Cardiovascular Pharmacology PDF

6. Diuretics For the main sites of pharmacological action see Rang et al, Pharmacology figure 30.4 Act on kidney to increase urine flow Reduce reabsorption of electrolytes by tubules Increase electrolyte excretion Increase water excretion osmosis Banned by the IOC figure 30.4 Thiazide diuretics...

6. Diuretics For the main sites of pharmacological action see Rang et al, Pharmacology figure 30.4 Act on kidney to increase urine flow Reduce reabsorption of electrolytes by tubules Increase electrolyte excretion Increase water excretion osmosis Banned by the IOC figure 30.4 Thiazide diuretics Bendrofluazide, hydrochlorothiazide, chlorothalidone, indapamide see Rang et al, Pharmacology figure 30.5C Moderately strong diuretic Action in the early segments of distal tubule Thiazide diuretics Binds Cl- site of the Na+/Cl- co-transport system and inhibit NaCl reabsorption Increase the excretion of Na+ and ClIncreased Na+ load in distal tubule stimulates Na+ exchange with K+ and H+ increased excretion of K+ and H+ will induce hypokalaemia and metabolic alkalosis figure 30.5C Pharmacokinetics All effective orally Excreted in urine tubular secretion Increase uric acid levels due to competition with uric acid during tubular secretion Max effect 4-6 hrs with duration 8 to 12 hrs Chlortalidone has a duration of 48 hrs and is given every other day Adverse effects of thiazides Weakness Skin rashes (sulphonamide group) Hypokalaemia Potassium supplements Combined therapy with K+ sparing diuretic Adverse effects of thiazides Increased uric acid levels - gout Increase plasma cholesterol levels Male impotence Hyperglycaemia Figure 30.5D Combined antihypertensive therapy ACE inhibitor or sartan plus; - calcium channel blocker - thiazide diuretic - -blocker -blocker plus dihydropyridine calcium channel blocker Thiazide diuretic plus calcium channel blocker or -blocker Combinations to avoid ACE inhibitor or sartan plus; - potassium sparing diuretic Verapamil plus -blocker ACE inhibitor plus sartan Blood Pressure targets Coronary heart disease, diabetes, micromacroalbuminuria, stroke or TIA <130/80 Others <140/90 Loop diuretics Frusemide, ethacrynic acid, bumetanide see Rang et al, Pharmacology figure 28.5B Most powerful of diuretics allowing 15-25% of filtrate to be excreted see Rang et al, Pharmacology figure 30.6B Inhibit NaCl reabsorption in thick ascending loop of Henle Loop diuretics Segment high capacity for absorbing NaCl Luminal membrane Inhibit coupled entry mechanism for Na+, Cl- and K+ Driven by Na+/K+-ATPase dependent pump figure 30.5B figure 30.6 Adverse effects Alkalosis Hyperglycaemic, hyperuricaemic Hypotensive Hypokalaemic - potassium loss considerable, hyponatraemia Hypovolaemia Ototoxicity can occur with frusemide Potassium sparing diuretics Aldosterone responsive segments of distal nephron see Rang et al, Pharmacology figure 30.5D K+ homeostasis is controlled by aldosterone Aldosterone stimulates K+ secretion Clinical uses to prevent K+ loss figure 30.5D Spironalactone Limited diuretic action Blocks binding of aldosterone Increase excretion of Na+ (Cl- and H2O) Well absorbed from GIT Plasma half life of 10 mins (its active metabolite canrenone has a half life of 16 hrs) Spironalactone Onset of action taking several days Used in heart failure, primary hyperaldosteronism and secondary hyperaldosteronism Side effects include GIT upset, hyperkalaemia, metabolic acidosis Steroid effects on other tissues can cause gynaecomastia, menstrual disorders, testicular atrophy Triamterene and amiloride Weak diuretic Decrease luminal membrane Na+ permeability Act on collecting tubules and ducts Increase excretion of Na+ (Cl- and H2O) Triamterene and amiloride Decreases K+ excretion hyperkalaemia Can be given with loop or thiazide diuretics Mildly uricosuric Triamterene well absorbed from GIT, onset of action 1-2 hrs, duration 12-16 hrs Triamterene and amiloride Amiloride is poorly absorbed with maximum