Colloq II Cardiovascular system - Aurora Killi.pdf

Hematological agents Aurora Killi 07.11.22 Class 7 Antiplatelets White thrombus Prevent thrombus formation Anticoagulants Red thrombus Prevent thrombus formation Thrombolytic agents Antihemorrhagic agents Antithrombotic agents 1. Thromboxane synthesis inhibitors Acetylsalicylic acid 2. GP IIb and II...

Hematological agents Aurora Killi 07.11.22 Class 7 Antiplatelets White thrombus Prevent thrombus formation Anticoagulants Red thrombus Prevent thrombus formation Thrombolytic agents Antihemorrhagic agents Antithrombotic agents 1. Thromboxane synthesis inhibitors Acetylsalicylic acid 2. GP IIb and IIIa receptor antagonists GP = glycoprotein Tirofiban ADP = adenosine diphosphate 3. ADP receptor antagonists Clopidogrel Ticagrelor Inhibitors of activated coagulation factors Indirect inhibitors 1. Non-selective indirect coagulation factor inhibitors Heparin (high molecular weight) Enoxaparin (low molecular weight) 2. Selective indirect inhibitors of factor Xa Fondaparinux Direct inhibitors 1. Selective direct inhibitors of factor IIa Dabigatran 2. Selective direct inhibitors of factor Xa Rivaroxaban Apixaban Zymogen synthesis inhibitors 1. Vitamin K antagonists Warfarin 1. Thrombolytic (fibrinolytic) agents Alteplase Antihemorrhagic (hemostatic) agents 1. Fibrinolysis inhibitors 1. Tranexamic acid 2. Vasopressin receptor agonists 1. Desmopressin White thrombus (arterial thrombosis) à consists of aggregated platelets. Forms in the blood vessels where blood flow is fast and blood pressure is high. Antiplatelets Red thrombus (venous thrombosis) à slower blood flow and lower blood pressure. Fibrin can get activated and form fibrin net to form blood elements, forming a gel like substance (red). Grows slower in the veins. Can detach at some point and with venous return to the heart, reach pulmonary circulation. Deep vein thrombosis à pulmonary embolism. To prevent red thrombus formation, we use anticoagulants Antithrombotic agents Aurora Killi 07.11.22 (1) Antiplatelets Platelet aggregates form the initial hemostatic plug at sites of vascular injury Platelets also contribute to the pathological thrombi that may lead to myocardial infarction, stroke etc. Inhibitors of platelet function prevents blood clots from forming by inhibiting platelet aggregation Thromboxane synthesis inhibitors Acetylsalicylic acid Thromboxane is vasoconstrictor à trigger platelet aggregation GP IIb/IIIa receptor antagonists Tirofiban Used IV in acute therapy of ACS GP = glycoprotein ADP = adenosine diphosphate ADP receptor antagonists Clopidogrel Ticagrelor Acetylsalicylic acid Mechanism of action o Irreversible inhibition of COX 1 à inhibition of thromboxane A2 synthesis o Antithrombotic (antiplatelet) effect Clinical use o Secondary prevention of cerebro- and cardiovascular thrombosis o Acute coronary syndrome Side effects o Bleeding from GIT Interactions o NSAIDs (reduce ASA binding to COX 1) o Aspirin can be used as a thromboxane synthesis inhibitors because it causes irreversible inhibition of COX 1 o Ibuprofen cannot be used in this case because it does not cause irreversible inhibition of COX 1, but rather reversible inhibition. Thus, not stable antiplatelet effect Tirofiban Mechanism of action o Selective antagonism of receptor o Blocks platelet activation in aggregation phase o Antithrombotic effect Clinical use o Acute coronary syndrome (in combination with coronary angioplasty) Clopidogrel Mechanism of action o Irreversible receptor antagonism (P2Y12 subtype) o Blocks platelet activation in aggregation phase o Prodrug (activated by CYP450) o Indirect inhibition of GP IIb/IIIa receptor complex Clinical use o Secondary prevention of cerebrovascular and cardiovascular thrombosis o Aspirin intolerance o Dual antiplatelet therapy for acute coronary syndrome (w/ Ticagrelor) Interaction o NSAIDs o GC Side effects o Bleeding Ticagrelor Mechanism of action o Reversible receptor antagonism (P2Y12) Aurora Killi 07.11.22 o Indirect inhibition of GP IIb/IIIa receptor complex o Antithrombotic effect Clinical use o Secondary prevention of cerebrovascular and cardiovascular thrombosis o Dual antiplatelet therapy for acute coronary syndrome (w/ Clopidogrel) Interaction o NSAIDs o GC Side effects o Bleeding (2) Anticoagulants Main target of anticoagulant activity is plasma serine protease thrombin Thrombus formation can be controlled by o Direct or indirect inhibition of thrombin o By inhibiting other factors in the coagulation cascade o Reducing zymogenic activity A complication of anticoagulant therapy is uncontrolled bleeding Indirect inhibitors of activated coagulation factors without intrinsic anticoagulant activity, act with antithrombin involvement Non-selective indirect Heparin (high molecular weight) coagulation factor Mechanism of action inhibitors o Forms a complex with antithrombin III à increases AT III activity o Heparin-AT III complex can further inhibit coagulation factors, but Heparin is a mixture of heparin itself cannot inhibit them different molecules. o Indirect inhibition à Xa and IIa (inhibition ratio 1:1) Unfractionated. o Inactivate other serine proteases IXa, XIa, XIIa IIa = thrombin Extracted from animal o Antithrombotic effect sources, too Clinical use complicated to be o Deep vein thrombosis (DVT) prevention and therapy synthesized. More o Acute coronary syndrome likely to cause side Side effects Heparin antidote à effects. o Hemorrhage protamine sulphate o Heparin-induced thrombocytopenia More fractionated. Low Enoxaparin (low molecular weight) molecular weight Mechanism of action heparin is more o Forms a complex with antithrombin III à increases AT III activity predictable in their o Indirect inhibition à Xa (mainly) and IIa (minimally) action. Can be used at o (Inhibition ratio 2:1 – 4:1) home by patients. o Antithrombotic effect Clinical use o Deep vein thrombosis prevention and treatment o Acute coronary syndrome o Unlike heparin à no monitoring of dose or therapy necessary Selective indirect Fondaparinux inhibitors of factor Xa Mechanism of action Fondaparinux o Forms a complex with antithrombin III à increases AT III activity o Indirect inhibition à Xa only (not IIa) Aurora Killi 07.11.22 Heparinoid, type of heparin o Antithrombotic effect Clinical use o Venous thromboembolism (VTE) prevention o Acute coronary syndrome Direct inhibitors of activated coagulation factors With intrinsic anticoagulant activity, act without AT involvement Selective direct Dabigatran inhibitors of factor IIa Mechanism of action Dabigatran o Prodrug o Inhibition of fibrinogen activation to fibrin Orally used o Reversible inhibition of factor IIa (thrombin) (secondary to point above) o Antithrombotic effect IIa = thrombin Clinical use o Deep vein thrombosis (DVT) prevention (hip, knee prothesis) o Pulmonary embolism (PE) prevention (hip, knee prothesis) o Stroke prevention (Afib) Selective direct inhibitors of factor Xa Rivaroxaban Apixaban Orally used Vitamin K antagonists Warfarin Do not have immediate effects. Onset of action is after 3 days (thrombin has lifespan of 3 days). No effect on previously synthesized coagulation factors, inhibit synthesis of new ones. INR is used to determine if Warfarin In cases of life-threatening or uncontrolled hemorrhage requiring rapid discontinuation of