Successfully reported this slideshow.
Your SlideShare is downloading. ×

Drugsforthe heart

Loading in …3

Check these out next

1 of 41 Ad

More Related Content

Slideshows for you (20)

Similar to Drugsforthe heart (20)


Recently uploaded (20)


Drugsforthe heart

  1. 1. Drugs for the Heart A brief run down of cardiac physiology and how to treat common conditions Brooke Sachs 2017 This presentation summarises key points featured in Drugs for the Heart
  2. 2. Purposeofthe heart  Pump blood round and round (to systemic and pulmonary vasculatures – 25/5mmHg in pulmonary and 120/80 in systemic, capillary pressure ~ 1mmHg)  Hormone balance (fluid balance, sodium balance)  Responding to bodily need (sympathetic and parasympathetic input) through exercise, stress, positional changes
  3. 3. Electricfunction oftheheart  SA node at junction of SVC and RA (embryologically R heart – R vagus n supply)  AV node at right posterior portion of the interatrial septum (embryologically L heart – L vagus n supply)  Three bundles of atrial fibres that contain purkinge- type fibres connecting the SA to AV nodes (tract of Wenckebach, tract of Thorel and anterior tract)  AV node continuous with bundle of His (L branch and R branch)
  4. 4. Pacemakercells  Lower resting membrane potential than cardiomyocytes  Primarily dependent on opening of calcium channels  Noradrenaline release activates B1-adrenoceptors in the SA, AV node, His-Purkinje conductive tissue and atrial and ventricular contractile tissue  Sympathetic activation causes chronotropy, dromotropy, iontropy  Acetylcholine from postganglionic parasympathetic fibres (vagus) activates nicotinic receptors on SA and AV nodes, as well as atrial muscle  reduces rate of transmission through AV node and atrial contractility.
  5. 5. Heartrate  Balance of sympathetic and parasympathetic input leads to a HR of about 70  Up to 150-180 bpm with unopposed sympathetic tone (e.g. atropine (nicotinic receptor antagonist), intense exercise)  In no sympathetic OR parasympathetic input, HR about 100 bpm
  6. 6. Beta-blockers
  7. 7. Beta- adrenoceptors  B1-r situated on cardiac sarcolemma, part of the G-protein coupled receptors  Linked to Gs (stimulates adenylyl cyclase) vs Gi (muscarinic stimulation following vagal activation)  Intracellular second messenger of B1-r is cAMP which opens calcium channels to increase the rate and force of myocardial contraction (+ve inotropy) and increased reuptake of cytosolic calcium into the SR.  SA node pacemaker current is increased (+ve chronotropy), rate of conduction accelerated (+ve dromotropy)  20-30% B-receptors in the heart are B2, this is upregulated with B1-blockade and in heart failure  B3-r endothelial receptors mediate vasodilation induced by NO in response to nebivolol
  8. 8. Beta-activation hasnatural limits  B-receptor stimulation has a negative feedback loop through activating B-adrenergic receptor kinase (B-ARK, aka GRK2)  phosphorylates the receptor that leads to recruitment of B-arrestin, which desensitises the stimulated receptor.  B-arrestin mediates desensitisation in heart failure  B-arrestin also acts physiologically as a signal transduce to induce anti-apoptotic signalling  Prolonged and excess B-adrenergic stimulation causes receptor internalisation and downregulation, which diminishes the inotropic response  Dobutamine (b-agonist) therapy had progressive loss of therapeutic efficacy (tachyphylaxis)  In sustained beta-blockade, there is resultant increase in B-receptors (? Explains improved systolic function with time)
  9. 9. How dobeta- blockerswork?  Improves coronary flow and myocardial perfusion by increasing the diastolic filling time, because of it’s -ve chronotropy  Unclear mechanisms for anti-hypertensive effects, however thought to be due to  inhibition of B-receptors on terminal neurons facilitating release of norad  CNS effects with decreased adrenergic outflow  Decreased activity of RAS system due to B-r mediated renin release  Because of the increased B-r density with blockade, any cessation of B-blockers should be slow as otherwise it will exaccerbate angina and may cause MI in at-risk patients
  10. 10. BetaBlockers  Can be B1-selective (for heart) or act on B1- and B2- adrenoceptors  The closest to an “all purpose” cardiovascular therapy, no lipid problems induced but be aware of hypoglycaemic unawareness, interactions in asthmatic patients. Can also induce diabetes (particularly in combination with diuretics e.g. thiazides)  Very good post-infarct protectiveness and mortality reduction in CHF  Early use of B-blockade in stable systolic heart failure will counter excessive adrenergic drive (best evidence for carvedilol, metoprolol and bisoprolol). Nebivolol is good in old patients for improving EF in systolic but not diastolic failure
  11. 11. Beta-blockers  B-blockade is very effective symptomatic treatment in CAD/angina however does not appear to slow progression of disease  Very effective ventricular antiarrhythmics (particularly sotalol as it also has class III anti-arrhythmic properties)