action at 6hrs with duration 24 hrs Both excreted unchanged in urine Side effects include hyperkalaemia, metabolic acidosis, skin rashes Osmotic diuretics Mannitol 25% (glycerol, glucose, urea) Interferes with osmosis Causes high osmotic pressure in the kidneys Non-toxic and excreted quickly Not reabsorbed from glomerular filtrate Osmotic diuretics Hydrophilic, cannot be given by mouth (osmotic laxative) Usually given intravenously Remain in blood and increase osmolarity of blood Used for oedematous states: intracranial pressure renal failure Osmotic diuretics Adverse effects Electrolyte imbalance Dehydration Hypervolaemia problem in cardiac failure Carbonic anhydrase inhibitors Acetazolamide Carbonic anhydrase catalyses the conversion of carbon dioxide into bicarbonate ion See Rang et al Pharmacology figure 30.5A CO2 + H2O H2CO3 H+ + HCO3- figure 30.5A Carbonic anhydrase inhibitors Non-competitive inhibitor Reaction occurs in the proximal tubule in the kidney Acid base balance Alkalinises the urine Dissolves renal calculi formed from acidic compounds (ie cysteine) Carbonic anhydrase inhibitors Enzyme also found in production of: aqueous humor (choroid plexus) and cerebrospinal fluid (fourth ventricle) Useful in the treatment of : Glaucoma Increased cranial pressure Carbonic anhydrase inhibitors Also used for treatment and prophylaxis of altitude sickness At high altitudes hypoxia occurs resulting in alkalosis Acetazolamide reverses alkalosis by reducing blood pH and maintaining arterial O2 Adverse reactions Stevens-Johnson syndrome Hepatic necrosis Hematological reactions paraesthesia Stevens-Johnson syndrome Potassium balance Extracellular K+ concentration is controlled rapidly and within narrow limits through regulation of K+ excretion in the kidney Affects function of heart, brain and skeletal muscle Normal excretion 50-100 mmol in 24 hrs (5- 1000mmol) Potassium balance K+ loss is increased: With thiazide and loop diuretics When Na+ reabsorption in the collecting ducts is increased Potassium balance K+ loss is decreased: When Na+ reabsorption in the collecting ducts is reduced When aldosterone action is inhibited - ACE inhibitors - Spironolactone Potassium supplements Normal plasma K+ levels 4 mmol/L Hyperkalaemia K+ levels > 5.0 mmol/L Hypokalaemia K+ levels < 3.5 mmol/L Potassium supplements Potassium chloride (Chlorvescent, Kay Ciel, K SR, Slow K, Span K) High potassium foods include bananas, leeks, fruit juices, nuts, sprouts, milk, meat, instant coffee Drugs for Heart Failure Symptom relief and improve exercise tolerance Start with ACE inhibitors (or Sartan) When stable add a -blocker If still symptomatic add an aldosterone antagonist Watch for fluid overload and treat with a diuretic Haemostasis and thrombosis Blood Coagulation Haemostasis The arrest of blood loss from a damaged blood vessel Vasoconstriction Adhesion and activation of platelets Fibrin formation Haemostatic plug Blood clot formation Occur in large tears in blood vessels Forms around the platelet plug Involves the transformation of blood from liquid to a solid gel Function is to support and reinforce platelet plug Solidify blood in wound channel Blood clot formation Initiated by injury to vessel when blood contacts underlying tissues Designated by Roman numerals in order they were discovered not order of reactions in clotting process Most clotting factors are produced by the liver Induces a cascade of chemical reactions Blood clot formation Inactive plasma proteins converted to activated proteolytic enzymes or cofactors for enzymes Involves the splitting of small peptide fragment from inactive protein precursor End product is the conversion of fibrinogen a large soluble plasma protein produced by the liver to insoluble fibrin strands by the enzyme thrombin Blood clot formation Fibrin forms long insoluble strands in a meshlike lattice that traps platelets, Requires plasma Ca2+, if removed from plasma, coagulation will not occur The clotting