anticoagulant Dabigatran, a specific anticoagulant neutralizer, idarucizumab, should be used Rivaroxaban Mechanism of action o Irreversible, free, thrombus-bound inhibition of factor Xa o Antithrombotic effect Clinical use o Deep vein thrombosis (DVT) treatment and prevention o Pulmonary embolism (PE) treatment and prevention o Stroke prevention If the hemorrhagic complication cannot be controlled by non-specific measures, the use of a specific factor Xa inhibitor neutralizer, a pharmacodynamic antagonist andexanet alfa, should be considered Zymogen synthesis inhibitors Warfarin Mechanism of action o Inhibition of vitamin K epoxide reductase à inhibits vitamin K conversion o Inhibition of synthesis of new coagulation factors o Prothrombin o VII, IX, X (zymogens) o Antithrombotic effect NB! Narrow o Inhibition of protein C and S therapeutic index Clinical use Vitamin K is antidote o DVT prevention and treatment o PE prevention and treatment o Stroke prevention o Secondary prevention of MI and prevention of thromboembolic complications after MI o Prevention of thromboembolic complications in patients with heart valve diseases and prosthetic valves Interaction Aurora Killi 07.11.22 works well. Target INR value > 1 o Antithrombotic effects are exacerbated or reduced by many medications and food Warfarin toxicology treatment o PCC à prothrombin complex concentrate o FFP à fresh frozen plasma IV o Phytomenadione (vitamin K) IV o Vitamin K will not have immediate effect as antidote, because it takes time to synthesize new coagulation factors (3) Thrombolytic (fibrinolytic) agents Antithrombotic agent Thrombolytic agents dissolve blood clots Can be used to treat heart attacks and stroke Thrombolytic agent Alteplase Alteplase Mechanism of action o Activated by fibrin binding to it o Induce activation of plasminogen into plasmin à promotes dissolution of fibrin clot o Fibrinolytic effect o Produced by recombinant DNA technology NB! Overdose Clinical use increases risk o Pulmonary embolism of intracranial o Acute coronary syndrome hemorrhage o Ischemic stroke treatment Antihemorrhagic agents Hemostatic agents Agents used to stop bleeding Fibrinolysis inhibitors are used to treat bleeding disorder by acting as competitive inhibitor of plasminogen that prevents activation of plasminogen into plasmin Fibrinolysis inhibitors Tranexamic acid Vasopressin receptor agonists Desmopressin Tranexamic acid Mechanism of action o Reversibly block lysine domain in plasminogen à inhibition of plasminogen activation to plasmin o Prevents binding of plasmin to fibrin and its degradation o Antifibrinolytic effect Clinical use o Complication of fibrinolytic therapy or hyperfibrinolysis o Massive bleeding or its prognosis Side effects o Seizures at high dose Interactions o Oral contraceptives à risk of thrombosis Desmopressin Mechanism of action o Synthetic analogue of vasopressin o V2 receptor agonist in endothelium Aurora Killi 07.11.22 o Increases concentration of o Factor VIII o Von Willebrand factor o Enhances platelet adhesion avascular in endothelium o Antihemorrhagic effect Clinical use o Scheduled surgery in patients with hemophilia A or von Willebrand´s disease o Bleeding control in patients with prolonged blood flow time Agents affecting kidneys Aurora Killi 07.11.22 Diuretics Diuretics 1. Osmotic diuretics Mannitol 2. Carbonic anhydrase inhibitors Acetazolamide 3. Loop diuretics Furosemide Torasemide 4. Thiazides and thiazide-like diuretics Hydrochlorothiazide Indapamide Mineralocorticoid receptor antagonists 1. Potassium sparing diuretics Spironolactone Eplerenone Na+ reabsorption in nephron Proximal tubule à 65% Na and HCO3 reabsorbed Thick ascending part of loop of Henle à 30% Na reabsorbed Distal convoluted tubule à 5% Na reabsorbed Collecting ducts à 1-2% Na reabsorbed in exchange for K+ (1) Diuretics Drugs that increase rate of urine flow Most clinical applications of diuretics are directed toward reducing extracellular fluid volume by decreasing total-body NaCl Most important indications à hypertension and edemas Osmotic diuretics Never used orally. Very osmotically Mannitol Mechanism of action o Osmotic diuretic effect Aurora Killi 07.11.22 active agent. Chemically similar to glucose but is not reabsorbed. Drags water with it Will increase total circulating volume in beginning, but it afterwards excreted and drags water with it so volume decreases. Forces diuresis. Carbonic anhydrase inhibitors Loop diuretics Potassium depleting diuretics Also called highceiling diuretics. The higher the dose, the more potent is the effects. Potent diuretics. Useful for emergency situations o Inhibits reabsorption of water (particularly) o Inhibits (minor) Na+ reabsorption (proximal renal tubules, Henle loop) o Anti-glaucoma effect o Stimulate intracellular water transport from tissues/organs to plasma (increased plasma osmolarity) o Stimulates return of intraocular fluid to the plasma Clinical use o Increased intracranial pressure o Acute glaucoma attack (alternative therapy) o Acute renal failure forced diuresis Side effects o Dehydration o Electrolyte imbalance o Hypernatremia, hyperkalemia (repeated overdoses or administration) Contraindicated for o Hypertensive patients because it causes hyperhydration Acetazolamide Mechanism of action o Diuretic effect o Inhibits carbonic anhydrase (proximal renal tubules) o Inhibits Na+ exchange for H+ o Increased release of water and Na+ o Promotes HCO3- excretion with urine o Antiglaucoma effect o Carbonic anhydrase inhibition in ciliary body o Decreases intraocular fluid production Clinical use o Oedema o Glaucoma o Acute glaucoma attack o Acute mountain sickness Side effects o Metabolic acidosis Furosemide, Torasemide Mechanism of action o Diuretic effect o Inhibition of Na+/K+/2Cl- transporter (ascending loop of Henle) o Promotes Na, K, Cl, Mg, Ca excretion with urine o Reduces uric acid excretion o Hypotensive effect o Decreases BP o Reduces vascular sensitivity to catecholamines Clinical use o Chronic heart failure o Arterial hypertension o Edema due to liver or kidney disease o Swelling of lungs, brain, burns Side effects o Hypokalemia (associated with arrythmias) o Hypocalcemia (associated with arrythmias) o Hyponatremia o Ototoxicity Aurora Killi 07.11.22 Thiazides diuretics Potassium depleting diuretics Hydrochlorothiazide, Indapamide Hydrochlorothiazide à thiazide diuretic Mechanism of action Indapamide à thiazide-like diuretic o Diuretic effect o Inhibition of Na/Cl transporter (distal renal tubules) Less potent than o Promotes excretion of Na, K, Cl, Mg loop diuretics. o Reduces excretion of Ca and uric acid Low-ceiling o Hypotensive diuretics. Blocks Na o Decrease in circulating blood volume reabsorption late Clinical use in the nephron, o Chronic heart failure thus not so big o Arterial hypertension effect. The only o Kidney stone disease caused by hypercalciuria difference is Side effects chemical structure. o Hypokalemia Interactions o NSAIDs (2) Mineralocorticoid receptor antagonist Mineralocorticoids cause Na and water retention (reabsorption) and K and H excretion Antagonists of these receptors decrease Na and water reabsorption Weak diuretics Potassium sparing diuretics Spironolactone, Eplerenone Mechanism of action à block aldosterone receptors in o Kidneys o Reduce Na+ channel