  12. 12. Don’tuseB- blockerswhen…  The patient is at high risk of CAD – has DM, chronic renal disease – as an anti-hypertensive  In prinzmetal’s angina  In older black adults  Not the best to combine with ACEI/ARB because both reduce renin levels (so no real gain)
  13. 13. Nitrates and anti- anginals
  14. 14. Whydowe get angina?  Imbalance between oxygen suppy and demand  inadequate myocardial blood flow  Deficiency of ATP leads to loss of K, gain of Na and Ca, with rapid onset of diastolic dysfunction
  15. 15. Fourclassesof anti-anginals  B-blockers (covered just prior)  CCBs  Nitrates  Metabolic agents (ivabradine, allopurinol, ranolazine)
  16. 16. Actby  Reducing HR  Reducing afterload  Reducing venous return and pre-load  Negatively inotropic  Vasodilating
  17. 17. Nitrates  Nitrates enter vessel wall, converted to NO, which stimulates guanylate cyclase to produce GMP  NO acts directly via S-nitrosylation of proteins and may be scavenged by superoxide (contributes to nitrate toxicity and tolerance)  NO causes coronary vasodilation and peripheral vasodilation  Reduce preload and afterload  Increase venous capacitance  pooling of blood in ther peripheries  less mechanical stress on the myocardial wall and therefore reduced myocardial oxygen demand  Beneficial to combine with hydralazine in heart failure (likely lessens tolerance)
  18. 18. Metabolic agents  Ranolazine – for chronic effort angina, may be combined with amlodipine, B-blockers or nitrates. It inhibits oxygen-wasting fatty acid metabolism and increases metabolism of protective glucose. Can prolong QTi. Metabolised by CYP3A – be aware of drug interactions  Trimetazidine – patial inhibitor of fatty acid oxidation without haemodynamic effects. Worsens Parkinson’s, improves chronic systolic heart failure.  Perhexiline – inhibits fatty acid oxidation at CPT-1 (enzyme that transports activated lon—chain fatty acids into the mitochondria). Beware hepatotoxicity, and peripheral neuropathy
  19. 19. Metabolic agents  Ivabradine – blocker of pacemaker current If – does not act directly on metabolism but indirectly by decreasing HR and therefore metabolic demand. No –ve inotropy nor BP reduction, nor rebound. Beware transient impaired night vision.  Nicorandil – both potassium channel activator and nitrate-like effect. Dilates large coronary arteries and reduces pre- and afterload.  Allopurinol – reduces myocardial oxygen consumption via inhibition of xanthine oxidase.
  20. 20. Calcium channel blockers
  21. 21. CCBactions  Vasodilation and reduction of peripheral vascular resistance  Selective inhibition of L-type channel opening in vascular smooth muscle and in the myocardium (prevents inward flow of calcium)  Non-DHP CCBs act at the nodes, reducing heart rate  DHP CCBs act more on vasculature, reducing blood pressure  CCBs are contraindicated in heart failure  CCBs give endothelial protecting and promote formation of NO, inhibitory effects on carotid atheromatous disease  S/E: headache, facial flushing, dizziness, constipation
  22. 22. Dihydropyridine s  Bind to the alpha1 subunit of the calcium channel  Side effect of headache (arteriolar dilation), ankle oedema (precapillary dilation)
  23. 23. Non- dydropyridines  Bind to alpha1-subunit of the calcium channel  Act on nodal tissue (tend to decrease the sinus rate)  Less vascularly selective  Better access to the binding site of the AV node when the calcium channel pore is open, which is in SVT/tachycardia  Verapamil inhibits one limb of the reentry circuit believed to underlie most pSVT.  HR drops only modestly at rest – big effect is during exertion  Negatively inotropic  Reduce proteinuria
  24. 24. Diuretics
  25. 25. Loopdiuretics  Frusemide/bumetanide/torsemide/ethacrynic acid  Lose more water than sodium  Small doses can be effective as monotherapy in hypertension  In AMI, high IV doses can be beneficial for haemodynamics  Frusemide is the diuretic of choice in severe heart failure and APO  Ethacrynic acid is the only non-sulfur diuretic  Torsemide and bumetanide have more reliable absorption orally (80-100%) vs frusemide (10-100%) but all have similar total duration of action, with varying peaks of diuresis  Diuretic-induced glucose intolerance is likely related to hypokalaemia, or total body K depletion. This can be minimised with concommitant ACEI/ARB therapy  Frusemide IV can be used to Rx hypercalcaemia
  26. 26. Thiazides  Most widely recommended first-line therapy for hypertension  Chlorthalidone is preferred for hypertension  Inhibit reabsorption of sodium and chloride in the more distal part of the nephron  Rapidly absorbed by the GIT to produce diuresis within 1- 2h, lasting 16-24 h with HCTZ  Maximal effect of thiazides is reached with relatively low doses  Much decreased capacity to work in renal failure (GFR <15-20)  HCTZ dose >25mg may precipitate hyperglycaemia  Thiazides block the nephron sites at which hypertrophy occurs during long term loop diuretic therapy  reduces resistance  Beware co-therapy with sotalol (induction of arrhythmias), aminoglycosides (nephrotoxicity potentiation), probenicid and lithium (block thiazide transport into the tubule)  Beware hypercalcaemia  Can be used to Rx nephrogenic diabetes inspidus
