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RBF > Dawes: Angiotensin Converting Enzyme Inhibitors > Flashcards

Dawes: Angiotensin Converting Enzyme Inhibitors Flashcards

1
Q

What is the function of the Renin-Angiotensin-Aldosterone-System?

A

Acts to regulate blood pressure, intravascular volume/Na+/K+ and fetal development.

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2
Q

Where is renin produced?

A

Renin is produced in the juxtaglomerular cells of the kidney.

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3
Q

Draw the RAAS pathway…

A
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4
Q

What does activation of AT-1 receptors lead to?

A
  • Vasoconstriction
  • Na+ Retention and therefore increased sympathetic tone
  • Oxidant Stress
  • Vascular smooth muscle hypertrophy
  • Vascular Fibrosis due to raised endothelin and aldosterone
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5
Q

What AT receptors does Angiotensin II antagonists work to inhibit?

A

Performs a Sartan Block which only blocks AT-1 Receptors

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6
Q

What is raised in the blood when an ACE inhibitor is used?

A

ACE inhibitors act to inhibit the function of the Angiotensin Converting Enzyme. As a result the negative feedback from aldosterone is lost so you get a build-up (increase) in the concentration of renin and angiotensin I.

Also get increased concentrations of bradykinin.

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7
Q

How does Angiotensin II lead to vasoconstriction?

A
  1. Angiotensin II binds to AT I receptor.
  2. Activates G Protein that converts GTP to GDP and activates phospholipase C.
  3. Phospholipase C cleaves PIP2 to IP3 and DAG.
  4. IP3 causes increased release of calcium leading to raised intracellular calcium concentrations. This spike causes vasoconstriction.
  5. DAG activates protein kinase C which starts a downstream phosphorylation cascade.
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8
Q

What are the pathophysiological effects of Angiotensin II on the cardiac myocyte?

A
  • Hypertrophy
  • Apoptosis
  • Cell Sliding
  • Increased Wall Stress
  • Increased O2 consumption
  • Impaired Relaxation
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9
Q

What are the pathophysiological effects of Angiotensin II on the fibroblasts?

A
  • Hyperplasia
  • Collagen Synthesis
  • Fibrosis
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10
Q

What are the pathophysiological effects of Angiotensin II on the peripheral arteries?

A
  • Vasoconstriction
  • Endothelial Dysfunction
  • Hypertrophy
  • Decreased Compliance
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11
Q

What are the pathophysiological effects of Angiotensin II on the coronary arteries?

A
  • Vasoconstriction
  • Endothelial Dysfunction
  • Atherosclerosis
  • Restenosis
  • Thrombosis
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12
Q

What does the binding of Angiotensin II to AT-2 receptors cause?

A
  • Antiproliferation
  • Tissue Repair
  • Apoptosis ‘
  • Vasodilation
  • Kidney Development
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13
Q

Where are AT-1 receptors found?

A
  • Heart
  • Kidney
  • VSM
  • Brain
  • Adrenal Glands
  • Adipocytes
  • Placenta
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14
Q

Where are AT-2 receptors found?

A
  • Heart
  • Adrenal Gland
  • CNS
  • Kidney
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15
Q

What are the effects of aldosterone on the cardiac myocytes?

A
  • Hypertrophy
  • Norepinephrine Release
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16
Q

What are the effects of aldosterone on the fibroblasts?

A
  • Hyperplasia
  • Collagen Synthesis
  • Fibrosis
17
Q

What are the effects of aldosterone on the peripheral arteries?

A
  • Vasoconstriction
  • Endothelial Dysfunction
  • Hypertrophy
  • Decreased Compliance
18
Q

What are the effects of aldosterone on the kidney?

A
  • Potassium Loss
  • Sodium Retention
19
Q

What are the benefits of using an ACE inhibitor?

A

In first few weeks you get a decreased concentration of Angiotensin II and Aldosterone. However, these return to normal due to chymase activity. Despite this bradykinin levels remain high.

This raised bradykinin leads to vasorelaxation and increased endothelial function.

20
Q

What are the different type of ACE inhibitors and Angiotensin II antagonists?

A
21
Q

What are the pharmacokinetics of ACE inhibitors?

