DRUGS USED IN - PowerPoint Presentation

1. DRUGS USED IN HEART FAILURE, ANTIARRHYTHMICS

2. Ischaemic Heart Disease CardiomyopathyArterial hypertensionSevere dysrrhytmiasmyocarditisAcute Coronary Syndroma (AIM…) pulmonary oedema cardiogennic shockHypertension crisisAcute arrhytmia….. right, left ventriclesCHRONICHeart Failurede novodecompensation of CHF Systolic failureDiastolic failure(decreased contractility)(more often in older patients) Vital organs chronically suffer from inadequate blood perfusion (caused by dysfunction of the myocard of ventricles due to various diseases)…ACUTE

3. Cardiac output CO =Stroke volume SV xHeart rate HR Heart FailureDecreased CO…. ↓ SV or ↓ HRPrimary compensation by ↑ HR… leads to ↑ metabolic demand…vicious circle Factors influencing SV…PreloadContractilityAfterload= fiber length-dependent activation…tension of the heart muscle before contraction (EDV)= Resistance to which the heart must pump blood= cardiac contractility (inotropy)

4. Compensatory mechanisms of HF…

5. Preload AfterloadVentricle volume overloadingVentricle pressure overloading↑ Contractility and Stroke volume  activation of sympathetic activity↑ Enddiastolic volume muscle contraction less efficient  RAAS activationHypertrophy of left vetricle Fluid and Na+ retentionPeripheral vasocontrictionMetabolic decompensationinotropicsdiureticsspironolaktonACEi/sartans

6. CHRONIC HEART FAILURE

7. Shortness of breath (at rest or exertion)FatigueOedematachycardia tachypnoeperipheral oedema hepatomegalyClinical symptoms…

8. ACEi /sartansTHE DRUG OF FIRST CHOICE FOR HEART FAILUREARNIValsartan + sakubitril (inhibitor of neprilisin)Nesiritide je rekombinant human natriuretic peptid type B .RAAS inhibition  affect heart remodelation ↓ vascular resistance (↓ volume + vasodilatation)↓ afterload↓ preload

9. Beta-blockersorBradins SFDecreased sympathetic activity (indicated only in patients with compensated HF) The pacient have to be haemodynamically stabilised before BB teratment. Start with low dose, that incease if tolerated ( 1-2 weeks interval)  dromotropic effect chronotropic effect

10. Aldosteron – antagonistsAntagonists of AR Inhibit fibroblast proliferation Second line tretament (ACEi a BB as firt choice) – some RCT show decreased mortality (low dose add-on therapy ) spironolakton Not combine with other potassium- sparing diuretics

11. Drugs with positive inotropic effect↑ contractility (inotropy)Cardiotonics KatecholaminsPDE-3 inhibitors↑ Ca2+ v sarcoplasma  ↑ Ca2+ influx´  beta-receptor stimulation  signaling pathway interferenceCalcium sensitizers2. ↑ binding of troponin C to the action of Ca2+

12. ACUTE HEART FAILURE

13. Acute Coronary Syndroma pulmonary oedema cardiogenic shockHypertensive crisisAcute arrhytmiaAcute myocarditiscardiomyopathyAortic dissectionAcute valvular regurgitation…ACUTE HEART FAILUREStrong diuretics – furosemid i.v. Bolus, continual infusionNitrates (nitroglycerin i.v. ) – BP monitoring !! Inotropics levosimendan dopamin  vasocontrction - incease BP + renovascular vasodilatationdobutaminAcute oedema Hypertensive crisis↑ contractilityAntiarrhytmicsbeta blockersamiodaron digoxinSevere systemic hypotensionnorepinephrin i.v. Cardial Intervention PTCA, PCI (angioplasty, stents)

14. DIURETICS and aldosteron antagonists

15. DIURETICSMechanism of antihypertensive action:- decrease in plasma volume- decrease in peripheral resistance- vasodilatation- act via several mechanisms directly in kidney on different parts of nephron: proximal tubules ascending limb of Henle loop distal tubules collecting ducts