cascade is triggered by intrinsic and extrinsic pathways Thrombin Converted from plasma protein prothrombin to thrombin by factor X 12 factors are involved in the formation of thrombin Cleaves fibrinogen to form fibrin Activates fibrinolipase which strengthens the fibrin crossbridges Thrombin Stimulates Platelet aggregation Cell proliferation Smooth muscle contraction Intrinsic pathway Initiated by Hageman factor (factor XII) which is activated when exposed to collagen All components necessary for this reaction are contained in the plasma see Rang et al, Pharmacology figure 25.2 figure 25.2 Extrinsic pathway Initiated by tissue damage and release of tissue thromboplastin (factor III) Cascade components depend on cellular elements Vitamin K Not involved in clot formation Required for the synthesis of four clotting factors by the liver Factors II, VII, IX and X For a diagram depicting the main events of the formation of arterial thrombosis see Rang et al, Pharmacology figure 25.1 figure 25.1 Thrombosis Pathological condition resulting from the inappropriate activation of hemostatic mechanisms Occurs in the absence of bleeding - venous thrombosis is usually associated with stasis of blood small platelet component and large fibrin factor - arterial thrombosis is usually associated with atherosclerosis and has a large platelet element Thrombosis Adhesion and activation of platelets Fibrin formation A portion of thrombus may break away, travel as an embolus and lodge downstream causing ischemia and infarction Natural anticoagulants Heparin is released from basophils and mast cells During clotting 85-90% of thrombin is adsorbed to fibrin threads the rest are bound to antithrombin III - prevents the clot spreading Heparin binds antithrombin III to increase thrombin binding 100-1000 fold Coagulation defects Hemophilia Failure of clots to form Genetic disease primarily among males Hemophilia A (80%) - failure to produce Factor VIII Hemophilia B - lack of factor IX Hemophilia Hemophilia C: affects males and females - lack of factor XI - less severe as an alternate activator of factor IX is available Treated with fresh plasma or concentrated preparations of the missing factor Pure forms of human factors available through recombinant technology Acquired clotting defects More common than hereditary forms Liver disease Vitamin K deficiency (neonates) Excessive oral anticoagulant therapy Treated with vitamin K Anticoagulants and antiplatelet drugs Used in thrombotic disorders Fast acting anticoagulants are used when intravascular clotting is a major problem Slow acting anticoagulants (warfarin) and antiplatelet drugs used for long term therapy for thrombotic disorders Parental Anticoagulants Heparin comes in a range of molecular weights up to 40 000. Family of sulfated glycosaminoglycans It is extracted from beef lung or pig intestine assayed against an international standard. Dose in units instead of mass Parental Anticoagulants Because of its size heparin cannot be absorbed from the gut and is given SC or IV (NOT IM) Given prophylactically following surgery Used in heart lung and dialysis machines Used post-operatively or to reduce deep vein thrombosis. Parental Anticoagulants Its mechanism of action is through the activation of antithrombin III by potentiating the binding of thrombin to antithrombin III. Also inhibits factor X T1/2 life 40-90 mins See Rang et al, Pharmacology figure 25.6 figure 25.6 Protamine Heparin overdose Protein derived from the sperm of salmon Binds heparin molecule to form complex Inhibits action of heparin Hypotension and bradycardia Rapid injection can cause analphylactic reaction Parental Anticoagulants Heparin fragments (LMWHs) are increasingly used instead of unfractionated heparin and have MW from 4000 to 15000. Enoxaparin, dalteparin, danaparoid Inhibits factor X only Given SC T1/2 life 3-4 hrs Parental Anticoagulants Problems with the clinical use of heparin are hemorrhage, osteoporosis