expression in collecting duct, apical side o Heart and BV o Mild diuretic effect o Antifibrotic effect o Antiandrogenic effect Clinical use o Chronic heart failure o Resistant arterial hypertension o Primary hyperaldosteronism (only spironolactone) o Hirsutism, acne (only spironolactone) o Edema Side effects o Hyperkalemia o Gynecomastia Interactions o ACE-I à hyperkalemia Aurora Killi 07.11.22 Antihypertensive agents for long-term blood pressure control Class 8 Angiotensin converting enzyme inhibitors Captopril Enalapril Enalaprilat Perindopril Angiotensin II type I receptor blockers Valsartan Candesartan Losartan Calcium channel blockers Nifedipine Amlodipine Diuretic agents Furosemide Hydrochlorothiazide Indapamide Spironolactone Selective α1 adrenoreceptor antagonists Doxazosine Selective α1, non-selective ß adrenoreceptor antagonists Labetalol Carvedilol ß adrenoreceptor antagonists Metoprolol, Bisoprolol (2nd gen) Nebivolol (3rd gen) Selective central α2 adrenoreceptor agonists Methyldopa Central α2 adrenoreceptor and imidazoline I1 agonists Clonidine Selective imidazoline I1 receptor agonists (SIRS) Moxonidine General information Main factors determining blood pressure 1. Cardiac minute volume (CMV) o CMV = systolic volume * HR o Systolic volume is affected by myocardial contractility, pre-, and postload 2. Total peripheral resistance (TPR) o Mostly determined by arterioles o Venous return does not contribute much 3. Volume of circulating blood Three major regulatory systems of blood pressure 1. Autonomic nervous system (ANS) 2. Renin-angiotensin-aldosterone system (RAAS) 3. Local chemical mediators in vascular endothelium (NO) These regulatory systems can o Cause acute and chronic BP changes o Work both short and long term Autonomic nervous system in BP control Blood pressure is physiologically regulated by the vasomotor center which controls NO modulators Sodium nitroprusside Glyceril trinitrate BP = CO * TPR In the heart o Sympathetic nervous system acts mainly on ß1 and ß2 adrenoreceptor o This increases myocardial contractility and heart rate, leading to increased CMV and BP o ↑ CMV, BP In the arterial system Aurora Killi 07.11.22 cardiac minute volume and blood vessel tone Renin angiotensin aldosterone system o Sympathetic stimulation causes a narrowing of arterioles by stimulation of postsynaptic α1 adrenoreceptors o Vasoconstriction of arterioles increases cardiac afterload and BP o ↑ Afterload, BP In the venous system o Sympathetic stimulation of postsynaptic α1 adrenoreceptors causes narrowing of veins o ↑ Preload, BP Slower than ANS Raises blood pressure in combination with o Vasoconstriction and o Increasing circulating blood volume Aldosterone promotes Na reabsorption (and water) and K loss Angiotensin I receptors can be found in heart and BV in addition to kidneys Compensatory reactions Compensatory reactions are responses when the medication used affects CMV or vascular tone or circulatory blood volume Early compensatory reactions o Drug causes vasodilation à compensatory reaction is increased HR o Drug decreases CMV (HR) à compensatory reaction is vasoconstriction Late compensatory reactions (aldosterone mediated) o Structural remodeling o Cardiovascular remodeling o Increased thickness of BV o Increased thickness of ventricular walls o We can prevent these mechanisms by blocking RAAS (since these are aldosterone mediated changes Antihypertensive agents for long-term blood pressure control Primary drugs o Angiotensin converting enzyme inhibitors o Angiotensin II type I receptor blockers ß adrenoreceptor antagonists o Calcium channel blockers o Diuretic agents Secondary drugs (used when primary drugs cannot be used) o Centrally acting o Selective imidazoline receptor agonist (SIRA) o Selective α2 adrenoreceptor agonist o Peripherally acting o Selective α1 adrenoreceptor antagonists o Mineralocorticoid receptor antagonist (MRA) Hypotensive activity of drugs is ensured by Reduction of preload o Venodilation o Accumulation of venous blood o Reduces diastolic pressure and end volume o Decreased preload o Decreased BP Reduction of afterload NB! Early compensatory reactions are terminated and end after the hemodynamic parameters have stabilized Centrally acting antihypertensive agents induce vasodilation without inducing reflex tachycardia Aurora Killi 07.11.22 o Arteriodilation o Decreased total peripheral resistance o Decreased afterload o Decreased BP Reduction of CMV o Reduces BP Angiotensin converting enzyme inhibitors They are prodrugs; thus, mechanism of action is not immediate à not suited for emergency medicine, rather used for chronic conditions Captopril is not a prodrug, thus acts quickly, but is therefore not appropriate for longterm hypertension treatment (requires drug administration multiple times a day) Do not change hemodynamics in the kidneys, can be used to decrease kidney damage in diabetic neuropathy patients Angiotensin II type I receptor blockers (ARB) These are competitive inhibitors of AT1 receptors. They have the same effects of ACE inhibitors, but do not affect bradykinin metabolism and thus do not have the dry cough side effect Calcium channel blockers (dihydropyridine) Since total peripheral resistance decreases, compensatory Enalaprilat, Captopril, Enalapril, Perindopril Mechanism of action o Inhibition of angiotensin converting enzyme o Venous and arterial vasodilation Enalaprilat à i/v ↓ Pre- and afterload Captopril à p/o, short acting o Hypotensive action Enalapril à p/o, pro-drug ↓ Aldosterone secretion Perindopril à p/o, pro-drug ↓ Cardiovascular remodeling Clinical use (Enalaprilat) o Arterial hypertension Clinical use (Captopril, Enalapril, Perindopril) o Arterial hypertension o Chronic heart failure (since they prevent cardiovascular remodeling) o Coronary heart disease o Diabetic nephropathy (Captopril) Side effects o Dry cough (↑ bradykinin (aldosterone normally breaks down inflammatory mediator bradykinin, by inhibiting aldosterone bradykinin will accumulate)) o Hyperkalemia (↓ aldosterone) o Teratogenic (cause birth defects, crosses placenta) Spironolactone is contraindicated in combination with Captopril because they both cause hyperkalemia Valsartan, Candesartan, Losartan Mechanism of action o Blocks angiotensin II binding to AT1 receptors o Venous and arterial vasodilation ↓ Pre- and afterload o Hypotensive action ↓ Cardiovascular remodeling ↓ Aldosterone secretion Clinical use o Arterial hypertension o Chronic heart failure Side effect o Hyperkalemia o Teratogenic Nifedipine, Amlodipine, Nicardipine Mechanism of action o Arterial vasodilators (↓ afterload) o Mechanism behind 1. Inhibits Ca2+entry into vascular smooth muscle cells 2. Calcium-calmodulin complexes do not form 3. Myosin light chain kinase not activated Aurora Killi 07.11.22 mechanism is to increase HR à tachycardia Nifedipine is short-acting (duration 1h), thus for chronic disease it is not suitable. Amlodipine is much longer acting (24h) ß adrenoblockers Metoprolol Bisoprolol Nebivolol (3rd) Carvedilol (3rd) Labetalol (3rd) These drugs decrease CO, thus compensatory mechanism is vasoconstriction (1st and 2nd gen) Diuretic agents Hydrochlorothiazide and Indapamide are first choice Selective α1 antagonists Improves outflow of urine in case of prostatic hyperplasia Peripherally acting Selective