer 16

• Driven by Na in principal cells
• More Na pumped into peritubular capillaries = more K pumped into principal cells then into urine by ATPase ROMK
• Traffic of Na changes membrane potential on either side = changes activity of
  a) Na/K/ATPase
  b) ROMK
  to increase secretion of K into urine
• More Na flowing past CT + absorbed into principal cells = > secretion of K

Question 17

What do drugs that reduce fluid volume help manage?

Answer 17

Congestive CF

Question 18

What effect do positive inotropes have?

Answer 18

Typically increase Ca in cardiomyocytes but reduce how hard heart has to work lessens potential for LVH