Cardiovascular Pharmacology Lecture Notes PDF

CARDIOVASCULAR PHARMACOLOGY 3002MSC Pharmacology 1 Learning objectives • Understand the mechanisms of physiological control of blood pressure • Knowledge of the drugs used to treat Angina with respect to mechanism of action and major side effects • Recognise the drugs used to treat dyslipidaemia w...

CARDIOVASCULAR PHARMACOLOGY 3002MSC Pharmacology 1 Learning objectives • Understand the mechanisms of physiological control of blood pressure • Knowledge of the drugs used to treat Angina with respect to mechanism of action and major side effects • Recognise the drugs used to treat dyslipidaemia with respect to mechanism of action and major side effects • Understand the physiological mechanisms associated with contraction and relaxation of blood vessels 2 1 Learning objectives • Understand the rationale behind the drug treatment for hypertension • Knowledge of mechanism of action of diuretics and causes of major side effects • Understand the drugs used to treat Heart Failure • Be familiar with the drugs used to treat excess blood clotting and platelet activity • Recognise causes of anaemia and iron deficiency • Know the drug treatment for iron deficiency anaemia 3 Basics of transmitters and ion channels involved in heart functioning • PHYSIOLOGY OF CARDIAC FUNCTION 4 2 Cardiac muscle • Myocardial oxygen consumption • at rest myocardium accounts for - 11% total body oxygen - receives 4% cardiac output - as coronary blood flow 5 Cardiac muscle Coronary blood flow Factors regulating coronary blood flow 1. Physical factors • Flow occurs during diastole. • Diastole is shortened during tachycardia  reducing time available for myocardial perfusion 6 3 Factors regulating coronary blood flow • The perfusion pressure = difference between aortic pressure and ventricular pressure • See Rang et al Pharmacology figure 22.5 7 figure 22.5 8 4 2. Vascular control by metabolites • A decrease in arterial PO2 and pH results in the release of vasodilator compounds • PGE2, • PGI2 • Adenosine 9 3. Neural and humoral control • Sympathetic innervation - Noradrenaline • Circulating catecholamines - Adrenaline • In large coronary vessels stimulation of 1adrenoceptors results in vasoconstriction while in smaller vessels activation of 2-adrenoceptors induces vasodilation • Purinergic, peptidergic, nitrergic neurones. 10 5 Factors regulating coronary blood flow • The vascular response to altered mechanical and metabolic cardiac activity predominates over neural and endocrine effects on coronary blood vessels. 11 Autonomic control of the heart 1. Sympathetic (adrenergic) nerve fibres • Terminals release noradrenaline onto 1adrenoceptors • Noradrenaline increases heart rate and force of contraction - increases impulse formation and reduces the time period between impulses - enhances electrical conductance 12 6 Autonomic control of the heart • • • Increased automaticity Increased cardiac oxygen consumption Reduced cardiac efficiency 13 Stimulation of 1adrenoceptors • Acts via cAMP • Activates protein kinase A • Phosphorylates 1-subunits of calcium channels Increases probability that channels will open Increases inward Ca2+ current 14 7 Stimulation of 1-adrenoceptors • Increases Ca2+ sensitivity of contractile machinery by • Phosphorylating tropinin C • Facilitates Ca2+ capture by sarcoplasmic reticulum • Increase amount of Ca2+ available for release by action potential 15 16 8 Sympathomimetics Sympathomimetic Drug Dose Receptor activity Alpha Beta1 Beta2 Physiological effect VD VC INT CHT dobutamine + +++ + ++ – +++ + Dopamine low – ++ + ++ – – – ++ intermediate + ++ + + ++ ++ high +++ ++ – – +++ ++ ++ + +++ ++ ++ – +++ ++ Adrenaline low +++ ++ – – +++ ++ + isoprenaline high – ++++ +++ +++ – +++ +++ noradrenaline ++++ + – – ++++ + + VD = vasodilation; VC = vasoconstriction; INT = positive inotropism; CHT = positive chronotropism + = agonistic effect; – = no agonistic effect Source; Australian Medicines Handbook 2009 17 Sympathomimetics Figure 15.4 18 9 2. Parasympathetic (cholinergic) nerves • • • • Vagal nerve fibres Terminals release acetylcholine Terminals located near sinoatrial node Acetylcholine slows heart rate and automaticity - inhibits AV conduction - decreased force of contraction (Atria only) 19 Parasympathetic (cholinergic) nerves • • Muscarinic M2 receptors Negatively coupled to adenylyl cyclase ( cAMP levels) to inhibit Ca2+ current Open potassium channels (KACh) hyperpolarises cells No cholinergic innervation of coronary vessels – indirect effect on coronary tone muscarinic M3 receptors on endothelial cells 20 10 Drug effects on cardiac action • • Alter the force of myocardial contraction increases - positive inotropic effect decreases - negative inotropic effect Change heart rate by altering rate of impulse formation in sinoatrial node increase HR - positive chronotropic effect decrease HR - negative chronotropic effect 21 Drug effects on cardiac action • Change conductance of electrical impulses through myocardium increases - positive dromotropic effect decreases - negative dromotropic effects 22 11 CORONARY ATHEROSCLEROSIS AND ITS CONSEQUENCES Angina https://www.google.com.au/search?q=angina+pectoris&client=firefoxa&hs=0lg&rls=org.mozilla:enUS:official&source=lnms&tbm=isch&sa=X&ei=KH4EUo6aGemgigeY0oD4Ag &ved=0CAkQ_AUoAQ&biw=1680&bih=920#facrc=_&imgdii=_&imgrc=AyD4 C6i8ZAA2lM%3A%3Bo8SjmErnvrr1AM%3Bhttp%253A%252F%252Fwww.m dguidelines.com%252Fimages%252FIllustrations%252Fangina.jpg%3Bhttp %253A%252F%252Fwww.mdguidelines.com%252Fanginapectoris%252Fdefinition%3B307%3B410 23 ANGINA • Occurs when the oxygen supply to the myocardium is insufficient for its needs • Secondary to coronary artery disease • Obstruction of at least 50% in at least one major coronary artery • Pain in chest, arm and neck • Brought on by exertion or excitement • K+, H+, adenosine all stimulate nociceptors 24 12 25 Risk factors • • • • • • • High LDL cholesterol High blood pressure Diabetes Family history of heart disease Smoking Obesity Sedentary lifestyle 26 13 Increased risk • Sudden death • Myocardial infarction 27 Types of Angina 1. Classic/ Stable/ Exertional Angina • Coronary arteries supply heart • Atheromatous plaques narrow arteries • Exercise increases oxygen consumption - not enough O2 supply - ischaemic muscle - pain - waste products 28 14 Types of Angina 2. Unstable Angina • Pain occurs with less and less exertion until pain at rest • Ruptured atheromatous plaque • Platelet-fibrin thrombus • Incomplete occlusion of coronary vessel • Risk of infarction substantial 29 Types of angina 3.Variant/ Prinzmetal’s/ Vasospastic Angina • vasospasm of coronary vessels • possible atherosclerosis 30 15 General lifestyle measures Treat precipitants of angina • Anaemia • Thyrotoxicosis • Hypertension Dietary measures • Reduce lipids • Increase natural antioxidants • Decrease weight 31 Treatment strategies • Reduce work of heart • Reduce O2 demand Rationale for drug use • Provide symptom relief • Reduced risk of death or MI 32 16 Anti-anginal drugs 1. Nitrates • Glyceryl trinitrate (nitroglycerine), isosorbide dinitrate, isosorbide mononitrate • First-line drugs • Induces peripheral vasodilation • Drugs are converted to nitric oxide (NO) 33 1. Nitrates • • • • • NO has a direct action on vascular smooth muscle to induce vasodilation Marked venorelaxation Reduced venous return (reduced preload) Arteriolar vasodilation (decreased afterload) Decreases ventricular volume and O2 demand 34 17 Mechanisms of nitrate relief of symptoms of angina 1. Vasodilation providing increased supply of O2 to tissues 2. Decreased demand due to reduced cardiac work 3. Redistribution of coronary flow to ischaemic areas 4. Relief of coronary spasm in variant angina 35 Mechanism of action • The liberation of NO from organic nitrates requires an enzymic reaction that involves tissue SH groups. • It then activates a soluble form of guanylate cyclase in vascular smooth muscle by interacting with the haem group in the enzyme. • cGMP formation is increased leading to dephosphorylation of myosin light chain, sequestration of Ca2+ and relaxation. 