imidazoline I1 receptor agonists (SIRA) Centrally acting antihypertensive agent Not first choice since they reduce sympathetic NS action. Beneficial 4. Smooth muscle relaxes Clinical use o Arterial hypertension o Prevention of stable angina attack o Coronary heart disease (vasospastic form) Side effects o Constipation (because they also affect Ca channels in intestines) o Peripheral ankle edema (arteries are dilated in lower parts of the body causes increased capillary pressure, however the venous return is not increased because the veins are not dilated à expulsions of fluid into surrounding tissues) o Reflex tachycardia BAB mechanisms that affect blood pressure 1. ↓ HR and contractility Decreases cardiac minute volume Can cause reflex vasoconstriction (1st and 2nd gen) 2. Block ß1 receptors on juxtaglomerular cells Renin secretion ↓ (reduces cardiovascular remodeling, reduces aldosterone mediated Na and water retention) 3. Peripheral arterial vasodilation Not direct BAB activity Additional activity of several BAB with hybrid effect (3rd gen) Hydrochlorothiazide, Indapamide, Furosemide, Spironolactone Diuretics affect blood pressure by 2 mechanisms Hydrochlorothiazide à thiazide diuretic Indapamide à thiazide-like diuretic 1. Affecting processes in nephron, Furosemide à loop diuretic thereby reducing circulating Spironolactone à mineralocorticoid volume receptor antagonist 2. Long-term effect on vascular smooth muscle Doxazosin Mechanism of action o Hypotensive effect o Vasodilation of arteries and veins o ↓ afterload o ↓ preload Clinical use o Arterial hypertension Side effects o First dose orthostatic hypotension and syncope o Reflex tachycardia NB! Imidazoline receptors are mainly concentrated in the ventrolateral part of medulla oblongata Moxonidine Mechanism of action o ↓ SNS activity à decreased BP Clinical us o Arterial hypertension Aurora Killi 07.11.22 because they do not cause compensatory mechanisms o Metabolic syndrome o (Tissue sensitivity to insulin) Side effects o No reflex tachycardia (centrally acting) Central non-selective α2 Clonidine and I1 agonists Mechanism of action Centrally acting o Equivalent affinity for α2 adrenoreceptor and I1 receptors antihypertensive agent o Hypotensive effect Clinical use Not first choice since o Antihypertensive therapy in urgent situations they reduce sympathetic Side effects NS activity o Bradycardia o Sedation o Dry mouth o No reflex tachycardia (centrally acting) Selective central α2 Methyldopa agonists Mechanism of action Centrally acting o Crosses BBB à decarboxylates to methyl-dopamine à inhibits dopaantihypertensive agent. decarboxylase Generally little used, o Accumulates (as a false mediator) presynaptically in vesicles and main benefit is that it is stimulates presynaptic α2 autoreceptors safe for pregnant women Clinical use o Gestational hypertension (safe for pregnant women) Side effects o No reflex tachycardia (centrally acting) Agents used in hypertensive emergencies NO modulators Sodium nitroprusside (short acting, i/v) Sodium nitroprusside is Mechanism of action an inorganic molecule o Direct vasodilator action that donates NO à o NO donor à increase cGMP à smooth muscle relaxation à relaxes vascular smooth vasodilation à decreased preload and afterload muscle Clinical use o Hypertensive emergencies rd 3 gen ß blocker Labetalol Mechanism of action o Combined α and β adrenoreceptor block Clinical us o Hypertensive emergencies (i/v) o Gestational hypertension Antianginal agents Class 9 Principles of CCS treatment 1. Use of anti-ischemic (antianginal) agents 2. Prevention of adverse cardiovascular events 1st choice 2nd choice Aurora Killi 07.11.22 Aurora Killi 07.11.22 Anti-ischemic (antianginal) agents The cause of angina is the disrupted balance of oxygen supply and oxygen consumption in the myocardium There are 2 ways to restore balance o Reduction of oxygen consumption o Increase in oxygen delivery Anti-ischemic activity is ensured by Reduction of oxygen consumption o Reduction of preload 1. Venodilation 2. Accumulation of venous blood 3. Decreased venous blood flow to heart 4. Decreased diastolic pressure 5. Decreased preload 6. ↓ myocardial oxygen demand o Reduction of afterload 1. Arteriodilation 2. Decreased total peripheral resistance 3. Decreased afterload 4. ↓ myocardial oxygen demand o CMV reduction 1. Negative chrono- and inotropy 2. ↓ myocardial oxygen demand Increase in oxygen supply/delivery o Coronary blood vessel dilation (coronarolytic activity) 1. Coronary dilation 2. Increased blood volume 3. Myocardial perfusion improves o Negative chronotropy 1. Negative chronotropy (HR) 2. Prolonged diastole (coronary blood vessels fill during diastole) 3. Increased oxygen extraction time Aurora Killi 07.11.22 4. Myocardial perfusion improves Characterization of anti-ischemic agent effects Reflex tachycardia can be caused by o Nitrates o Dihydropyridines calcium channel blockers Reflex tachycardia is typically not caused by o Non-dihydropyridines calcium channel blockers Targets for anti-ischemic drugs o Heart o Arteries o Veins Anti-ischemic (antianginal) agents Organic nitrates/NO Glyceryl trinitrate (GTN) (fast and short acting, sublingual) donors Mechanism of action NO is a b/v o Antianginal, hypotensive effect NO à increased cGMP endothelial relaxation o Venodilation in small and high doses à dephosphorylation of factor o Arteriodilation in high doses myosin light chain à b/v o Antianginal effect relaxation Organic nitrates are o Dilation of coronary blood vessels prodrugs Clinical use Reflex tachycardia can o Angina attack be triggered, that is Nitrate tolerance why these drugs o A nitrate-free interval is required à 10-12 h should be used in low Side effects doses to prevent o Headache (due to dilation of blood vessels in brain) triggering this reflex o Hypotension (tachycardia is not o Reflex tachycardia good for angina o Redness of skin patients) Interaction o PDE-5 inhibitors à life-threatening hypotensive reaction o They inhibit degradation of cGMP, thus increasing cGMP amount o Taking organic nitrates and this together cause hypotension o Viagra (brand name) or Sildenafil is PDE-5 inhibitors Isosorbide mononitrate (ISMN) (long acting, 6-8h, GTN metabolites) Mechanism of action o Antianginal, hypotensive effect NO à increased cGMP o Venodilation in small and high doses à dephosphorylation of o Arteriodilation in high doses myosin light chain à b/v o Antianginal effect relaxation o Dilation of coronary blood vessels Clinical use o Prevention of angina attack Side effects o Headache (due to dilation of blood vessels in brain) o Hypotension o Reflex tachycardia o Redness of skin Interaction o PDE-5 inhibitors à life-threatening hypotensive reaction Aurora Killi 07.11.22 Dihydropyridines Calcium channel blockers Nifedipine, Amlodipine (duration of action 24h) Dihydropyridine drugs Mechanism of action are vasoselective CCB à o Antianginal, hypotensive effect vasodilating effect o Dilation of peripheral arteries Within therapeutic o Antianginal effect dose, these are more o Dilation of coronary arteries effective in arteries o Inhibits Ca2+ influx in vascular smooth muscle cells Clinical use o Prevention of angina attacks o Prevention of vasospastic angina attack Side effects o Hypotension à reflex tachycardia o Headaches o Facial