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17. CLASSIFICATIONTHIAZIDES (distal tubules)LOOP DIURETICS POTTASIUM-SPARING DIURETICS ALDOSTERON RCP: ANTAGONISTSCARBOANHYDRASE INHIBITORS (proximal tubulus)OSMOTIC DIURETICS

18. Cl-/Na+ symport inhibition in distal tubules. Inhibition of Na+ resorbtion  inhibition of H2O reabsorbtion  ↑ diurhesis Na+ transport capacity in distal tubulus (5-8%)  lower diuretic effectThiazides (distal tubules) MECHANIS OF ACTIONif ↓ GFR 0,5ml/s…loop diuretics indicated slow onset af antihypertensive effect

19. ThiazidesPK - well absorbed, excreted in proximal tubules- diuretic effect lasts up to 12 hours, hypotensive effects with 3-4 days delay- latency occurs also in withdrawalINDICATIONHypertension (essential), manly in combinationHeart Failure (prevention of cardial oedema) AEhypokalaemia, metabolic alkalosis, hyperuricemia, hypovolemia

20. hydrochlorothiazidchlortalidon longer half-life than hydrochlorothiazidindapamid metipamidindapamid in combination with ACEi in DM patients (prospective RCT)DRUGSThiazides

21. Inhibition of 4 ions contransport (Na, K, 2xCl)Loop diureticsMECHANIS OF ACTIONvery strong, short effects (significant loss of ions)RAA system activation – long-term treatment is not recommended.

22. Loop diureticsfurosemidStrong effect Also in patients with ↓ GFDRUGINDICATIONlung oedemacongestive heart failurehypercalcemia (furosemid)chronic renal failureforced diuresis (intoxications)post-operative anuria

23. AEDRUG INTERACTIONSIon imbalance (loss of Na+, Cl-, K+, Ca2+, Mg2+)Osteoporosis Hypovolemia  risk of trombosisFurosemid bounds to albumin  ↑ plasmatic level of metformin, amiodaron, digoxin,…↑ Nephrotoxicity of cefalosporinsLoop diuretics

24. Na+/K+ antiport inhibition through direct channel affecting, or as aldosterone receptor inhibitorsPotassium sparing diureticsaldosteron. rcp. antagonistsMECHANISM OF ACTIONPotassium sparing diureticsAntagonists of aldosteron receptorsaldosteron receptor antagonisationDirectly ion channel

25. inhibition of resorbtion Na+ ionts + H2O inhibition of excretion K+ ionts → potassium sparingAntagonists of aldosteron receptors:Extrarenal effect - inhibition of fibroblast proliferation in myocard and vesselsMg2+ sparingIndicated for pts. with HF

26. DRUGPotassium sparingamilorid Weaker effect, used in combinations with other potassium-loss causing diuretics Hypertension in combination Prevention of cardial oedemaINDICATION

27. DRUGAntagonist of aldosteronspironolakton (often combined with furosemide)positive effects on remodelation → in heart failure also in monotherapyAntiandrogenic effectInhibition of bounding of testosteron to rcp.Inhibition of P-glp efflux pump AE - gynecomastia, menstruation problems

28. eplerenon MoA:Selective antagonist of mineralokortikoid receptorsHypertension (in combination with furosemid, e.g. resistent HT form)Primary hyperaldosteronismHeart failureINDICATION

29. Advantages: useful combinations with others AHTincrease effect of other AHT effectsno influence on CNScheap Disadvantages: metabolic effects (thiazides)low tolerance (elderly)Diuretics in general

30. AE: potassium depletion (except K+ sparing)hyperuricemia (thiazides, loop diuretics)weakness, nauseaimbalance in glycid and lipid metabolism (thiazides)hypovolemia, hypotension (furosemid)hyperkalaemiaa (amiloride, spironolactone)Chronic therapy – disruption of kidneys functioningCI: gout (thiazides)renal failure, hyperkalaemia (K+ sparing)relative: pregnancy, metabolic syndromeDiuretics

31. INDICATION of diuretics (general)Loop diureticsHT older pts.Systolic isolated HTChronic heart failure in combination HT in renal insufficiencyChronic heart failure HyperkalcemiaPulmonary oedemaK-sparingAldosteron antagonistsResistent form of hypertension (spironolakton)HT and primary hyperaldosteronism (spironolakton)Chronic heart failureThiazides+