36 18 figure 21.3 37 Nitrates short acting nitrates • Glyceryl trinitrate • 30 min duration • More effective in preventing attacks • First pass effect - sublingual administration (tablet or spray) - transdermal patch 38 19 Nitrates Long acting nitrates • Isosorbide dinitrate • T1/2 4hrs • Acute treatment of unstable angina • Several hours duration • Taken 2 x day for prophylaxis • Also available in slow release form for once daily dosing 39 Adverse effects of nitrates • • • • • Arterial dilation - facial flushing Headaches Postural hypotension Reflex tachycardia Prolonged dosage – methaemoglobinaemia 40 20 Adverse effects of nitrates • Tolerance due to depletion of tissue SH groups Use lowest possible dose 10 hr or longer nitrate free per day • Do not use with sildenafil citrate (Viagra®) 41 Figure 21.3 42 21 Other clinical uses of organic nitrates: • Acute heart failure • Chronic heart failure 43 2. -adrenoceptor antagonists • • • • • • Prophylactic treatment Atenolol, metoprolol, oxprenolol, propranolol Not useful for vasospastic angina Exerts a negative chronotropic effect Slows the heart rate thereby decreasing O2 consumption If used in conjunction with nitrates will reduce reflex tachycardia 44 22 2. -adrenoceptor antagonists Adverse effects of -adrenoceptor antagonists • Bronchoconstriction • Insomnia • Depression • AV block • Fatigue • Bad dreams • Sexual dysfunction • DO NOT USE IN PATIENTS WITH ASTHMA 45 3. Calcium antagonists • • • • • Amlidopine, diltiazem, felodipine, nifedipine, nimodipine, perhexiline, verapamil Useful in unstable angina and angina at rest Calcium entry blockers No effect on intracellular actions Use-dependence 46 23 3. Calcium antagonists • • • • Main effects confined to cardiovascular system Bind 1 subunit of the L type channel (antagonists) Act only on the vascular smooth muscle and heart Phenylalkyamines: verapamil – useful in the heart 47 3. Calcium antagonists • • Dihydropyridines: nifedipine – targets smooth muscle – causes reflex tachycardia Benzothiapenes: diltiazem – intermediate effect on both blood vessels and heart 48 24 Cardiac actions of calcium antagonists • • • • Antidysrhythmic action Impaired AV conduction Cardiac slowing Negative inotropic effect -  contractility 49 3. Calcium antagonists Vascular actions of calcium antagonists • Arteriolar dilation Pharmacokinetics • Well absorbed from the GIT 50 25 3. Calcium antagonists Adverse effects of calcium antagonists • Headache • Constipation • Ankle oedema - nifedipine • Heart failure - verapamil or diltiazem 51 Other clinical uses of calcium antagonists: • Dysrhythmias • Hypertension 52 26 4. Potassium channel activators • Nicorandil • Combined activation of KATP channel and NO donor • Allows efflux of K+ • Hyperpolarises membranes • Arteriole and venous dilator 53 4. Potassium channel activators • SE include headache, flushing and dizziness • Used for patients who remain symptomatic in spite of other medications • Contraindicated in people with cardiogenic shock, left ventricular failure and hypotension 54 27 Combination antianginal therapy • -blocker and long acting nitrate • -blocker and dihydropyridine (calcium antagonist) • calcium antagonist and long acting nitrate • do not combine -blocker and verapamil or diltiazem 55 Angina Treatment of underlying disease (unstable angina) • Statins • Antiplatelet drugs 56 28 Lipid Lowering Drugs 57 PLASMA LIPIDS • cholesterol (C) + triglycerides (T) transport in blood - complexed to proteins - called lipoproteins 58 29 Basis of classification depends on ultracentrifugation • • • • High density lipoproteins (HDL) Low density lipoproteins (LDL) Very low density lipoproteins (VLDL) Chylomicrons • For a schematic diagram of cholesterol transport in tissues and the main sites of action of lipid lowering drugs please refer to see Rang et al, Pharmacology figure 23.1 59 Control of exogenous lipids 1. Chylomicrons transport T and C from the GIT to tissues (muscle or adipose tissue) 2. T are hydrolysed by lipoprotein lipase and tissues take up released free fatty acids 3. C is taken to the liver where they are endocytosed and stored or oxidised to bile acids or released to VLDL (endogenous pathway) 60 30 figure 24.1 61 Control of endogenous lipids 1. Very low density lipoproteins (VLDL) transport C and newly synthesized T from the liver to tissues, muscle and adipose tissues. T is taken up as an energy source while VLDLs become LDLs 2. Low density lipoproteins (LDL) provide C for incorporation into cell membranes or synthesis of steroids and bile acids 62 31 Control of endogenous lipids 3.Cells take up LDL by endocytosis via LDL receptors that recognise LDL apolipoproteins 4.high density lipoproteins absorb C from broken down cells and transfer them to LDLs or VLDLs. 