flushing o Fatigue o Peripheral edema (ankle) o Constipation Non-dihydropyridines Verapamil, Diltiazem Calcium channel Mechanism of action blockers o Strong cardio depression (antianginal, Non-dihydropyridine hypotensive action) drugs are nonWithin therapeutic o Peripheral arterial dilation (antianginal, vasoselective CCB à dose, these are more hypotensive action) cardiodepressant effect effective in heart. No o Coronary artery dilation (antianginal effect on heart, thus action) *Contractility in phase 2 do not cause reflex o Diastole prolongation (antianginal action) of AP (inhibits Ca2+ influx) o Reduce AV conduction (*antiarrhythmic action) Clinical use o Prevention of angina attacks o Prevention of vasospastic angina attacks ß blockers Propranolol (I), Metoprolol, Bisoprolol (II) (cardiodepressants) Mechanism of action o Antianginal, hypotensive action o Reduce CMV (HR and contractility) during rest and physical activity o By reducing oxygen consumption o Antianginal action o Prolong diastole o Antiarrhythmic activity o Reduce AV conduction Clinical use o Prevention of angina attacks Side effects o Bradycardia o AV block o Bronchospasms o Cold extremities Sinus node inhibitors Ivabradine (bradines) Mechanism of action Do not induce o Inhibits Na+ flow in sinus node (in 4th phase of vasoconstriction or NB! Elevated SF AP) by inhibiting HCN channels affect contractility (>70x/min) increases o Antianginal action Aurora Killi 07.11.22 cardiovascular risk and mortality. Not all patients are able to reduce HR by less than 60 x/min when treated with BAB Late sodium flow inhibitors NB! Ischemia induces an increased accumulation of Na+/Ca2+ ions in myocardium Hypolipidemic agents Reduce lipids in blood stream LDL transports cholesterol and TAGs throughout the body, however, if LDL is high, it is associated with atherosclerotic plaque formation When we block cholesterol synthesis in liver, the liver will respond by increasing its LDL receptors to take up LDL in plasma. This is because we need cholesterol in the body as it is a precursor of steroid hormones o Dose-dependent negative chronotropy o Prolong diastole (increase O2 supply) o Decrease O2 consumption Clinical use o Prevention of stable angina attack o BAB intolerance or contraindication, as well as in combination Side effects o Light phenomena in retina (photopsy) o Photopsia is seeing light without light being present o Ivabradine interacts with visual system by inhibiting hyperpolarization in retinal cells o Pronounced bradycardia Ranolazine Mechanism of action o Late block of Na+ channels o Indirectly reduces intracellular Ca2+ concentration à o Decreased myocardial diastolic tension o Decreased oxygen consumption which improves myocardial perfusion in diastole o Reduces need of GTN use Agents for prevention of adverse cardiovascular events Atorvastatin Mechanism of action o Inhibition of HMG-CoA reductase o Blocks synthesis of mevalonic acid in liver (precursor of cholesterol) o Up-regulates LDL receptor expression in hepatocytes à decreased LDL in plasma o Has pleiotropic effects (e.g., plaque stabilization, antioxidant effect etc.) Clinical use o Dyslipidemias o Prevention of cardiovascular events Side effects o Hepatic function impairment (hepatopathy) o Myopathy Fenofibrate à Fibric acid derivative 2nd choice drugs if PPAR-α agonist statins cannot be Mechanism of action used 1. Activates PPAR-α receptor in b/v endothelium 2. LPL gene expression 3. Serum lipoprotein lipase activation 4. Lipolysis 5. ↑ LPL receptor expression in hepatocytes Ezetimibe à cholesterol absorption inhibitor Mechanism of action 1. Inhabits transport protein NPC1L1 in enterocyte villi 2. By this inhibiting cholesterol absorption in small intestine 3. Does not affect absorption of Fat soluble vitamins Aurora Killi 07.11.22 Triglycerides Bile acids 4. ↓ LDL (reduces absorption of cholesterol in small intestine) Evolocumab à PCSK9 inhibitor (proprotein convertase Subtilisin/Typexin 9) Mechanism of action o PSCK9 is LDL receptor-degrading enzyme o It is a human IgG 2 monoclonal antibody o Selectively binds PSCK9 and inhibits its binding to LDL receptor à prevents PSCK9-mediated degradation of LDL receptors o Increase in density of hepatic LDL receptor à decrease in serum LDL cholesterol Monoclonal antibodies are proteins and should not be taken orally Agents used in treatment of ischemia and non-obstructive CAD (INOCA) Vasospastic angina Calcium channel blockers Long-acting organic nitrates (Isosorbide mononitrate) Microvascular angina With structural changes o ß blockers o ACE inhibitors o Statins (hypolipidemic agent Atorvastatin) With functional changes o Calcium channel blockers o Long-acting organic nitrates CCB toxicology Calcium channel blockers CCB decrease Ca2+ entry through L-type voltage gated Ca2+ channels on vascular smooth muscle in heart and pancreas, leading to o Coronary vasodilation o Peripheral vasodilation o Reduced cardiac contractility o Reduced AV node conduction o Reduced SA node activity CCB are metabolic poisons o Increases hearts dependance on carbohydrate metabolism (heart usually uses FFA) o Also inhibits insulin release (Ca+ channel blockers block calcium channels in pancreatic ß cells as well, inhibiting insulin release) Drug interactions that may cause toxicity o (Overdose) Dihydropyridines + RAAS inhibitors à hypotension o ß blockers + Verapamil (non-dihydropyridine) à life-threatening bradyarrhythmia o Both are cardiodepressants o Macrolide antibiotics, grapefruit juice, cytochrome CYP3A4 inhibitors à increases levels of calcium antagonists (e.g., Verapamil) Clinical presentation Hypotension o Peripheral vasodilation (vasodilatory shock) o Reduced cardiac contractility o Slowed heart rate (cardiogenic shock) o Dihydropyridines à vasodilatory shock Aurora Killi 07.11.22 o Non-dihydropyridines à vasodilatory and cardiogenic shock Bradycardia o Sinus bradycardia o II- or III-degree AV block o Sinus arrest o Most commonly with non-dihydropyridines Non-cardiac manifestations o Nausea, vomiting o Metabolic acidosis (due to hypotension) o Hyperglycemia (due to blockage of insulin) Treatment 1. Calcium chloride or calcium gluconate i/v 2. Vasopressors 3. High-dose insulin euglycemic therapy (HIET) Aurora Killi 31.10.22 Heart failure agents Class 10 Reduction of heart load Drug group ACE-1 ARB ARNI MRA 2nd gen BAB 3rd gen BAB SGLT2-inhibitors Diuretics Sinus node inhibitor Cardiac glycoside ß1 agonists Calcium sensitizer PDE-3 inhibitors Organic nitrates Dilation of arteries Dilation of veins + + + + + + + + + + + + High doses Sodium nitroprusside + Reduction of circulatory volume Promoting heart performance Negative Positive chronotropy inotropy (HR) (contractility) + + + + + + + + + + + + + + + + + + All doses + Delay of remodeling + + + + Principles of treatment of acute and chronic heart failure (AHF/CHF) In the treatment of acute and chronic heart failure we use cardiac function enhancement with the following mechanism of action 1. Stimulation of cardiac performance (increase in ejection volume and fraction) à acute heart failure ↓ end-systolic volume à increasing myocardial contractility (positive chronotropy) ↑ preload à increase of diastolic volume o When preload reserve is high enough 1 Aurora Killi 31.10.22 o Prolongation of ventricular filling time