Flashcards in Harper Cardiology Deck (81):
Inhibit the Na-K ATPase, increasing the intracellular Na concentration. This slows Ca removal by the NCX transporter so more Ca is sequestered into the SR. More Ca is released upon stimulation therefore increasing the force of contraction. Narrow therapeutic window - higher doses can trigger after depol and arrhythmia.
Digoxin, digitoxin and ouabain
Cardiac glycosides. Increase force of contraction.
How does sympathetic stimulation affect the heart?
NA and Adr act on B1 receptors to increase force of contraction. PKA phosphorylates: a) L-type Ca channels (increase Ca due to increased open channel probability and increase number of ryanodine receptors activated). b) phospholamban (remove inhibition of the SERCA pump, therefore greater Ca storage and so greater release on stimulation) c) Slow, delayed rectifier K channels (increase rate of repol and shorten the AP)
How do phosphodiesterase inhibitors affect the heart?
Increase cAMP (prevent the breakdown). Increase force of contraction and the HR. Can lead to arrhythmias.
What is stroke volume?
The volume of blood ejected during each beat.
What is preload?
Extent of stretch due to ventricular filling in the diastole.
What is starlings law?
With all other factors constant, the stoke volume increases with end diastolic volume. (More blood, more stretch, greater force of contraction and more blood into aorta)
How does sympathetic stimulation affect the ventricular function curve?
NA acts on b1 receptors to increase contraction force so curve shifts to the left.
How does sympathetic stimulation cause venoconstriction and what effect does this have on venous return?
NA acts at alpha-1 receptors. Normally, as CVP increases, the pressure gradient from capillary to vein is low so flow is low. With sympathetic stimulation, the venous return increases for higher CVP. Venoconstriction moves blood from the periphery to the central system.
What is the Guyton cross plot?
Starlings law graph combined with the graph for changing CVP with venous return. At steady state CO=VR. As sympathetic stimulation increases, NA acts at b1 receptors to increase force of contraction shifting the Starling law plot to the left. NA acts at a1 receptors to cause venoconstriction. Overall the Guyton-cross-plot curve shifts to the right.
What is after load?
The stress against which cardiac myocytes must shorten. Partially dependent on ABP.
How is mean arterial blood pressure calculated?
ABP = CO x TPR
What effect does increasing or decreasing after load have on the stroke volume?
Increasing - decrease SV. Decreasing - increase SV.
How and where does Adr cause vasoconstriction and vasodilatation?
Vasoconstriction via action on Gq coupled a1 receptors. Vasodilatation via action on Gs coupled b2 receptors. b2 mainly expressed only on arterioles of skeletal muscle, liver and heart.
Osmotic diuretic. Filtered but not reabsorbed so it increases the osmotic pressure of the fluid, decreasing water reabsorption. Acts at the proximal tubule.
Carbonic anhydrase inhibitors e.g. acetazolamide
Act at proximal tubule as weak diuretics. Catalyse H2CO3 formation in the cell and catalyse H2CO3 to H20 and CO2 outside. Increase the pH of the urine as less HCO3- is reabsorbed.
Loop diuretic acting in the thick ascending limb. NaCl normally actively reabsorbed. Inhibits the Na/K/Cl co-transporter. Reduces the NaCl and H20 reabsorption. But can cause hypokalemia
Thiazide diuretics e.g. hydrochlorothiazide
Acts in distal convoluted tubule. Inhibits the Na/Cl co-transporter. Binds to the Cl binding site. Reduces H20 and NaCl reabsorption. But less powerful than loop diuretics so less hypokalemia.
How does aldosterone affect the collecting ducts?
Activates the Na channel in the apical membrane and the Na/K-ATPase in the basal membrane. Greater NaCl reabsorption.
Aldosterone antagonist. Acts at collecting ducts to prevent activation of ENaC or Na/K ATPase, reducing NaCl reabsorption. Weak diuretic but synergistic with loop or thiazide diuretics. Can lead to dysrhymias or hyperkaelemia.
Blocks ENaC in collecting ducts. K sparing diuretic.
How is angiotensin II formed?
Angiotensin is secreted by the kidney. It is cleaved to angiotensin I by renin, a proteolytic enzyme secreted by the juxtamedullary apparatus. Ang I is converted to angiotensin II by ACE (angiotensin converting enzyme).
What stimulates renin secretion?