63 Dyslipidaemias • Is associated with pathological conditions, with a rise in plasma lipoproteins and plasma cholesterol increasing the risk of developing atherosclerosis Types of hyperlipoproteinaemia primary - genetically determined secondary - is a consequence of disease, diabetes mellitus, alcoholism or drugs See Rang et al, Pharmacology Table 24.2 for the WHO classification of hyperlipoproteinaemia. 64 32 Common types are Type IIa • Characterised by high levels of cholesterol and LDL in blood • Ischaemic heart disease common in this type • HMG-CoA reductase inhibitors  ezetimibe 65 Type IIb • • • • • Characterised by high VLDL and LDL High triglyceride and cholesterol levels Ischaemic heart disease may result Dietary modification Fibrates, HMG-CoA reductase inhibitors, nicotinic acid 66 33 Type IV • High VLDL • Hypertriglyceridaemia • Peripheral vascular disease and ischaemic heart disease • Fibrates 67 Table 24.2 68 34 Lipid-lowering drugs • The aims of drug therapy with lipidlowering drugs is to decrease plasma LDLcholesterol. • Adjunct to low fat diets • Drug choice depends upon: • Predominant form and severity of dyslipidaemia 69 A. Hypercholesterolemia 1. HMG-CoA reductase inhibitors • • • • • Simvastatin, fluvastatin, pravastatin, atorvastatin HMG-CoA reductase is rate limiting enzyme in cholesterol synthesis Catalyses conversion of HMG-CoA to mevalonic acid inhibit cholesterol production 30-50% reduction (HMG-CoA; 3-hydroxy 3-methylglutaryl Coenzyme A) 70 35 HMG-CoA reductase inhibitors • • • • Increased synthesis of LDL receptor on hepatocytes Increased clearance of LDL from plasma Taken orally at night Simvastatin is a prodrug 71 HMG-CoA reductase inhibitors • • Side effects include GIT disturbance, increased liver enzymes, insomnia, rash, myalgia Rare side effect – rhabdomyolysis and angiodema 72 36 Other actions of statins • • • • Improved endothelial function Reduced vascular inflammation Reduced platelet aggregation Increased vascularisation of ischaemic tissue 73 Other actions of statins • Stabilisation of atherosclerotic plaque • Antithrombotic action • Osteoclast apoptosis and increased synthetic activity in osteoblasts • Immune suppression 74 37 Australian Medicines Handbook 75 2. Inhibitors of cholesterol absorption Bile acid resins • Cholestyramine, colestipol • Anion exchange resins • Bind bile acids in the GIT • Prevent reabsorption and enterohepatic circulation • Increase the metabolism of endogenous cholesterol into bile acids in the liver • Reduce LDL by 15-25% 76 38 Bile acid resins • • • • • Leads to increased expression of LDL receptors on liver cells and increased removal of LDL from blood Side effects include nausea, abdominal bloating, constipation/diarrhoea These drugs may interfere with the absorption of some drugs (fat soluble vitamins, chlorthiazide, digoxin, warfarin) should be take at least 1 hr before or 4-6 hrs after resin May worsen hypetrigylceridaemia if > 3 mmol/L Useful in combination therapy 77 3. Ezetimibe • Inhibits biliary and dietary absorption of cholesterol from GIT tract • Blocks a transport protein (NPC1L1) in brush border of enterocytes • Does not alter absorption of fat soluble vitamins or triglycerides • Metabolised in liver with active metabolite • 20% undergoes enterohepatic circulation prolongs duration of action • Decrease LDL by 18% 78 39 Ezetimibe • t1/2 22hrs • Side effects include headache, diarrhoea, rare allergic reactions • Indicated for hypercholesterolaemia when treatment with Statin alone is inadequate or not tolerated • Adjunct to diet 79 4. PCSK9 Inhibitors • Alirocumab, evolocumab • Bind to protoprotein convertase subtilisin/kexin type 9 to inhibit its activity • Activated PCSK9 binds to LDL receptors and promotes lysosomal degradation following LDL uptake into the hepatocytes • Preventing recycling of LDL receptors • Reduces LDL sequestration into the liver 80 40 PCSK9 Inhibitors • Increases LDL clearance from blood • Used for hypercholesterolaemia • Add on for high risk