à negative chronotropy, diastole extension o Increase in volume of circulating fluid Mechanism of therapy for acute heart failure o Most used in life-threatening situations because it does not improve the actual status of the heart o Cannot be used in long-term treatment (CHF) 2. Reduction of heart load à chronic heart failure Negative chronotropy ↓ afterload (by arteriodilation) ↓ preload (reduction of diastolic end-volume, can be achieved in two ways) o Vasodilation o Reducing circulating fluid amount (diuretic effect) Mechanism of therapy for chronic heart failure o Also, does not improve status of the heart, but used most in treatment of chronic heart failure 3. Delay in cardiac remodeling and fibrosis Chronic heart failure Cardiac function enhancers Angiotensin converting enzyme Angiotensin II receptor blocker (ARB) inhibitors (ACE-I) Valsartan Captopril Candesartan Enalapril Losartan Ramipril RAAS activity reducing agents Mechanism of action o Antifibrotic, remodeling inhibitory activity Pharmacological effect o Dilation of arteries o Dilation of veins o Delay of remodeling Clinical use o Chronic heart failure (CHF) Angiotensin receptorValsartan + Sacubitril neprilysin inhibitors [ARB + neprilysin inhibitor] Neprilysin is an enzyme (ARNI) General information responsible for NP, AT-II, and o Sacubitril is a prodrug bradykinin degradation Natriuretic peptide (NP) o Biologically active form is is a biochemical stress Sacubitrilate Due to increase in AT-II marker secreted by Mechanism of action concentration, Sacubitril is cardiomyocytes. It has o Reduce heart load combined with ARBs because antagonistic effect on o Antifibrotic, remodeling inhibitory they inhibit AT-II (competitive RAAS activity inhibition) Vasodilation Pharmacological effect Na excretion o Dilation of arteries ACE-I is not used with Diuresis o Dilation of veins Sacubitril because both Anti-fibrotic effect o Reduction of circulatory volume increase bradykinin levels à o Delay of remodeling risk of angioedema Clinical use o Chronic heart failure ß blockers Metoprolol, Bisoprolol (II), Nebivolol, Carvedilol (III) Mechanism of action 2 Aurora Killi 31.10.22 Given in low doses or dose titration (increasing dose over time) Contraindicated for acute heart failure, and not used in advanced stages of heart failure. The earlier we start giving ß blockers, the better the body will adapt by reducing sympathetic tone, increasing parasympathetic tone, and reduce angiotensin system Mineralocorticoid receptor antagonists (aldosterone receptor antagonists, MRA) SGLT2 inhibitors Sodium-glucose cotransport protein 2 Primarily designed to reduce blood glucose and therefore initially used in diabetes mellitus patients o Enhance heart performance o Reduce heart load o Antifibrotic activity, inhibits remodeling Pharmacological effect o 2nd gen BAB (ß1) ® Negative chronotropy ® Delay of remodeling o 3rd gen BAB (α1, ß) ® Dilation of arteries ® Dilation of veins ® Negative chronotropy ® Delay of remodeling Clinical use o Chronic heart failure Although the diastole lengthens with BAB, systolic volume overall decline, but may also increase paradoxically NB! Frank-Stalling’s law The bigger the heart chamber filling in diastole à the greater blood volume and greater the force will be ejected into the subsequent systole Spironolactone (non-selective), Eplerenone (selective) General information o Steroid drugs o Weak diuretics, rather beneficial effects of aldosterone blockage on myocardial fibrosis inhibition and improved vasodilatory function in blood vessels o MC receptors are also expressed in heart and b/v Mechanism of action o Reduce heart load o Antifibrotic activity, inhibits remodeling o Antiandrogen effect (only spironolactone) Pharmacological effect o Reduce circulatory volume o Delay remodeling Clinical use o Chronic heart failure (II-IV) Side effects o Hyperkalemia o Gynecomastia (antiandrogenic activity) Interactions o RAAS inhibitors à risk of severe hyperkalemia Dapagliflozin, Empagliflozin Mechanism of action o Reduce heart load (due to the diuretic effect) o Antifibrotic activity, inhibits remodeling Pharmacological effect o Dilation of arteries o Reduce circulatory volume o Delay remodeling Clinical use o CHF Side effects o Urinary tract infections (increased glucose in urine is a more beneficial environment for bacterial growth) 3 Aurora Killi 31.10.22 SGLT2 inhibitor in renal proximal tubules o = sodium/glucose co-transport protein 2 (normally reabsorbs glucose) o Inhibits/reduces reabsorption of filtered glucose o Causes glycosuria, we pee out the glucose o Weak osmotic diuretic effect (glucose drags water with it) NHE-1 inhibitor in the heart o = sodium-hydrogen exchanger 1 o Reduces intracellular Na+ o Indirectly reduces Ca2+ concentrations à reduced inotropy SGLT1 inhibitor in the heart o = sodium/glucose co-transport protein 1 o Reduces intracellular Na+ o Indirectly reduces Ca2+ concentrations Reduces body weight o Less glucose Furosemide (short acting), Torasemide Hydrochlorothiazide, Indapamide Loop diuretics (K+ depleting diuretics) Thiazide and thiazide-like diuretics (K+ Mechanism of action depleting diuretics) o Reduce heart load Mechanism of action Pharmacological effect o Reduce heart load o Reduce circulatory volume Pharmacological effect Clinical use o Reduce circulatory volume o AHF (only Furosemide) Clinical use o CHF o CHF Side effects Side effects o Hypokalemia o Hypokalemia o Hypocalcemia o Ototoxicity Ivabradine Due to Frank-Starling´s Mechanism of action law, cardiac performance o Enhance heart performance will be increased with o Reduce heart load condition that the patient Pharmacological effect is not hypervolemic. There o Negative chronotropy is no characteristic Clinical use negative inotropic effect o CHF Diuretic agents Used for hypervolemic patients (volume overload) Sinus node inhibitors NB! Frank-Stalling’s law The bigger the heart chamber filling in diastole à the greater blood volume and greater the force will be ejected into the subsequent systole Cardiac glycosides Inotropic, cardiotonic agents Digoxin Mechanism of action o Enhance heart performance o Reduce heart load Increased inotropy will Pharmacological effect decrease sympathetic o Negative chronotropy (n. vagus parasympathomimetic effect) activation while o Positive inotropy (inhibits ATP pump à inhibits Na/Ca exchange à increase increased i/c Ca2+ à more Ca binds troponin C) parasympathetic effect, Clinical use thus decreasing heart o AHF rate o CHF Side effects 4 Aurora Killi 31.10.22 Also has positive bathmotropic effect (this an unwanted effect) which can lead to extra systoles. Third choice drug today The drug binds tightly to its site of action (K site of the ATPase), and the amount of K in blood rises. Thus, drug cumulation is common overdose is easy ß1 agonists Inotropic, cardiotonic agents Dopamine drug and neurotransmitter are two different things. Dopamine drug does not cross the BBB, and therefore will never have effect on D2 receptors in the brain Calcium sensitizers Inotropic, cardiotonic agents Levosimendan binds to troponin C and increases sensitivity of troponin C to calcium. It does not increase Ca amount, but increases Ca effect, which is positive inotropy PDE-3 inhibitors Inotropic, cardiotonic agents o Cardiac ® Rhythm disorders in 