Lecture 6 LV Dysfunction and Heart Failure II Flashcards Preview

CDL301 Cardiovascular Pharmacology > Lecture 6 LV Dysfunction and Heart Failure II > Flashcards

Flashcards in Lecture 6 LV Dysfunction and Heart Failure II Deck (45)
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1

What is significant about the target for therapeutics in heart failure

Therapeutics don’t target the heart itself but the compensatory response that the body triggers

2

The compensatory mechanism triggered by a drop in cardiac out during heart failure can be divided into the two regions it effects. What are these

Cardiac – effects on the heart itself, system – effects on the vasculature and other organs

3

Why is the compensatory mechanism triggered in heart failure often derogatory

Heart attacks are a relatively recent occurrence, only seen in the last 200 years. As such the body hasn’t evolved to deal with it appropriately. However a number of the changes that occur during heart failure are similar to what is seen during blood loss, something which the body has adapted to. As such the body notices the decrease in cardiac output and other changes occurring during heart failure and wrongly assumes this is due to blood loss. This is why the neurohumoral response is a key target in heart failure treatment

4

There are two compensatory mechanisms triggered in heart failure, the sympathetic nervous system and the RAAS system. Which occurs first

The sympathetic nervous system stimulation is rapid and occurs immediately whereas the RAAS system is much slower and involves protein synthesis and multiple steps

5

Describe how the RAAS acts to compensate for the effects of heart failure

The juxtaglomerular apparatus in the kidney releases renin in response to the decreased cardiac output. Renin acts on angiotensinogen released by the liver, converting it to angiotensin I. Then the ACE enzymes in the lungs convert angiotensin I to angiotensin II. Angiotensin II is a potent vasoconstrictor acting via AT-1 receptors to increase peripheral resistance. Angiotensin II also acts to release aldosterone which promotes Na+ retention and with-it water. This acts to increases blood fluid volume

6

Describe how the SNS acts to compensate for the effects of heart failure

The sympathetic nervous system releases noradrenaline in an attempt to maintain arterial blood pressure and central circulation. This in order to look after the major organs such as the brain, kidney and liver. As blood pressure is controlled by peripheral resistance and cardiac output, noradrenaline acts on both peripheral resistance and cardiac output to increase blood pressure. Firstly is a powerful vasoconstrictor via the α1 adrenergic receptors in vascular smooth muscle, but it also has a positive inotropic effect by stimulation of the β adrenoceptors in the heart.

7

Outline the interplay that exists between the sympathetic nervous system and RAAS systems

Noradrenaline stimulates renin release in the kidney meanwhile, angiotensin II encourages the release of noradrenaline from sympathetic nerve endings. This sort of positive feedback loop acts to amplify the response

8

How are the effects of RAAS and sympathetic nervous system beneficial in blood loss

The sympathetic nervous system stimulation results in a tachycardia which increase cardiac output. It also has a positive inotropic effect increasing the force of contraction which also increases cardiac output. Meanwhile noradrenaline also causes vasoconstriction to increase blood pressure. Finally as a result of RAAS there is a stimulation of Na+ and water retention which acts to increase blood volume and hence blood pressure

9

How are the effects of the RAAS and sympathetic nervous system derogatory in heart failure

The tachycardia caused by the sympathetic nervous system also increases the workload and oxygen demand of the heart, as does the positive inotropic action also. In addition, vasoconstriction increases the afterload which therefore also increases work and oxygen demand of the heart. Meanwhile Na+ and water retention as a result of aldosterone increases preload which due to the shallow Frank-Starling relationship actually does very little to increase cardiac output. Finally, chronic adrenergic stimulation has a toxic effect on the myocytes and causes arrhythmia

10

What are the six different pharmacology’s that can target aspects of the sympathetic nervous system and RAAS system

Diuretics, aldosterone antagonists, ACE inhibitors, angiotensin receptor blockers, β adrenoceptor antagonists or renin inhibitors

11

Below is some data from the RALE trial of aldosterone antagonists in heart failure. Describe what these results show

Placebo – 25% 1-year mortality, Spironolactone – 17.5% 1-year mortality. Hence Aldosterone antagonists correlate with a decreased mortality in patients in heart failure. The curves are continuing to diverge indicating there is an ongoing benefit of aldosterone antagonists

12

Below is some data from the CONSENSUS trial of ACE inhibitors in heart failure. Describe what these results show

Placebo group had a 60% mortality rate over 1 year. This was an extremely severe heart failure patient cohort with NYHA type IV heart failure. However, the patient group treated with the ACE inhibitor enalapril had a 40% mortality rate. Hence the ACE inhibitor reduced the mortality rate in the patients by 1/3.

13

Below is some data from the AIRE trial of ACE inhibitors in heart failure. Describe what these results show

12-month mortality in placebo patients – just under 20%. There as a significant improvement in patients treated with Ramipril with around a 15% mortality

14

Below is some data from the SOLVD trial of ACE inhibitors in heart failure. Describe what these results show

10% rate of death or hospitalisation after 1 year in placebo patients. Improved with enalapril. Greater the annual mortality, the greater the benefit with enalapril

15

What are the clinical indications of ACE inhibitors

Heart failure, hypertension, diabetic nephropathy

16

Give some examples of ACE inhibitors

Captopril, Ramipril, enalapril

17

Which ACE inhibitor is most commonly used

Ramipril

18

ACE inhibitors are used once daily in hypertension, why are they used twice daily in heart failure

Because whereas patients with hypertension really only need the effects on blood pressure during the day, heart failure patients need its effects throughout the night when often it gets worse

19

What are the two broad categories of side effects with ACE inhibitors

Angiotensin II-related and kinin potentiation-related

20

Describe the angiotensin-II related side effects of ACE inhibitors

Hypotension, acute renal failure, hyperkalaemia, teratogenic effects in pregnancy (contraindicated),

21

Describe the kinin potentiation-related side effects of ACE inhibitors

Coughing (dry cough) – will persist until drug not taken, characteristic rash and  anaphylactoid reactions, angioedema

22

Why can ACE inhibitors lead to acute renal failure

Angiotensin II in the kidney is responsible for keeping up GFR pressure. Hence ACE inhibitors may lead to a decrease in GFR

23

Why can ACE inhibitors lead to a dry cough

This is due to the potentiation of kinins such as bradykinin. ACE is a non-specific enzyme that also breaks down bradykinins, so inhibiting ACE increases kinin levels. These bradykinins stimulation sensory nerve endings in the airways causing coughing

24

What are the clinical indications of angiotensin II receptor blockers

Heart failure (if ACE inhibitors contraindicated), hypertension and diabetic nephropathy

25

Give some examples of angiotensin II receptor blockers

Losartan, candesartan, valsartan, Irbesartan, telmisartan

26

What are the side effects of angiotensin II receptor blockers

Symptomatic hypotension (especially in volume depleted patients – blood loss and dehydration), hyperkalaemia, potential for renal dysfunction, rashes and angioedema

27

Angiotensin II receptor blockers are generally well tolerated, when are the contraindicated

In pregnancy

28

Which receptors do angiotensin II receptor blockers specifically block

AT-1

29

Give some examples of β blockers licenced for heart failure

Carvedilol, bisoprolol and metoprolol

30

What is different about the doses of β blockers given in heart failure

Unlike hypertension and angina, very small doses of β blockers are given in heart failure. These doses are then gradually increased over time. This is to prevent too much inhibition of the sympathetic nervous system at the early stage which could be supporting the heart failure patients