patients with high cholesterol despite optimal lipid lowering therapy • SC every 2 weeks • Side effects injection site reactions, rash, nasopharyngitis 81 B. Hypertriglyceridaemia 1. Fibrates • • • • Gemfibrozil, fenofibrate Agonists at peroxisome proliferator activated receptor  (PPAR) Stimulate lipoprotein lipase increasing the hydrolysis of triglyceride in chylomicron and VLDL particles Reduce hepatic VLDL production 82 41 Fibrates • • • • • Inhibits vascular smooth muscle inflammation (inhibits NF-B expression) Adverse effects include myositis and mild GIT symptoms Contraindicated in severe renal impairment Combination with Statins increases risk of serious adverse side effects Decrease TG by 40-80% 83 Fibrates • • • • • Marked decrease in VLDL levels and increase in hepatic LDL uptake Decrease in plasma LDL (10%) Increase in HDL (10%) Reduces plasma fibrinogen Improves glucose tolerance 84 42 2. Nicotinic acid • Decreases hepatic lipoprotein synthesis • Inhibits hepatic triglyceride production and VLDL secretion • Decreases LDL by 15-30% and increases HDL levels by 20-35% • Used in gram quantities • Adverse effects include flushing, headache, skin rash • Limited use because of side effects 85 3. Fish Oils (-3 marine triglycerides) • • • • • • Decrease production of VLDL triglycerides May increase cholesterol Mechanism of action not known Reduces blood clotting and inflammation Adverse effects – increased bleeding times Contraindicated in type IIa hyperlipoproteinaemia due to increase in LDL 86 43 Dietary plant sterol Demonstrated to reduce absorption of cholesterol (moderate reduction) 87 Plasma lipid targets (mmol/L) No prior CV disease CV disease High TGs Chol LDL TG HDL <5 <4.0 <3.5 <2.5 <2 <2 <4 >1 >1 88 44 BASIC TRANSMITTERS AND ION CHANNELS AND MECHANISMS INVOLVED IN BLOOD VESSEL FUNCTIONING 89 Control of vascular smooth muscle tone • Vascular smooth muscle is controlled by mediators secreted by: Sympathetic nerves Vascular endothelium Circulating hormones • Contraction of vascular smooth muscle occurs when the intracellular calcium concentration [Ca2+]i rises. 90 45 • Calcium entry into the cell occurs via voltage-gated Ca2+ channels and receptor operated channels. • Calcium activates myosin-light-chain kinase causing phosphorylation of myosin • Or sensitization of myofilaments to Ca2+ by inhibition of myosin phosphatase • Ca2+ removal from the cell is via Na+/Ca2+-ATPase and by Na+/Ca2+ exchange • The main storage sites for Ca2+ in the cell are the sarcoplasmic reticulum and the mitochondria 91 • Drugs may interact with any of these physiological systems either through direct actions or via second messenger systems. • For a diagram showing the control of vascular smooth muscle tone see Rang et al Pharmacology, figure 4.9 92 46 figure 4.9c 93 Autonomic nervous system Parasympathetic nervous system • Vasodilation (NO mediated effect) Sympathetic nervous system • 1-adrenoceptor • Contraction of vascular smooth muscle • 2-adrenoceptors • Vasodilation 94 47 Blood pressure control Principle determinants of blood pressure Arterial pressure = Cardiac output x Peripheral resistance Cardiac output is influenced by 1. Heart rate 2. Force of contraction 3. Blood volume 4. Venous return 95 1. Baroreceptor reflex • Sympathetic nervous system • Keep blood pressure at preset level • Circuit operates as follows: a. Baroreceptors in aortic arch and carotid sinus sense the status of the blood pressure and relay this information to the brainstem 96 48 1. Baroreceptor reflex b.A decrease in BP results in an increase in sympathetic outflow from brainstem c.stimulation of: 1-adrenoceptors in heart 1-adrenoceptors in blood vessels d.Postjunctional 2-adrenoceptors involved in reflex process 97 https://www.google.com.au/sear ch?q=baroreceptor+reflex&client =firefoxb&biw=1024&bih=657&source=l nms&tbm=isch&sa=X&sqi=2&ve d=0ahUKEwi6ypG7oNvOAhUDJ ZQKHT0CBykQ_AUIBigB#imgrc =l7KjdBgQw8TuEM%3A 98 49 2. Renin-AngiotensinAldosterone system 99 3. Vascular endothelium • Prostanoids • PGI2 – vasodilation Inhibits platelet aggregation • PGE2 – vasodilation Inhibits NA release PGG2 and PGH2 contraction via thromboxane receptors 100 50 Rang and Dales Pharmacology; Figure 23.1 101 3. Vascular