with long term use and the occasional allergic reaction Activated partial thromboplastin time (APTT) is measured Fondaparinux Synthetic inhibitor of factor X SC formulations Prevention of VTE following orthopaedic surgery to the leg Treatment of VTE Many side effects including bleeding Direct Thrombin inhibitors Hirudens are direct thrombin inhibitors derived from anticoagulant derived from the medicinal leech Bivalirudin is a hiruden analogue Lepirudin is a recombinant form of hiruden http://www.biolib.cz/IMG/GAL/44327.jpg Bivalirubin Unstable Angina IV bolus and infusion Reduced clearance in renal impairment Adverse reactions include nausea, thrombocytopaenia Oral Anticoagulants Warfarin Prevention and treatment of VTE and stroke vitamin K antagonist see Rang et al, Pharmacology figure 25.3 Prevents synthesis of vitamin K dependent coagulation factors II, VII, IX and X. onset of action takes several days and depends on the elimination half lives of the affected clotting factors figure 25.3 Oral Anticoagulants inhibits vitamin K reductase see Rang et al, Pharmacology figure 25.5 factor VII (T1/2 6 hrs), IX (T1/2 24 hrs), X (T1/2 40 hrs), and II (T1/2 60 hrs) Orally active Strongly bound to plasma proteins Oral Anticoagulants Metabolised by hepatic mixed function oxidase Warfarin passes placental barrier and it is teratogenic in the first months of pregnancy causes intracranial hemorrhage in the baby during delivery Appears in milk during lactation Oral Anticoagulants Periodic determination is essential of blood coagulation. has the potential to cause many drug interactions. Unwanted effects are essentially haemorrhage Drugs that potentiate warfarin Inhibit hepatic drug metabolism (CYP2C9) Inhibit platelet function Displace Warfarin from binding sites on plasma albumin Inhibit reduction of vitamin K Decrease availability of vitamin K Drugs that decrease effect of warfarin Vitamin K Induce hepatic P450 enzymes (CYP2C9) Reduce absorption Coagulants Vitamin K Fat soluble vitamin Used in warfarin overdose Essential for the formation of clotting factors II, VII, IX and X Oral or IV injection Requires bile salts for absorption Direct Thrombin inhibitors Dabigatran Prevention of VTE (hip or knee surgery) Non-valvular atrial fibrillation with high risk of stroke Reversibly inhibit both free and fibrin bound thrombin Prevent conversion of profibrin to fibrin SE; gastritis, dyspepsia, GI bleeding Oral administration Factor Xa inhibitors Rivaroxaban Prevention of VTE (hip or knee surgery) Non-valvular atrial fibrillation with high risk of stroke Selectively inhibit Factor Xa Blocks thrombin production SE; peripheral oedema, itch, skin blisters Oral administration figure 25.10 Antiplatelet drugs Figure 25.7 Aspirin Acute coronary syndrome Symptomatic atherosclerosis Binds COX irreversibly Inhibits TXA2 synthesis Dose 75-300 mg/day Replacement of platelets takes 7-10 days Side effects include GIT disturbances http://gsk.co.nz/images/product-cartia1.jpg Dipyrimadole Prevention of stroke and TIA Phosphodiesterase inhibitor Increases cAMP Reduces platelet adhesiveness Oral or IV formulations Headache and GIT problems are common side effects Abciximab Monoclonal antibody to glycoprotein GPIIb/IIIa receptor on platelet cell membrane Administered IV Used in high risk patients undergoing angioplasty Adjunct to heparin and aspirin Side effects are haemorrhagic problems due to thrombocytopenia Immunogenicity Tirofiban Unstable angina and non-STEMI Binds glycoprotein IIb and IIIa receptors to prevent platelets binding together IV applications Side effects include bleeding Clopidogrel Prevention of vascular ischaemic events Prodrug Irreversible inhibitor ADP receptors P2Y12 receptor Prevents platelet aggregation Oral formulations Side effects includes bleeding Red Blood Cell Disorders Anaemia Oxygen carrying capacity of blood decreased (hematocrit 30%, [Hb]< 13.5 g/dl adult males and <11.5 g/dl in adult females) Iron deficiency lack of