Lecture 6 Flashcards
how do the renin-angiotensin system and the sympathetic nervous system work together?
produce angiotensin 2 and noradrenaline
increase peripheral resistance and increase cardiac output
how does angiotensinogen get converted into angiotensin 1 ?
o Needs renin – produced from kidney if it thinks perfusion pressure to the kidney has decreased
o Assumes blood loss has occurred
o Also releases renin if there is a lower amount of Na going out into the distal tubules – implying total body Na or water is reduced = volume loss
o Angiotensin 1 – quite inactive
o Sympathetic nervous system helps to release renin
how does angiotensin 1 get converted to angiotensin 2?
ACE
Helps sympathetic nervous system to release noradrenaline
What is the action of angiotensin 2?
v powerful vasoconstrictor – contributes substantially to peripheral resistance
helps with salt retention – aldosterone release, tubular sodium reabsorption
what occurs to compensate for acute blood loss?
- Tachycardia -> increased cardiac output - Support blood vol and increases blood pressure
- Positive inotropic effect -> increased cardiac output - Force of contraction of the heart is increased = Increased blood pressure
- Vasoconstriction -> increased blood pressure - Try maintain vital organs e.g. brain, switch off others like skin, muscle, gut
- Sodium and water retention -> increased circulatory volume - Support blood vol
What bad compensations occur in LV Systolic Dysfunction?
- Kidneys sense loss of perfusion pressure – think theres loss of blood
- Tachycardia -> increased workload and oxygen demand - Heart becomes more inefficient
- Positive inotropic effect -> increased workload and oxygen demand
- Vasoconstriction -> increased afterload - Increased resistance to each output from the heart – harder to eject
- Sodium and water retention -> increased preload and oedema - Heart stretches more, contracts more – demands more oxygen
- Chronic adrenergic stimulation -> myocyte toxicity and arrhythmia - Kills myocytes
what are the benefits of aldosterone?
- Purely for the retention of water and sodium
* Symptomatic relief of congestion
what are the benefits of aldosterone antagonists?
- Weak diuretics
- Specific effect blocking the renin-angiotensin system
- Block reabsorption of sodium and water retention
what are the benefits of vasodilators?
- Decrease resistance
* Anything that blocks angiotensin system = vasodilators – inhibit the vasoconstriction that theyre trying to cause
action of ACE inhibitors?
Block ACE enzyme and therefore angiotensin 2
impact of ACE inhibitors in heart failure?
- 31% mortality reduction
main clinical indications for ACE inhibitors?
o Hypertension
o Heart failure
o Diabetic nephropathy
examples of ACE inhibitors?
Ramipril
Enalapril
Perindopril
Trandolapril
what are the main adverse effects of ACE inhibitors - related to reduced angiotensin 2 formation?
a) Hypotension
Lower bp too much
b) Acute renal failure
Angiotensin 2 causes constriction efferent arteriole – increase glomerular filtration pressure
Inhibit angiotensin 2 – reduce pressure – acute renal failure
c) Hyperkalaemia
Angiotensin 2 causes aldosterone release – loss of K
Block that process – retain K+ - rhythm disturbances
d) Teratogenic effects in pregnancy
ACE enzymes important for foetal development
what are the main adverse effects of ACE inhibitors - related to increased kinins?
a) Cough - 10% of patients – wont go away until you stop drug
b) Rash
c) Anaphylactoid reactions
why do you get increased kinins with ACE inhibitors?
ACE = non specifc enzyme
Breaks down bradykinins into inactive peptides
If you inhibit ACE – reduce angiotensin 2 but theres build up of kinins
what were the effects of beta-blockers in heart failure?
• Patients already being treated with ACE inhibitors and diuretics
o Already seeing a benefit from some drugs, looking for an additional benefit
o Patients on heart failure drugs were kept on it, and then given either placebo or carvedilol
• Placebo – 10% mortality – degree of heart failure less but were pre-treated
• Improved survival and hospital admissions (event free survival)
• Mortality benefits demonstrated for carvedilol, bisoprolol and metoprolol
what are the main clinical indications for beta-adreno receptor blockers?
o Ischaemic heart disease (IHD) – angina
o Heart failure
o Arrhythmia
o Hypertension – less
examples of beta-adrenoreceptor blockers?
- Bisprolol
- carvedilol
- metoprolol
- atenolol
- propranolol
- nadolol
what is the selectivity of Beta-adrenoceptor blockers ?
o B1 selective or Non selective
o Selectivity is relative rather than absolute
o As you increase dose – become more non-selective
o The term “cardioselective” is often used to imply β-1 selectivity
Only affects heart – not acc true – industry made it up
o This is a misnomer since up to 40% of cardiac β-adrenoceptors are β-2
what are the adverse effects relating to blocking adrenaline for beta-adrenoreceptor blockers?
o Fatigue
o Headache – if cross BBB
o Sleep disturbance/nightmares
what are the adverse effects relating to slowing heart rate for beta-adrenoreceptor blockers?
o Hypotension – bp too low
o Cold peripheries - Bodies response to bradycardia by preserving internal blood pressure
what are the other adverse effects for beta-adrenoreceptor blockers?
Erectile dysfunction Worsening of: - Asthma (may be severe) or COPD - PVD – Claudication or Raynaud’s - Heart failure – if given in standard dose or acutely
what are the features of the use of Ivabradine in Heart Failure?
• Blocks the If current in the sinus node
• Slows sinus node rate
• Used in angina and heart failure (HR>70 at rest)
o Suggests you haven’t overcome sympathetic drive
• Used if after taking other drugs – heart rate still high
• Hospitalisations – reduced
• Death from heart failure – reduced
• Combination – reduced
• General mortality – small impact/ neutral