endothelium • Nitric oxide - NO • Peptides – C Natriuretic peptide - vasodilator – Adrenomedullin – vasodilator – Angiotensin II – vasoconstrictor 102 51 3. Vascular endothelium Endothelin • ET1 paracrine mediator • Endothelial cells • Released continuously in resistance vessels • Contributes to vasoconstrictor tone • ETA and ETB receptors are G-protein coupled receptors • ETA – vasoconstrictor • ETB – vasodilation 103 HYPERTENSION 104 52 Definition and diagnosis Hypertension is defined as: Systolic blood pressure > 140 mmHg or Diastolic blood pressure > 90 mmHg 105 Classification of Hypertension category normal high normal hypertension STAGE 1 (mild) STAGE 2 (moderate) STAGE 3 (severe) STAGE 4 (very severe) Systolic (mmHg) < 130 130-139 Diastolic (mmHg) <85 85-89 140-159 160-179 180-209 > 210 90-99 100-109 110-119 >120 When systolic BP and diastolic BP fall into two different categories, classification is based on the higher category. 106 53 Hypertension Primary/ Essential - no obvious causative factor - kidneys - lifelong treatment Secondary renal or endocrine disease Malignant develops quickly lethal complications – cerebral oedema MAO inhibitors and preeclampsia 107 High blood pressure • • • • • Decreased life expectancy Coronary thrombosis Stroke Renal failure Retinopathy 108 54 Control measures • • • • • Reduced salt Reduced weight Cessation of smoking Exercise Alcohol restriction 109 Blood Pressure determinants Principle determinants of blood pressure Arterial pressure = Cardiac output x peripheral resistance cardiac output is influenced by 1. Heart rate 2. Force of contraction 3. Blood volume 4. Venous return 110 55 DRUG TREATMENT OF HYPERTENSION 111 Treatment of Hypertension • Generally start treatment of confirmed hypertension with a single drug at the lowest recommended dose (this will provide satisfactory reduction of BP in about 25–50% of people). • The presence of coexisting conditions may affect the choice of antihypertensive. • For uncomplicated hypertension, unless there is a contraindication or a specific indication for another drug first consider: An ACE inhibitor (or sartan) or A dihydropyridine calcium channel blocker or If 65 or older, a thiazide diuretic (low dosage) 112 56 Treatment of Hypertension • Choose an agent given once daily. • Generally allow 4–6 weeks to gauge response to treatment. For those with marked hypertension or high cardiovascular risk, consider a shorter review period. 113 Figure 23.9 114 57 Figure 23.4 115 ACE Inhibitors - Captopril Brazilian pit viper (Bothrops jararaca) 116 58 1. ACE inhibitors • • • • Captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, trandolapril Block renin-angiotensin system Inhibit angiotensin converting enzyme Prevents the formation of angiotensin II 117 1. ACE inhibitors • • Vasodilation - arterioles > veins Reduced aldosterone release - increases the excretion of Na+ - increases the excretion of H2O 118 59 1. ACE inhibitors Side effects • First dose hypotension • Cough • Hyperkalaemia • Fetal injury • Angiodema 119 1. ACE inhibitors • Contraindicated in renal stenosis • Avoid potassium sparing diuretics • Stop potassium supplements 120 60 2. Angiotensin receptor antagonists • Candesartan, eprosartan, irbesartan, losartan, telmisartan • Antagonists of AT-1 receptor • Useful in ACEI clients who suffer cough • Candesartan is more potent than irbesartan or losartan 121 2. AT-1 receptor antagonists • Adverse effects headache hypotension GIT disturbances • Maximum effect occurs at 4-6 weeks 122 61 3. 1-adrenoceptor antagonists • • • • Prazosin, doxazosin, phenoxybenzamine, phentolamine, terazosin Block sympathetically mediated vasoconstriction Reduces both arteriolar and venous resistance Can be used for an hypertensive crisis 123 3. 1-adrenoceptor antagonists • terazosin and doxazosin - longer-acting drugs - reduce LDL/HDL ratio 124 62 3. 