iron Megaloblastic lack of folic acid or Vitamin B12 Pernicious insufficient hematopoiesis due to lack of intrinsic factor Anaemia Hemorrhagic loss of red blood cells through hemorrhage Hemolytic red blood cell membranes rupture prematurely Aplastic destruction or inhibition of red bone marrow Sickle-cell abnormal hemoglobin Iron Deficiency Anaemia The diagnosis and management of iron deficiency anaemia (IDA) remains a challenge. It is an important public health problem in Australia, with the World Health Organization (WHO) estimating that; 8% of preschool children, 12% of pregnant women and 15% of non-pregnant women of reproductive age in Australia have anaemia, with IDA a major cause. Med J Aust 2010; 193 (9): 525-532. Iron Has 2 properties: 1. An ability to exist in several oxidation states Fe2+ = ferrous Fe3+ = ferric 2. A tendency to form stable complexes The chief function of iron in the body is the synthesis of hemoglobin (65%) Normal daily requirements Men Women* & Children Pregnant Women *during reproductive years mg/day 5 15 30 Iron Iron intake An average diet provides 10-20 mg iron/day Of this 10% is absorbed Dietary sources Meat (especially liver and kidney) Green vegetables, peas, beans, oatmeal, eggs, chocolate and dried fruits Iron absorption The GIT absorbs iron as Fe2+ bound in heme Non-heme iron is in the Fe3+ state and must be converted to ferrous form prior to absorption Gastric acid lowers pH converts Fe3+ to Fe2+ form The main site of Fe2+ absorption is by epithelial cells of the upper duodenum Iron absorption Active transport sites Erythropoietin increases iron absorption by the intestinal cells Iron is stored in epithelial cells to a protein called ferritin Mucosal cells have some control over absorption During iron deficiency Fe2+ absorption is increased Iron transport Ferritin passes Fe3+ to transferrin (a globulin protein, 2 binding sites) In the liver and spleen Fe3+ is conveyed from transferrin to ferritin in cells Ferritin can aggregate to Hemosiderin (saturated stores of iron) Iron stores All iron is protein bound Or Incorporated into protein structures Total body iron is 2000 6000 mg See Rang et al Pharmacology Table 26.1 Table 26.1 Iron Apart from iron absorbed by epithelial cells from diet, iron is made available to the body when old erythrocytes (120 days) are destroyed. Carried out by the reticulo-endothelial system in spleen (ie mononuclear phagocytes) Intestinal absorption and mobilisation of iron from storage depots contribute only small amounts of circulating iron Iron loss No excretory mechanism as iron is recycled Iron is lost through: Shedding or exfoliation of : Epidermal cells of skin, hair & nails Mucosal cells of gut and respiratory tracts Epithelial cells of urinary and genital tracts Bile, sweat and urine See figure 26.1 Iron distribution and turnover figure 26.1 Drugs affecting iron absorption Interfere with iron absorption from gut Phosphates Tannates (Tea) Tetracyclines Enhance iron absorption from the gut Ascorbic acid Iron deficiency anaemia Blood hemoglobin falls below normal range Symptoms include: Weakness Lethargy Headache Dizziness Rapid weak pulse Palpitations Iron deficiency anaemia Further evaluation includes determination of concentrations of ferritin Iron vitamin B12 folic acid Treatment of iron deficiency anaemia Iron supplements (150-200 mg/day) Ferrous fumarate, ferrous sulphate RBC defect repaired in 30-60 days Treatment takes 3-6 months Oral formulations Best taken on an empty stomach Treatment of iron deficiency anaemia May be given with orange juice Do not combine with milk, antacids or tea May stain teeth (black discolouration) Constipation a side effect Blood transfusions Red cell transfusion is inappropriate therapy for IDA Unless an immediate increase in oxygen delivery is required Such as when the patient is experiencing end-organ compromise (eg, angina pectoris or cardiac failure), or IDA is complicated by serious, acute ongoing bleeding.