70% of overdose cases Risk of drug ® Extra systoles cumulation ® Atrial tachycardia ® Bradycardia ® AV block o Extracardiac ® Nausea ® Diarrhea ® Visual disturbances Interactions o K-depleting diuretics potentiate cardiotoxicity (thiazide, loop) Dobutamine (selective ß1 agonist) Mechanism of action o Enhance heart performance Pharmacological effect o Positive inotropy (increased i/c Ca2+ concentration) o Mild positive chronotropy Clinical use o AHF Dopamine (non-selective D1, ß1, α1 agonist) D1 ß1 α1 Mechanism of action o Enhance heart performance Dose and receptor ® Low doses à improves renal microcirculation affinity ® Medium doses à positve inotropic effect ® High doses à vasopressor effect Pharmacological effect o Positive inotropy Clinical use o AHF (medium and high dose) Levosimendan Binding to troponin C Mechanism of action in cardiomyocytes o Enhance heart performance increases myofibrillar o Reduce heart load sensitivity against Ca2+ o Triple action ® Positive inotropy (w/o oxygen consumtion increase) ® Vasodilation due to activation of K channels (repolarization) ® Cardioprotection (long term it protects myocardium from generation of free radicals) Pharmacological effects o Dilation of arteries o Dilation of veins o Positive inotropy Clinical use o AHF Milrinone PDE = phosphodiesterase Mechanism of action o Enhance heart performance o Reduce heart load Pharmacological effect 5 Aurora Killi 31.10.22 NO donors Additional agents for treatment of AHF o Dilation of arteries o Dilation of veins o Positive inotropy Clinical use o AFH Glyceril trinitrate (GTN), Sodium nitroprusside Mechanism of action o Reduce heart load Pharmacological effect o Dilation of arteries (high dose) o Dilation of veins (all doses) Clinical use o AHF Most commonly used agents for AHF treatemnt are o Vasodilators o Vasopressors o Inotropic agents Morphine o Opioid receptor agonist o Reduces tachypnoea o Mechanism of action ® Inhibits respiratory center ® Release of histamine ® Sedative/euphoric agent ® Analgestic o Clinical use ® AHF Norepinephrine o Vasopressor agents in hypotentive patients Cardiac glycosides toxicology (Digoxin) Mechanism of toxicity 1. Cardiac glycosides inhibit Na+/K+ pump After acute overdose à hyperkalemia With chronic intoxication à serum K+ is normal or low due to concurrent diuretic therapy 2. Direct effects and potentiation of vagal tone Results in slowing sinus rate Decreased sinus and AV node conduction speed 3. Increased atrial and ventricular automaticity, occurs because of Accumulation of intracellular Ca2+ Enhanced diastolic depolarization Development of after-depolarizations These effects are increased by hypokalemia and hypomagnesemia 4. Digoxin has a narrow therapeutic window Dosing must be carefully managed T1/2 = 30-50 h and is dependent on renal function 5. Drug interactions A number of drugs that are often co-administered with digoxin inhibit its metabolism and/or its cellular transport via P- glycoprotein This increases serum levels and may induce toxicity Examples: amiodarone, verapamil, diltiazem, macrolide antibiotics etc. 6 Aurora Killi 31.10.22 Clinical presentation Signs and symptoms depend on Intoxication may occur after acute accidental, suicidal ingestion, or the chronicity of the intoxication with chronic therapy Acute overdose Acute overdose o Nausea o Vomiting o Hyperkalemia o Cardiac arrythmias Bradyarrythmias include à associated with inotropy increase o Sinus bradycardia o Sinoatrial arrest o Second- or third-degree AV block o Asystole Tachyarrhythmias include à associated with elevated Ca in the cells o Atrial tachycardia w/ AV block o Ventricular tachycardia o Ventricular fibrillation Chronic intoxication Extracardiac symptoms o Nausea o Anorexia o Abdominal pain o Visual disturbances (flashing lights, halos, green-yellow perceptual impairment) o Weakness o Fatigue o Mental status change (in elderly) ® Confusion ® Depression ® Hallucinations Cardiac symptoms o Sinus bradycardia o Atrial fibrillation o Atrial tachycardia w/ block is often seen o Ventricular arrythmias ® Ventricular tachycardias ® Ventricular fibrillation Electrocardiographic features of Digoxin Increased PR interval o Decrease in AV conduction speed Shortened QR interval o Shortened duration of action potential in the ventricular myocardium ST segment depression o “Hockey stick configuration” After-depolarization o At toxic concentrations, digoxin can cause after-depolarization throughout the myocardium leading to ® Extra systoles ® Tachycardia Treatment 7 Aurora Killi 31.10.22 Emergency and supportive measures o Maintain open airway o Treat hyperkalemia with o Digoxin specific antibodies o Calcium i/v o Sodium bicarbonate o Glucose i/v + insulin o Hypokalemia and hypomagnesemia should be correct as they can contribute to cardiac toxicity o Treat bradycardia or heart block with atropine i/v o Ventricular tachyarrhythmias may respond to correction of low K or Mg o Lidocaine, Phenytoin (anti-arrhythmic properties) o Digoxin-specific antibody is the preferred treatment for life-threatening arrythmias Drugs and antidotes o Fab fragments of digoxin-specific antibodies reverse toxicity and are indicated for significant poisoning that include o Hyperkalemia o Symptomatic arrythmias o High-degree AV block o Ventricular arrythmias Digoxin antibodies rapidly o Hemodynamic instability bind to digoxin and o Digoxin antibodies should be considered inactivate complex that is o In digoxin toxic patients with renal failure formed is excreted rapidly o For prophylactic treatment in patient with massive oral in the urine overdose and high serum levels 8 Aurora Killi 10.11.22 Antiarrhythmic drugs Class 11 Electrophysiological characterization SA and AV node Phase 0 o Depolarization o Ca2+ influx Phase 3 o Repolarization o K+ outflux Phase 4 o Slow diastolic repolarization o Na+ influx through HCN channels o Ca2+ influx ECG characterization Systole corresponds with AP 0-3 phase in ventricular cardiomyocytes Diastole corresponds to AP phase 4 in ventricular cardiomyocytes P wave à atrial depolarization QRS complex à ventricular depolarization (phase 0) ST segment à ventricular plateau phase (phase 2) T wave à ventricular repolarization (phase 3) PR interval à impulse conduction time in the anterior chamber and AV node QT interval à ventricular depolarization and repolarization TP segment à cardiac diastole (phase 4) Contractile myocardium Phase 0 o Rapid depolarization provided by o Na+ influx via fast Na+ channels Phase 1 o Early repolarization o K+ outflux Phase 2 o Plateau phase o Ca2+ flow Phase 3 o Late repolarization o K+ outflux Phase 4 o Polarization/resting phase Aurora Killi 10.11.22 1. 2. 3. 4. Normal heart rate Rhythm is generated in the sinus node Heart rate is within normal range (55-80 x/min) Impulses are formed rhythmically (regularly) Excitation or conduction in the heart spread in a certain order and speed, causing successive excitation of individual parts of the heart Classification of arrythmias Terminology 1. 2. 3. 