A

They are prodrugs such as cilazapril and enalapril that are activated via liver hydrolysis. They have variable half-lives and are excreted by the kidneys and therefore accumulate in renal failure.

22
Q

What are the pharmacokinetics of the Angiotensin II Antagonists?

A

Some such as losartan and candesartan are active metabolites. They have variable half-lives and have variable routes of excretion. It is important that renally impaired patients treatment is approached with care and that electrolyte checks are performed.

Losartan and Candesartan are excreted 60% via the renal systemand 40% via the bile.

23
Q

What are the pharmacodynamics of Angiotensin II Antagonists?

A

They block AT-1 receptors in a non-competitive way.

24
Q

When is an ACE inhibitor used?

A
  • In hypertensive patients an ACEi and Diuretic are often used as a combination therapy.
  • In congestive heart failure it is often used as part of a multidrug therapy in combination with beta-blockers, diuretics, aldosterone antagonists and possibly angiotensin-II antagonists.
25
Q

When is an Angiotensin II Antagonist used?

A
  • In individuals who are intolerant to ACE inhibitors.
  • Hypertension
  • Heart Failure - Candesartan licensed and used in combination with an ACE inhibitor.
26
Q

What are the common treatment regimes for hypertension?

A

Diuretic + ACE inhibitor + Vasodilator

27
Q

Overall what do ACEi and AIIA do?

A
  • Vasodilation
    • decrease arterial and venous pressure
    • decrease ventricular preload and afterload
  • Decrease blood volume
    • natriuresis (pee out sodium)
    • Diuresis (very minor, often not noticed)
  • Decrease sympathetic activity (no associated tachycardia is good)
  • Decrease cardiac and vascular hypertrophy
28
Q

What are the common treatment regimes for heart failure?

A

Diuretic + ACE inhibitor + beta blocker + spirnolactone +/- AII antagonist.

29
Q

Have drug trials proved the efficacy of using ACE inhibitors in hypertension and cardiac heart failure?

A

YES! Improve mortality and morbidity in congestive heart failure.

30
Q

What are the side effects of ACE inhibitors and AII Antagonists?

A
  • Dry Cough
    • ​bradykinin/Sub p
    • not dose dependent
    • can start months after starting treatment
  • Hyperkalemia (due to reduced aldosterone)
  • Renal Function Deterioration
  • Hypotension
  • Angio-oedema (due to rise in bradykinin levels)
    • tongue, gut mucosa and airways swellling up
  • Contra-indicated Pregnancy - STOP IF PREGNANT
31
Q

What are the greatest risks when using either a ACEi or AII Antagonist?

A
  • Renal Impairment - Due to a reduction in perfusion pressure and therefore filtration.
  • Hyperkalemia
  • Volume Depletion / Diuresed Patients -(essentially blocking the system trying to fix this)

Absolute Contraindication with bilateral renal artery stenosis and pregnancy.

  • normally angiotensin II causes vasoconstriction of efferent arteriole to maintian a perfusion pressure in the glomerulus.
  • in affferent stenosis this vasoconstricion is increased to maintian a correct perfusion pressure
  • If you give an ACEi you reduce perfusion massively and cause AKI
  • So you must measure creatinine compared to basline in the first couple of weeks-months
32
Q

What is the effects of AII Antagonists and ACEi use in pregnancy?

A

Able to cross the placenta and cause fetal renal defects, oligohydramnios, fetal death and fetal hypotension in the 2nd and 3rd trimesters.

33
Q

What are the non-BP lowering effects of ACEi?

A
  • Cardio-protective effect - Beneficial CVS effects independent of lowering blood pressure.
  • Reduce the incidence of developing new diabetes.
34
Q

What is the relationship between Angiotensin II and Diabetes?

A

Angiotensin II predisposes an individual to diabetes due to it causing…

  • Oxidant Stress
  • Being Pro-Inflammatory
  • Increasing Sympathetic Activity
  • Impaired Insulin Signalling
  • Impaired Pancreas Function
  • Reduced Insulin Sensitivity
35
Q

What is the future direction of RAAS pathway effectors?

A
  • Renin Inhibitors such as Aliskerin
  • Neprolysin Inhibitors

RBF (32 decks)

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