52. Hypertension & Cardiac Failure 💦 Flashcards
What is the major store of calcium within the cardiomyocyte?
Sarcoplasmic reticulum
The heart has two signalling pathways that are involved in elevating the level of two intracellular second messengers. What are these second messengers?
Ca2+ and cAMP
Which plasma membrane proteins allow calcium to enter the cell in response to depolarisation?
Dihydropyridine receptors
What happens to the calcium once it has passes into the cell viathis channel?
It binds to ryanodine receptors on the sarcoplasmic reticulum and cause calcium release from the SR
How does the calcium stimulate contraction?
It binds to troponin on the thin filament
What are the different ways in which calcium is removed from the myoplasm after it has stimulated contraction? Which method is responsible for the majority of calcium removal?
Plasma membrane calcium ATPase Na+/Ca2+ exchanger SERCA2a (sarcoendoplasmic reticulum calcium ATPase) –responsible for >70% of calcium removal
What features of contraction is SERCA2a responsible for andwhy?
Rate of calcium removal and so it’s responsible for the rate of cardiac muscle relaxation Size of calcium store, which affects the contractility of the subsequent beat
What regulates the action of SERCA2a and how does it do this?
Phospholamban (PLN) Phospholamban phosphorylation is stimulated by beta-adrenergic activity It is a target for phosphorylation by protein kinase A When dephosphorylated it is an inhibitor of SERCA2a When phosphorylated it dissociates from SERCA2a and activates the Ca2+ pump As a result, the rate of cardiac relaxation is increased and, on subsequent beats, contractility is in proportion to the elevation in the size of the SR calcium store
What is phospholamban dephosphorylated by?
Protein phosphatase 1
What are the three main channels that are responsible for the action potential in the sinoatrial node?
If channel – hyperpolarisation-activated cyclic nucleotide-gated (HCN) channel Calcium channel (T and L type) Potassium channel
Describe how these channels are responsible for the action potential of the sinoatrial node.
If channel is a sodium channel that opens at the most negative membrane potential Opening of the sodium channel causes sodium influx, which begins to depolarise the membrane and stimulates the opening of calcium channels, which further depolarises the membrane Potassium channels are responsible for repolarisation
What are beta adrenoceptors coupled with?
Adenylate cyclase – it increases cAMP, which is important in the opening of the If channel to begin depolarisation
How does the parasympathetic nervous system affect heart rate and contractility?
It is negatively coupled with adenylate cyclase
What are the determinants of myocardial oxygen supply?
Arterial oxygen content Coronary blood flow
What are the determinents of myocardial oxygen demand?
Heart rate Contractility Preload Afterload
What effect do beta-blockers and calcium channel blockers haveon the channels responsible for the SA node action potential?
Beta-blockers decrease If and calcium channel activity Calcium channel blockers only decrease calcium channel activity
Name a drug that decreases If activity.
Ivabradine (blocks the If channel)
What effect does this drug have on contractility?
It has no effect on contractility because it doesn’t affect the calcium channels
What are the two types of calcium channel blocker? Name the drugs in each category including their drug class.
Rate slowing Phenylalkylamines – verapamil Benzothiazepines – diltiazem Non-rate slowing Dihydropyridines – amlodipine
What is a consequence of non-rate slowing calcium channel blockers?
Reflex tachycardia (baroreceptor reflex)
How do organic nitrates cause vasodilation?
Organic nitrates are substrates for nitric oxide production The NO then diffuses into the smooth muscle and causes smooth muscle relaxation by activating guanylate cyclase They are often in angina patients before they exercise
How do potassium channel openers work?
They open the potassium channels and hyperpolarise the vascular smooth muscle so that it is less likely to contract
How do vasodilation and venodilation reduce myocardial oxygen demand?
They reduce the pressure against which the heart is pumping (reduce afterload) and it also causes reduce venous return to the heart (reduced preload) meaning that contractility is decreased
As these drugs reduce the myocardial oxygen demand, what condition can they all be used to treat?
Angina pectoris
State some unwanted effects of beta-blockers.