4. Arrythmias Changes in localization of rhythm origin Changes in heart rate Irregular rhythm Electrical impulse spreading (conduction) disturbances 1. Rhythms and arrythmias of the sinus node 2. Supraventricular rhythms Atrial arrhythmias independent of AV node AV node dependent arrythmias 3. Ventricular arrythmias 4. Disorders of intratrial and interatrial conduction 5. Atrioventricular conduction disorders 6. Intraventricular conduction disorders Automatism à chronotropy o Ability of cells to spontaneously generate an electrical impulse o Normally, automatism of only charactered for the cardiac conduction system o The SA node normally generates impulses at a frequency of 55-80 x/min Conduction à dromotropy o Ability to conduct the impulse from one cell to another Excitability à bathmotropy o Reflects the ability of cells to respond to electrical stimuli o ARP à absolute refractory period is a period of time when the cell is not excitable (phase 0 to mid 3rd phase) o RRP à relative refractory period is the time period when the cells are able to excite by very strong stimulus (end of phase 3) Contractility à inotropy o Ability of cardiomyocytes muscle fibers to shorten and extend after receiving an impulse o Contractility is manifested in phase 2 Singh-Vaughan Williams General principles of treatment of arrhythmias classification Providing hemodynamics (rhythm and frequency control) Classification based on their Providing hemostasis (coagulation control) impact on action potential in myocardial cell Class Ia à inhibits Na+ flux in CM phase 0 and K+ flow in CM phase 3 Class Ib à inhibits Na+ flux in CM phase 0 Class Ic à inhibits Na+ flux in CM phase 0 Class II à inhibits Ca2+ flux in SA and AV phases 0 and 4 Class III à inhibits K+ flux in CM phase 3 Class IV à inhibits Ca2+ flux in SA and AV phase 0 and 4 Class Ia Examples Procainamide Supraventricular arrhythmias + Ventricular arrhythmias + Ib Lidocaine - + Ic Flecainide + + Aurora Killi 10.11.22 Propafenone ß blockers II III IV Amiodaron Sotalol Vernakalant Calcium channel blockers + + + + + Only Amiodarone and Sotalol - Antiarrhythmic agents Class Ia Na+ channel blocker QRS «, QT ↑ Additional side effect for all class I drugs is negative inotropy Class Ib Na+ channel blocker QT ¯ Class Ic Na+ channel blocker QRS « Class II ß blockers Procainamide Mechanism of action o Na+ channel blocker w/ medium dissociation kinetics ® Delay Na+ flux in CM phase 0 by expanding QRS complex o K+ channel blocker ® Inhibits K+ flux in CM phase 3 by prolonging QT interval ® Additional cholinolytic effect Clinical use o Supraventricular arrythmias (SVA) treatment Class Ia has o Ventricular arrythmias (VA) treatment proarrhythmic effect à Side effects ability to provoke a new o Hypotension arrythmia or aggravate o Lupus erythematosus syndrome a pre-existing one o Torsades de pointes (TdP) Lidocaine Mechanism of action o Na+ channel blocker w/ fast dissociation kinetics ® Delay Na+ flow in CM phase 0 Lidocaine has ® QRS remains unchanged because of fast DK high first pass ® Decreased QT metabolism à Clinical use do not use p/o o VA treatment Side effects o CNS toxicity (seizures) Propafenon, Flecainide, Ethacizine Mechanism of action o Na+ channel blocker w/ slow dissociation kinetics ® Delay Na+ flow in CM phase 0 by expanding QRS o K+ channels and repolarization are not affected Clinical use o SVA treatment (including control of Afib) o VA treatment?? Side effects o Heart failure Propranolol, Metoprolol, Bisoprolol Mechanism of action (reduce effect on SANS) o Negative chronotropy ® Delay Ca2+ flux in SA phases 0 and 4, prolongs PR interval o Negative dromotropy Aurora Killi 10.11.22 Class III K+ channel blockers ® Inhibit Ca2+ flux in AV phases 0 and 4, prolongs PR interval o Negative inotropy ® Inhibit Ca2+ flux in CM phase 2 Indications o SVA frequency control (Afib, sinus tachycardia) o VA treatment Amiodarone T1/2 = 25-60 days Mechanism of action o K+ channel blocker ® Inhibits K+ flux in CM phase 3, prolongs QT interval ® Class III mechanism o Na+ channel blocker w/ medium DK ® Inhibits Na+ flux in CM phase 0, expands QRS ® Matches class Ia mechanism o ß blocker ® Inhibits Ca2+ flux in SA phases 0 and 4, prolongs PR (chronotropy) ® Inhibits Ca2+ flux in AV phases 0 and 4, prolongs PR (dromotropy) ® Inhibits Ca2+ flux in CM phase 2 (inotropy) ® Matches class II mechanism o Ca2+ channel blocker ® Inhibits Ca2+ flux in SA phases 0 and 4, prolongs PR (chronotropy) ® Inhibits Ca2+ flux in AV phases 0 and 4, prolongs PR (dromotropy) ® Inhibits Ca2+ flux in CM phase 2 (inotropy) ® Matches class IV mechanism Indications o SVA treatment o VA treatment Side effects o Hypothyroidism (hyperthyroidism) o Pneumofibrosis o Phototoxicity o Hepatotoxicity o Blue skin pigmentation (smurf skin) o Corneal deposition o Rarely TdP Vernakalant Mechanism of action o K+ channel blocker ® Inhibits K+ flow in CM phase 3, prolongs QT interval ® Class III mechanism o Na+ channel blocker w/ fast dissociation kinetics ® Delay Na+ flux in CM phase 0 ® QRS remain unchanged due to fast DK ® Matches class Ib mechanism o Selective extension of atrial AP (only anterior chamber) Indications o Acute Afib treatment (SVA) o Not used for VA Side effects o Hypotension o Bradycardia Aurora Killi 10.11.22 Class IV Ca2+ channel blockers (non-dihydropyridines) Non-classified Verapamil, Diltiazem Mechanism of action o Ca2+ channel blocker ® Delay Ca2+ flux in SA node phases 0 and 4, prolongs PR chronotropy ® Inhibits Ca2+ flux in AV node phases 0 and 4, prolongs PR dromotropy ® Inhibits Ca2+ flux in CM phase 2 inotropy Indications o Frequency control of SVA (Afib, sinus tachycardia) o Not used for VA Magnesium sulphate o Reduces Ca2+ flow in ventricular cardiomyocyte o Indication à TdP treatment Atropine o Non-selective M-cholinoreceptor antagonist o + chronotropy o + dromotropy o Indications à sinus bradycardia, AV block Epinephrine o Non-selective adrenoreceptor agonist o + inotropy o + chronotropy o + dromotropy o Indications à CPR (cardiopulmonary reanimation) Digoxin o + inotropy (Na/K pump inhibition à Na/Ca inhibition) o - chronotropy and dromotropy (n. vagus) o Indication à SVA (Afib) ® However, not effective enough in case of increased SANS activity (e.g., during exercise) ® Can be used in complementary therapy with BAB and CCB o Digoxin overdose ® Potassium, magnesium aspartate for prophylaxis ® Phenytoin and digoxin antibodies in severe toxicity (ventricular tachycardia) Amiodarone toxicity Class III Mechanism of toxicity Clinical presentation Tend to cause bradyarrhythmias o In addition to its class III antiarrhythmic effect, Amiodarone also has class Ia, II, and IV mechanisms, thus it tends to cause bradyarrhythmias Many side effects o Many diverse complications associated with long-term use o Very long half-life (50 days) and large volume of distribution Highly lipoid soluble o Accumulates in high concentrations o Fat, muscle, liver, lungs, and skin Acute overdose o Bradyarrhythmias o Hypotension Aurora Killi 10.11.22 Treatment o Asystole Chronic intoxication o Ventricular arrhythmias (ventricular tachycardia) o Bradyarrhythmias (sinus arrest, AV block) Pulmonary toxicity o Most important life-threatening toxicity from Amiodarone o High fatality rate Other o Hypothyroidism/hyperthyroidism o Hepatitis o Photosensitivity o Corneal deposits o Tremor o Ataxia o Peripheral neuropathy Sodium bicarbonate i/v o For patients with QRS prolongation, bradyarrhythmias, hypotension o Sodium bicarbonate reverses cardiac depressant effects caused by inhibition of fast sodium channels Magnesium i/v o Torsades de pointes