1-adrenoceptor antagonists • Side effects – – – – – Postural hypotension Nasal congestion Pupil constriction Fatigue Sexual or bladder dysfunction 125 4. Calcium antagonists • • Nifedipine, amlodipine Relaxation of vascular smooth muscle 126 63 Principle determinants of blood pressure Arterial pressure = Cardiac output x peripheral resistance cardiac output is influenced by 1. Heart rate 2. Force of contraction 3. Blood volume 4. Venous return 127 5. -adrenoceptor antagonists • • Propranolol, atenolol, metoproplol Decrease cardiac output 128 64 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 129 figure 30.4 130 65 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 131 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 132 66 figure 30.5C 133 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 134 67 Adverse effects of thiazides • • • Weakness Skin rashes (sulphonamide group) Hypokalaemia Potassium supplements Combined therapy with K+ sparing diuretic 135 Adverse effects of thiazides • • • • Increased uric acid levels - gout Increase plasma cholesterol levels Male impotence Hyperglycaemia 136 68 Figure 30.5D 137 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 138 69 Combinations to avoid • ACE inhibitor or sartan plus; - potassium sparing diuretic • Verapamil plus -blocker • ACE inhibitor plus sartan 139 Blood Pressure targets • Coronary heart disease, diabetes, micromacroalbuminuria, stroke or TIA <130/80 • Others <140/90 140 70 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 141 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 142 71 figure 30.5B 143 figure 30.6 144 72 Adverse effects • • • • • • Alkalosis Hyperglycaemic, hyperuricaemic Hypotensive Hypokalaemic - potassium loss considerable, hyponatraemia Hypovolaemia Ototoxicity can occur with frusemide 145 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 146 73 figure 30.5D 147 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) 148 74 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 149 Triamterene and amiloride • • • • Weak diuretic Decrease luminal membrane Na+ permeability Act on collecting tubules and ducts Increase excretion of Na+ (Cl- and H2O) 150 75 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 151 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 152 76 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 153 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 154 77 Osmotic diuretics Adverse effects • Electrolyte imbalance • Dehydration • Hypervolaemia – problem in cardiac failure 155 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- 156 78 figure 30.5A 157 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) 158 79 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 159 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 160 80 Adverse reactions • • • • Stevens-Johnson syndrome Hepatic necrosis Hematological reactions paraesthesia 161 Stevens-Johnson syndrome 162 81 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) 163 Potassium balance K+ loss is increased: • With thiazide and loop diuretics • When Na+ reabsorption in the collecting ducts is increased 164 82 Potassium balance • K+ loss is decreased: When Na+ reabsorption in the collecting ducts is reduced When aldosterone action is inhibited - ACE inhibitors - Spironolactone 165 Potassium supplements • Normal plasma K+ levels 4 mmol/L • Hyperkalaemia K+ levels > 5.0 mmol/L • Hypokalaemia K+ levels < 3.5 mmol/L 166 83 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 167 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 168 84 Haemostasis and thrombosis 169 Blood Coagulation Haemostasis • The arrest of blood loss from a damaged blood vessel • Vasoconstriction • Adhesion and activation of platelets • Fibrin formation • Haemostatic plug 170 85 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 171 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 172 86 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 173 Blood clot formation • • • Fibrin forms long insoluble strands in a meshlike lattice that traps platelets, RBC’s and WBC’s. Requires plasma Ca2+, if removed from plasma, coagulation will not occur The clotting cascade is triggered by intrinsic and extrinsic pathways 174 87 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 175 Thrombin Stimulates • Platelet aggregation • Cell proliferation • Smooth muscle contraction 176 88 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 25.2 177 figure 25.2 178 89 Extrinsic pathway • Initiated by tissue damage and release of tissue thromboplastin (factor III) • Cascade