Sympathetic innervation acting on b1 receptors. Reduced blood pressure in the afferent arteriole. Increased NaCl in the macula densa (close to the juxtamedullary apparatus).
What effect do renal sympathetic nerves have?
Act at a1 receptors to stimulate Na reabsorption in the proximal tubule by increasing activity of the Na-H exchanger. Act via a1 receptors on glomerular arterioles to cause vasoconstriction, therefore reduced glomerular filtration and increased NaCl reabsorption.
What does Angiotensin II do?
Stimulates increased NA release from symp nerves via pre-junctional receptors. Stimulates thirst. Stimulates Na reabsorption. Stimulates aldosterone secretion. Increases cardiac contractibility. Increases vasoconstriction on efferent arterioles and resistance arterioles.
Longer acting ACE inhibitor. Only effect in patients with increased renin secretion. Does also inhibit the breakdown of bradykinin causing dry cough.
Shorter acting ACE inhibitor. Only effect in patients with increased renin secretion. Does also inhibit the breakdown of bradykinin causing dry cough.
Losartan and rosartan
AT2R1 inhibitors. Reduce hypertensive effects of Ang II without the bradykinin accumulation.
What are the 8 possible treatments for hypertension?
ACE inhibitors. AT2R1 antagonists. B1 antagonists. a1 antagonists. Aldosterone antagonists. Centrally acting a2 and a1 agonists. Ca-channel blockers. Diuretics.
How may the usefulness of b1 antagonists in hypertension be decreased?
Also act in heart to have positive chronotropic and ionotropic effect so would inhibit this and/or decreased plasma renin.
A1 adrenoreceptor antagonists in hypertension?
Prazosin. Block sympathetic mediated vasoconstriction.
Centrally acting a2 receptor antagonists used in hypertension?
Clonidine - but actually maybe acts at imidazoline I1 receptors.
What is chronic heart failure?
The inability to maintain sufficient tissue perfusion.
What can cause left ventricular failure?
Cardiomyopathy. Myocardial damage. Increased after load due to hypertension. Coronary artery disease.
What are the possible consequences of left ventricular failure?
Pulmonary congestion and oedema. Increased pressure in pulmonary circulation.
What can cause right ventricular failure?
Increased pulmonary hypertension, increased after load on R ventricles. Left ventricular failure.
What are the possible consequences of right ventricular failure?
Peripheral oedema. Fluid in abdominal cavity. Exercise intolerance.
Why are arrthymias a common cause of death in patients with chronic heart failure?
Upregulation of Na/Ca exchanger, down regulation of inward rectifying K channels, leaky ryanodine receptors. Leads to disruption of normal ventricular rhythm which can trigger delayed after polarisation.
What compensatory mechanisms occur in chronic heart failure?
Increased sympathetic stimulation - vasoconstriction, venoconstriction, activation of renin-angiotensin-aldosterone system, increased preload and increased circulating Adr. Also decreased breakdown of aldosterone.
Where are ANF and BNF secreted from and what do they do?
ANF - atrial myocytes, BNF - ventricular myocytes when dilated. They reduce the renal retention of NaCl and H2O reducing blood volume.
Why can chronic heart failure cause intolerance of exercise?
Sympathetic stimulation already in use. Diastolic relaxation and ventricle filling slowed. Cardiac responsiveness to NA is reduced due to desensitisation and down regulation of B1 receptors.
What are the 4 main aims of pharmacological treatment of chronic heart failure?
Decrease cardiac work and therefore decrease myocardial oxygen demand. Increase SV. Decreased oedema. Decrease the occurrence of dysrhythmia.
What are the 5 main classes of pharmacological treatment for chronic heart failure?
B1 adrenoceptor antagonists such as bisoprolol. B1 adrenoceptor agonists such as dobutamine. Loop diuretics such as furosemide. Inhibitors of the renin-angiotensin-aldosterone system (ACE inhibitors, AT2R1 antagonists and aldosterone antagonists). Cardiac glycosides - increase contractibility but have a narrow therapeutic window e.g. digoxin - especially used in atrial fibrillation.
What is atherosclerosis?
Progressive disease involving focal arterial lesions and chronic inflammation. Vascular smooth muscle cells migrate into the intima and proliferate - deposit connective tissue components such as collagens.
What is the main cause of ischaemic heart disease?