32. ACEi /sartansPrevious lectureDRUGS with POSITIVE INOTROPIC EFFECTS Cardiac glycosides (cardiotonics) KatecholaminesPDE-3 inhibitorsCa2+ sensitizers

33. Cardiac glycosides (cardiotonics) MECHANISM OF ACTION: Inhibition of Na+/K+ ATPasa pump  increase intracellular sodium concentration (Na+/Ca+ exchange transporter  secondary rise of Ca2+ -  increased contractility  ↑inotropic effect efekt Activation of parasympatics (n. vagus) and ACH release  SA node, AV conduction slow ↓ chronotropy ↓ dromotropy  antiarrhytmic effect DRUGdigoxin

34. Cardiac glycosides (cardiotonics)

35. PHARMACOKINETICSt1/2 = 36 hoursTDM (plasma level 0,5–1,5 ng/ml) Variable bioavailability (50-70 %)P-glp pump substrate (drug interaction ! )Binding to the albumin 20-40%Renal elimination, GFR depending Liver metabolization app. 20 %

36. ADVERSE EFFECTSCardial, CNS and GI – clinically significantDIGITALIS INTOXICATIONCardial signs↓ intracelullar K+ leds to ↑ excitability (tachyarrhytmia)Parasympatic activation (sinus bradycardia, AV blocades)Others :CNS: Visual disturbance (yelow colors, disorientation, confusionGI: Anorexia, nausea, vomiting

37. DRUG INTERACTIONSStrong or moderate Pglp pump inhibitors …should increase plasmatic level of digoxinverapamil, amiodaron, propafenon, telmisartan, cyklosporin, antimycotics (ketokonazol), macrolides ATB (clarithromycin) DIGITALIS INTOXICATIONHypocalemia should leads to digoxin intoxication

38. INDICATIONCONTRAINDICATIONAV blockades Cardial insufficiency with bradycardiaDigoxin intoxication RELATIVE: aIMChronic HF Sinoatrial tachyfibrilation

39. Catecholaminesnorepinephrin α1 rcp. agonist increase BPDose-dependentD rcp.  renovascular dilatationβ1 rcp.  inotropic effect↑ dose α1 rcp. Agonist  increase BP dopaminINDICATION Severe hypotension (NA)Vasodilatation of renal vessels (dopamin)

40. Catecholaminesadrenalin, dobutamin INDICATIONAcute HF, cardiopulmonal resuscitationstimulation β1 rcp. β2 rcp. ↑contractility (inotropy)vasodilatation PK:Low bioavailability  i.v. administrationShort half-life (2 minutes) AE:Arrhytmogenic effect

41. cAMP-dependent phosphodiesterase- myocardial isophorm3 - inhibitorarterial dilatation (reduction of afterload) cardiostimulation (+ chrono-, ino- a dromotropic effects)PDE-3 inhibitorsDRUGSmilrinonAE:Decreased BP, headacheProarrhytmogenic effect – less usedMECHANISM OF ACTIONINDICATION Treatment of acute and refractory HF

42. ↑ the force of contraction of the heart by binding troponin C and sensitising it to the action of Ca2+  Binds to the KATP channel – membrane hyperpolarization  ↓ opening of the CaL channel  vasodilatation (systemic, lung) Calcium sensitizers agentDRUG:levosimendanMECHANISM OF ACTIONINDICATIONAcute HFPK:i.v. infusion Metabolised to active metabolite with long half-life (80hrs)

43. ANTIARRHYTMICS

44. Antiarrhythmic agents Vaughan-Williams classification (based on electrophysiological effects, 1970)Active agentsClinical useMoAClass I aPrajmalinLimited useInterfere with Na+ channel / effects on cardiac potentialsClass I b Lidocain Ventricular tachycardiaClass I c PropafenonAtrial fibrilation, reccurent tachyarrhythmiasClass IIB –blockers (metoprolol, atenololTachyarrhythmiasdecrease conduction through the AV nodeClass IIIAmiodaron, SotalolDronedaronIbutilidVetnricular tachycardiaAtrial fibrilation - the most effective AA K+ channel blocker, prolong repolarisation ( QT int.) Class IVCa channel blockersAtrial fibrilation - rate reductionParoxysmal supraventricular tachycardia preventionCa++ channel blocker