components depend on cellular elements 179 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 25.1 180 90 figure 25.1 181 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 182 91 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 183 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 184 92 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 185 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 186 93 Acquired clotting defects • • • • • More common than hereditary forms Liver disease Vitamin K deficiency (neonates) Excessive oral anticoagulant therapy Treated with vitamin K 187 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 188 94 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 189 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. 190 95 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 25.6 191 figure 25.6 192 96 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 193 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 194 97 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 195 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 196 98 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 197 Bivalirubin • • • • Unstable Angina IV bolus and infusion Reduced clearance in renal impairment Adverse reactions include nausea, thrombocytopaenia 198 99 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 199 figure 25.3 200 100 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 201 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 202 101 Oral Anticoagulants • Periodic determination is essential of blood coagulation. • has the potential to cause many drug interactions. • Unwanted effects are essentially haemorrhage 203 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 204 102 Drugs that decrease effect of warfarin • Vitamin K • Induce hepatic P450 enzymes (CYP2C9) • Reduce absorption 205 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 206 103 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 207 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 208 104 figure 25.10 209 Antiplatelet drugs 210 105 Figure 25.7 211 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 212 106 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 213 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 214 107 Tirofiban • Unstable angina and non-STEMI • Binds glycoprotein IIb and IIIa receptors to prevent platelets binding together • IV applications • Side effects include bleeding 215 Clopidogrel • • • • • • • Prevention of vascular ischaemic events Prodrug Irreversible inhibitor ADP receptors P2Y12 receptor Prevents platelet aggregation Oral formulations Side effects includes bleeding 216 108 Red Blood Cell Disorders 217 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 218 109 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 219 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. 220 110 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%) 221 Normal daily requirements • Men • Women* & Children • Pregnant Women mg/day 5 15 30 *during reproductive years 222 111 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 223 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 224 112 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 225 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) 226 113 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 26.1 227 Table 26.1 228 114 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 229 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 26.1 230 115 Iron distribution and turnover figure 26.1 231 Drugs affecting iron absorption Interfere with iron absorption from gut • Phosphates Tannates (Tea) Tetracyclines Enhance iron absorption from the gut • Ascorbic acid 232 116 Iron deficiency anaemia • • • • • • • • Blood hemoglobin falls below normal range Symptoms include: Weakness Lethargy Headache Dizziness Rapid weak pulse Palpitations 233 Iron deficiency anaemia • Further evaluation includes determination of concentrations of • ferritin • Iron • vitamin B12 • folic acid 234 117 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 235 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 236 118 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. 237 119