(Coronary artery disease). Stenosis of an artery by an atherosclerotic plaque. Leads to downstream ischaemia.
How is cholesterol synthesised?
Acetyl CoA + acetoacetylcoA to HMG CoA to Mevalonate to cholesterol
What is LDL and what is it used for?
Low density lipoprotein - provides cholesterol to cells for cell membranes and to synthesise steroids. Also taken up by arteries during atherogenesis.
Inhibit HMG CoA reductase (normally converts HMG CoA to mevalonate).
Statin. Reversible inhibitor of HMG CoA reductase.
Statin. Longer lasting reversible inhibitor of HMG CoA reductase.
Decrease VLDL and LDL. Bind to PPARa receptor - ligand activated nuclear receptor that regulates genes that control fatty acid metabolism and lipoprotein synthesis. Inhibits VLDL secretion from hepatocytes. Increases LDL hepatic uptake. Increases lipoprotein lipase activity. Increases HDL production.
Give 2 examples of fibrates
Bile acid binding resins
Decrease cholesterol absorption by sequestering bile acids
Inhibits NPC1L1, a transporter in the duodenum. This reduces cholesterol uptake.
Fish oils high in omega-3
Decrease plasma triglyceride levels but increase cholesterol.
What are the 5 main treatments for ischaemic heart disease?
Statins. Fibrates. Bile acid binding resins. Ezaetimibe. Fish oils rich in omega-3.
What is angina pectoris?
Chest pain triggered by insufficient supply of oxygen to the myocardium. Commonly due to atherosclerosis in coronary artery causing narrowing.
What effect does NO have in angina pectoris?
Venodilatation (decreases preload). Relaxation of large arteries (decreases after load). Dilatation of coronary arterioles increasing oxygen perfusion of myocardium.
Release NO. Venodilatation (decrease preload). Vasodilatation of large arteries (decrease after load). Dilatation of coronary arterioles increasing oxygen perfusion of myocardium.
Organic nitrate. Given sublingually. Fast to metabolise by liver.
Organic nitrate. Given orally, longer acting. Prophylaxis.
L-type Ca channel blockers.
Verapamil - heart. Nifedipine - blood vessels. Dilitiazem - both.
B1 adrenoceptor antagonists
Atenolol, bisoprolol. Decrease HR - more time for cardiac perfusion. Reduce contractibility - decreased myocardial O2 demand.
Blocks If current in the SA node, decreased HR and therefore improved cardiac perfusion.
Reduces late Na current during AP, reduces Ca overload in ischaemic myocytes. Also improves cardiac perfusion. Doesn't affect HR - more suitable for patients with heart failure or risk of arrhythmia.
What are the 5 main pharmacological treatments for angina pectoris?
Organic nitrates. L-type Ca channel antagonists. B1 antagonists. Ivabradine. Ranolazine.
What causes myocardial infarction?
Blockage of coronary artery. Often due to formation of a thrombus on a ruptured atherosclerotic plaque.
What are the 5 main treatments for myocardial infarction?
Balloon angioplasty - open up the blocked vessel. Given with anti-platelets to prevent thrombosis and re-occlusion. Fibrolytics also can cause vessel opening. Organic nitrates. Opioids - reduce pain and therefore sympathetic activity acting on the heart.
What is a thrombus?
Clot inside the lumen of a blood vessel. Arterial - platelets covered in a fibrin mesh 'white thrombus'. Venous - more due to coagulation - traps red blood cells - 'red thrombus'.
How does a thrombus form?
Platelets adhere to glycoprotein receptors on collagen. Activated and secrete secretory factors (ATP, ADP, TxA2 and 5-HT). Activate surrounding platelets. Activation of major plasma fibrinogen A11bB3 which cross-links platelets leading to aggregation.
non-selective COX inhibitor. Prevents the formation of TxA2. At high doses (>300mg, inhibits platelet aggregation). At chronic low doses (75mg, prevents thrombosis).
Irreversible P2Y12 antagonist. Prodrug, the metabolite inhibits receptor. Some patients insensitive due to genetic differences in cytochrome P450 enzyme cascade.
Irreversible P2Y12 antagonist. Similar to clopidogrel.
GP11b/111a receptor on platelet surface. hybrid monoclonal antibody
mimics RGD sequence of fibrinogen binding sequence.
Block the receptor to which fibrinogen binds preventing aggregation.
Inhibit thrombin receptor.