Bradycardia Hypotension Hypoglycaemia in diabetics on insulin Cold extremities (because of beta-2 blockade) Bronchoconstriction Fatigue Impotence Depression CNS effects
Under what circumstance must caution be taken when giving beta-blockers?
Cardiac failure – because they reduce heart rate and contractility it can have catastrophic consequences in cardiac failure patients
What are the side effects of verapamil?
Bradycardia and AV block Constipation
What are the side effects of dihydropyridines?
Ankle oedema Headaches/flushing Palpitations
What is a simple classification of arrhythmias?
Based on its point of origin Supraventricular, Ventricular and Complex
What is the main classification of anti-arrhythmic drugs and how are the drugs ordered?
Vaughan-Williams classification I – sodium channel blockers II – beta-blockers III – prolongation of repolarisation (mainly due to potassium channelblockade) IV – calcium channel blockers
What is adenosine used to treat?
It is used to terminate supraventricular tachycardia
How does adenosine work?
Adenosine binds to adenosine receptors in the cardiac muscle and vascular smooth muscle Adenosine receptors are negatively coupled with adenylate cyclase Reducing the cAMP in nodal tissue will impact on depolarisation within the AV node
What is verapamil used to treat?
Supraventricular tachycardia Atrial fibrillation
What is the target of verapamil and how does it work?
L-type calcium channel Reducing calcium entry means that the speed with which the tissue is depolarise is reduced
What is amiodarone used to treat?
Supraventricular tachyarrhythmia Ventricular tachyarrhythmia
How does amiodarone work?
It works by blocking many ion channels Its main effect seems to be through potassium channel blockade This prolongs repolarisation, so you’re prolonging the time during which the tissue can’t depolarise
Describe re-entry.
Some damaged cardiac tissue will make it difficult for depolarisation to pass through it in one direction, but it will allow the action potential to propagate in the opposite direction This could mean that you get a miniature circuit set up within the tissueand you get re-entry of action potentials
What is the target of cardiac glycosides like digoxin?
Na+/K+ ATPase
How does digoxin work and what are its effects on the heart?
By blocking Na+/K+ ATPase it causes an accumulation of Na+ in the cell The excess Na+ is then removed by Na+/Ca2+ exchanger, thus increasing the intracellular calcium concentration This has an inotropic effect It also causes vagal stimulation, which has a chronotropic effect
What is an important factor to consider before starting treatment with digoxin?
Hypokalaemia Digoxin binds to the potassium binding site on the extracellular component of Na+/K+ ATPase so it competes with potassium for the binding site If hypokalaemic, there is less competition for digoxin and so the effects of digoxin are exaggerated
What is digoxin used to treat?
Atrial fibrillation Atrial flutter
What is an adverse effect of digoxin?
Dysrrhythmia
What are cardiac inotropes? Name two.
They increase the contractility of the heart (it is used in acute heart failure in some cases) Dobutamine (beta-1 agonist) Milrinone (phosphodiesterase inhibitor)
Name three drug classes that interfere with the renin-angiotensin system.
Renin inhibitors ACE inhibitors Angiotensin receptor blockers
Describe the action of aldosterone in collecting duct tubule cells.
Aldosterone passes through the plasma membrane and binds to mineralocorticoid receptors intracellularly and increases the synthesis of Na+ channels and Na+/K+ pumps This causes an increase in sodium reabsorption
What are the uses of ACE inhibitors?
Hypertension Heart Failure Diabetic Nephropathy Post-MI Progressive Renal Insufficiency Patients at high risk of cerebrovascular disease
Give an example of an ACE inhibitor.
Enalapril
What are the anti-hypertensive effects of ACE inhibitors?
They reduce the production of angiotensin II, which is a potent vasoconstrictor It also reduces the production of aldosterone, thus reducing salt and water retention This means that there is a decrease in blood volume, hence a decrease in venous return
What law links venous return to contractility?
Starling’s Law
What is diabetic nephropathy caused by?
It is due to significant damage to the kidney glomerulus because of toxic products NOTE: hyperglycaemia increases the risk of exposure to oxygen free radicals
Name three drug classes that interfere with the renin-angiotensin system.
Renin inhibitors ACE inhibitors Angiotensin receptor blockers
Describe the action of aldosterone in collecting duct tubule cells.