45. Drug classMechanism of actionDrugCardiac glycosidesParasympathetic activation digoxinBradins↓ depolarization of SA pacemakerivabradinAgonists of β1 rcppositive chronotropic, dromotropic, bathmotropic effectscatecholamines↓ depolarization of SA and decreased AV conductionadenosinOthers…

46. THE PHASE OF ACTION POTENCIALPhase 0: rapid depolaritionPhase 1: partial repolarizationPhase 2: plateauPhase 3: final repolarizationPhase 4: resting stage

47. IV. class Ca2+III. class K+I. class Na+II. class Four classes of antiarrhytmics

48. ANTIARRHYTMICS class I Subgroups:IA prajmalinRisk of torsade de pointesIB lidokainIC propafenonProphylaxy and treatment of supraventricular arrhytmias Class I drug block sodium channelInhibit action potential propagation in excitable cellsMembrane-stabilising activity  reduce the maximum rate of depolarisationNow seldom used

49. ANTIARRHYTMICS class IIAntiarrhytmic effect caused by lowering of proarrhytmogenic effect of sympathetic activity (negative chrono-,dromo- a bathmo-tropic effects)Leads to:Increase the refractory period of the AV node Prevent reccurent attacks of SVT  prolongation of repolaritazionINDICATION:Prophylaxy of supraventrikular and ventricular tachyarrhytmias Sinoatrial fibrillation

50. ANTIARRHYTMICS class IIIClass III inhibit potassium channel involved in cardiac repolarization, mainly Ikr  prolong the cardiac action potential  prolong repolarizationThe most often usedDRUGSamiodaron, sotalolINDICATIONPharmacological cardioversion (fibrillation or flutter) Prophylaxy of fibrillation or fluttersuperior in reducingthe recurrence of ventricular arrhythmias and atrial fibrillation – but many Aes !

51. Amiodaron pharmacokinetic:Active metabolite (desmetylamiodaron) highly lipophilic  accumulates in the liver, skin and fatBioavailability of amiodarone is quite variable (ranges 22 to 95%, with better absorption when it is given with food)Loaded dose (3-6x higher for weeks, orally)Extensively bound in tissuesLong elimination half-life (40-50 days)Biotransformation - izoenzymes CYP (mainly CYP2C9, CYP2D6, CYP3A4) P glp inhibitorLiver eliminationDrug interaction

52. amiodaron x digoxinDRUG INTERACTIONS↑ digoxin plasma levelDose changesP-glp. pumpamiodaron x statins(simvastatin)amiodaron x CCBamiodaron x BB (lipophylic)↑ plasma level – clinically significantP-glp. pump + CYP3A4

53. Adverse effects dose-dependentMoAdysrrhytmia decreased heart contractility2. Specific AEs reverzible corneal depositsblue´discoloration of the skin is (10%) irriversible severe lung fibrosis3. Thyreoid toxicity Hypothyreosis (10%) Typerthyreosis (less common) All antiarrhytmicsto avoid sun exposure due to photosensitivity

54. ANTIARRHYTMICS class IVBlocking voltage-sensitive calcium-channelSlow conduction in the SA and AV nodesShorten the plateau of the action potentialReduce the force of contractionAntiarrhytmic effect of verapamil is better than diltiazemNot indicated for patients with left vetricle dysfunction of heart failure

55. Other antiarrhytmicsadenosinMÚ: activation of adenosin rcp. A1 in SA a AV nodes slow conduction Activation of rcp. A2 – vasodilatation I: re-entry arrhytmiasPK: i.v. bolus centrally atropin (parasympatolytic effect)MoA: competitive inhibition of M2 rcp in SA a AV nodesI: treatment of sinus bradycardiaPK: i.v. administration

56. Thank you for your attention