  27. 27. Potassium sparingagents  Amiloride (ENaC) and triamterene (Na-H exchanger) - reduced K loss. Side effects – hyperkalaemia, acidosis. Do not have risk of hyperglycaemia and gout. Amiloride is particularly useful in black patients with low-renin, low-aldosterone hypertension and genetic defect in the ENaC channel.  Spironolactone and eplerenone – aldosterone blockers that spare K by blocking mineralocorticoid receptor that binds aldo/cortisol/deoxycorticosterone. Eplerenone is more specific and prevents gynaecomastia and sexual dysfunction (seen in 10% Rxd with spiro). No reflex sympathetic activation.  Eplerenone as effective as enalapril in regressing LVH and lowering BP
  28. 28. Aquaretics  Antagonists of AVP-2 receptors in the kidney – promote solute-free water clearance to correct hyponatraemia  Tolvaptan, conivaptan, satavaptan, lixivaptan  Evidence is still pending as to improved mortality in heart failure patients
  29. 29. RAA-system inhibitors
  30. 30. RAAS  Angiotensin I originates in the liver from angiotensinogen  Its production is influenced by renin (protease) formed in renal JG cells  ACE activity chiefly in vascular endothelium of lungs (but occurs in all vascular beds)  ACE converts Angiotensin I to Angiotensin II  Angiotensin II can be formed by other pathways (chymase activity)  Angiotensin II receptor stimulus causes phosphodiesterase to activate protein kinase C, which in turn activates inositol trisphosphate signalling in blood vessels, which liberates calcium which causes vasoconstriction. Phosphodiesterase activation also stimulates ventricular remodelling pathways.
  31. 31. RAAScontinued  Two Angiotensin II receptors – AT-1 and AT-2  ARBs are AT-1 blockers  AT-1 activation in the diseased heart causes stimulation of contraction, vasoconstriction, myocyte hypertrophy, fibrosis, antinaturiesis  AT-2 role involves inhibition of growth in the late fetal phase and otherwise is unclear
  32. 32. RAAScontinued  Stimulation for release is caused by hypotension, decreased sodium reabsorption in the DT, decreased blood volume, increased beta1sympathetic activity  Aldosterone stimulation means release of sodium- retaining aldosterone from renal cortex
  33. 33. Bradykinin  Acts on receptors in the vascular endothelium and promotes the release of two vasodilators (NO and vasodilatory PGs – prostacyclin and PGE2)  Indomethacin can therefore reduce the hypotensive effect of ACEIs by inhibiting PGE synthesis that would be released by bradykinin  Bradykinin is inactivated by two kinases, kininase II is identical to ACE  ARBs may not be quite as good at ACEIs as a result, though they do lack the adverse effects of cough and angioedema
  34. 34. ACEIs  Good because:  Prolong life  Reduce maladaptive LV remodelling  Less new DM  Reduce proteinuria in T1DM, delays onset of microalbuminuria  Beware:  Angioedema – 0.3-1.6% - can be fatal  Teratogenic  Can cause neutropaenia (usually with high-dose captopril)  Contraindicated in:  Bilateral renal artery stenosis  Pregnancy  Hyperkalaemia  Serum Cr >220-265
  35. 35. Antiarrhythmics
  36. 36. Class1A Quinidineand similar  Quinidine, procaiamide, disopyramide  Inhibit fast Na channel  Depress phase 0 of the action potential  Prolong duration of the AP (mild class III effect)  Proarrhythmic in prolonging the QTi  May increase mortality, or at least be neutral
  37. 37. ClassIB Lignocaine  Inhibit fast sodium current while shortening the action potential duration in non-diseased tissue  No QT prolongation  Interrupt reentry circuits  Hypokalaemia must be corrected for maximal efficacy  Only used in sustained VT  Phenytoin is an alternative Class IB but is rarely used, except in patients who have concurrent epilepsy
  38. 38. ClassIC  Powerful inhibitors of the fast sodium channel  Marked inhibitory effect on His-Purkinje conduction with QRS widening  May variably prolong the action potential duration by delyaing inactivation of the slow sodiu, channel and inhibition of the rapid repolarising current  Good in paroxysmal supraventricular tachyarrhythmias (AF, Vas)  Should not be used in patients with structural heart disease
  39. 39. ClassII B-blockers  See section on B-blockers  At present, B-blockers are the closest to an ideal class of anti-arrhythmic because of their broad spectrum of activity and established safety record
  40. 40. ClassIII Amiodarone andsotalol  Lengthen the APD and hence lengthen the effective refractory period  Prolong the QTi  Amiodarone is a significant sodium and calcium channel inhibitor  Sotalol is a B-blocker
  41. 41. ClassIV  Verapamil and diltiazem (see earlier descriptions)