Aldosterone passes through the plasma membrane and binds to mineralocorticoid receptors intracellularly and increases the synthesis of Na+ channels and Na+/K+ pumps This causes an increase in sodium reabsorption
What are the uses of ACE inhibitors?
Hypertension Heart Failure Diabetic Nephropathy Post-MI Progressive Renal Insufficiency Patients at high risk of cerebrovascular disease
Give an example of an ACE inhibitor.
Enalapril
What are the anti-hypertensive effects of ACE inhibitors?
They reduce the production of angiotensin II, which is a potent vasoconstrictor It also reduces the production of aldosterone, thus reducing salt and water retention This means that there is a decrease in blood volume, hence a decrease in venous return
What law links venous return to contractility?
Starling’s Law
What is diabetic nephropathy caused by?
It is due to significant damage to the kidney glomerulus because of toxic products NOTE: hyperglycaemia increases the risk of exposure to oxygen free radicals
Why are ACE inhibitors used in diabetic nephropathy?
ACE inhibitors reduce the angiotensin II-mediated vasoconstriction of the efferent arteriole This reduces the blood pressure at the glomerulus and hence reduces the accumulation of toxic products at the glomerulus
Give an example of an angiotensin receptor blocker.
Losartan
What is the most common side effect of ACE inhibitors?
COUGH
State some other side effects of ACE inhibitors and ARBs.
Hypotension Urticaria/Angioedema (ACEi – very rare) Hyperkalaemia Fetal injury Renal failure in patients with renal artery stenosis (due to both)
Describe the excitation-contraction coupling of vascular smooth muscle cells.
Deplarisation causes the opening of voltage-gated calcium channels (VGCC) This leads to calcium influx The calcium then binds to calmodulin forming a Ca2+-CaM complex This complex activates Myosin Light Chain Kinase (MLCK), and the MLCK-mediated phosphorylation leads to smooth muscle contraction
What type of calcium channel blocker is more selective for blood vessels? Give an example.
Dihydropyridines – nicardipine
Give two examples of non-rate slowing CCBs.
Nicardipine Nitrendipine Amlodipine Nisoldipine
Which part of the calcium channel do the different CCBs bind to?
Dihydropyridines bind to the extracellularly component of the calcium channel Diltiazem and verapamil binds to the intracellular component so for a CCB to have an effect on the heart it needs to be able to penetrate the membrane and act on the receptor inside the cell
Why are non-rate slowing CCBs preferred to rate-slowing CCBs in the treatment of hypertension and heart failure?
They have a more powerful effect on vascular smooth muscle
What type of receptor is a beta adrenoceptor?
G-protein coupled receptor (Gs protein linked)
What are the effects of noradrenaline that cause an increase in blood pressure?
Increase in heart rate and cardiac contractility (leads to increase in CO) via beta-1 receptors in the heart Stimulation of beta-1 receptors in the kidneys promotes renin release –> increase in angiotensin II
What is hypertension in younger patients normally caused by?
Increased sympathetic drive
State some uses of beta-blockers.
Angina Post-MI Cardiac dysrhythmias Chronic heart failure Hypertension Also thyrotoxicosis, glaucoma, anxiety states, migraine prophylaxis, benign essential tremor
Give an example of a cardio-selective beta-blocker.
Atenolol
What are mixed beta-alpha blockers? Give an example.
They are beta-1, beta-2 and alpha-1 blockers Carvedilol You get extra vasodilation due to alpha-1 blockade
Give an example of an alpha-1 blocker.
Prazosin
Give an example of a non-selective alpha blocker.
Phentolamine
Why is it important for alpha-1 blockers to be selective?
Alpha-2 receptors are the negative feedback receptors of the SNS Blocking them will result in enhancement of sympathetic activity
Give an example of a drug that is used to treat migraine and explain how it works.
Sumatriptan It is a 5-HT (serotonin) receptor agonist, which causes vasoconstriction of some of the large arteries in the brain and inhibits trigeminal nerve transmission NOTE: painful stimuli is transferred by the trigeminal nerve and profound vasodilation is also associated with migraine
When is sumatriptan contraindicated?
Coronary disease