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Pharmacology II Lecture 7 Cardiovascular system Dr. Mahmoud H. Taleb Assistant Professor of Pharmacology and Toxicology Head of Department of Pharmacology and Medical Sciences, Faculty of Pharmacy- Al azhar University Dr. Mahmoud H. Taleb 1 I - Treatment of Congestive Heart Failure Congestive heart failure (CHF) is a condition in which the heart is unable to pump sufficient blood to meet the needs of the body. CHF by an impaired ability of the cardiac muscle to contract or by an increased workload imposed on the heart. CHF is accompanied by abnormal increases in blood volume and interstitial fluid; the heart veins, and capillaries are therefore generally dilated with blood. Hence the term " congestive " heart failure, since the symptoms include pulmonary congestion with left heart failure, and peripheral oedema with right heart failure. Underlying causes of CHF include atherosclerosis, heart diseases, hypertensive heart diseases , valvular heart diseases, dilated cardiomyopathy and congenital heart diseases. The therapeutic goal for CHF is to increase cardiac output. Dr. Mahmoud H. Taleb 2 Compensatory physiological response in CHF The failing heart evokes three major compensatory mechanism to enhance cardiac output Increased sympathetic activity: Baroreceptor sense a decrease in blood pressure, and trigger activation of β- adrenergic receptors in the heart. This results in an increase in heart rate and a greater force of contraction of the heart muscle, in addition, vasoconstriction enhances venous return and increases cardiac preload. and therefore , can contribute to further decline in cardiac function. 2- Fluid retention: A fall in cardiac output decreases blood flow to the kidney, prompting the release of rennin, with a resulting increase in the synthesis of angiotensin II and aldosterone. This results in increased peripheral resistance and retention of sodium and water. Blood volume increases, and more blood is returned to the heart. If the heart is unable to pump this extra volume, venous pressure increases and peripheral oedema and pulmonary oedema occur. 3- Myocardial hypertrophy: The heart increases in size and the chambers dilate. Initially, stretching of the heart muscle leads to a stronger contraction of the heart. However, excessive elongation of the fibers results in a weaker contraction 4 Dr. Mahmoud H. Taleb 3 Three classes of drugs have been shown to be clinically effective in reducing symptoms and prolonging life : 1- vasodilators that reduse the blood in myocardium 2- diuretic agents that decrease extracellular fluid volume and 3- inotropic agents that increase the strength of contraction of cardiac muscle these agents relieve the symptoms of cardiac insufficiency but do not reverse the underlying pathological condition. Dr. Mahmoud H. Taleb 4 Figure (2) Compensatory physiological response in CHF Dr. Mahmoud H. Taleb 5 Therapeutic strategies in CHF CHF is typically managed by reduction in physical activity, low dietary intake of sodium and treatment by vasodilators, diuretics and inotropic agents e.g. cardiac glycosides. Dr. Mahmoud H. Taleb 6 1- Cardiac glycosides ( Digoxin, Digitoxin, Quabin) The cardiac glycosides exert their effects through actions both on the rate and rhythm and on the force of contraction of the heart. Inhibition of Na+- K+-ATP ase an enzyme responsible for transport of Na+ & K+ in & out the cell. Na+ - input → ↑ Sodium concentration inside the cells → increased transmembrane exchange of sodium & calcium increase the intracellular Ca2+ →Increase contraction of cardiac muscle ( +ve inotropic effect),. An increased myocardial contraction leads to decrease in end diastolic volume, thus increasing the efficiency of contraction, resulting improved circulation, leads to reduced sympathetic , which then reduced peripheral resistance. Vagal tone is also enhanced so the heart rate decreases, and myocardial oxygen demand is diminished (Positive inotropic effect). Therapeutic uses: Digoxin therapy is indicated in patients with severe left ventricular systolic dysfunction after initiation of diuretic and vasodilator therapy. Dr. Mahmoud H. Taleb 7 Mechanism of action of cardiac glycoside: Figure ( 3 ) Mechanism of action of cardiac glycosides Dr. Mahmoud H. Taleb 8 The cardiac glycosides exert their effects through actions both on the rate and rhythm and on the force of contraction of the heart. Inhibition of Na+- K+-ATP ase an enzyme responsible for transport of Na+ & K+ in & out the cell. Na+ - input → ↑ Sodium concentration inside the cells → increased transmembrane exchange of sodium & calcium increase the intracellular Ca2+ →Increase contraction of cardiac muscle ( +ve inotropic effect),. An increased myocardial contraction leads to decrease in end diastolic volume, thus increasing the efficiency of contraction, resulting improved circulation, leads to reduced sympathetic , which then reduced peripheral resistance. Vagal tone is also enhanced so the heart rate decreases, and myocardial oxygen demand is diminished (Positive inotropic effect). Therapeutic uses: Digoxin therapy is indicated in patients with severe left ventricular systolic dysfunction after initiation of diuretic and vasodilator therapy. Dr. Mahmoud H. Taleb 9 Toxicity of cardiac glycoside ** Symptoms: 3 group of symptoms occur in digitalis toxicity: GIT effects: Anorexia- nausea, vomiting, diarrhea and abdominal cramp. CNS effects: headache, malaise, lethargy, fatigue, dizziness, stupor, delusion , parasthesia ,various type of scotoma, neurological pain, hallucination, yellow or green vision. Cardiac effects: Bradycardia. Partial or complete heart block, arrhythmias. Ventricular extrasytole, paroxysmal tachycardia and ventricular tachycardia. ** The cardiotoxic effects of digitalis are probably due to an excessive loss of K+ ( intracellular) , resulting from inhibition of membrane Na+- ATP ase ** Treatment of cardiac arrthymia due to digitalis toxicity: 1- Stop administration of digitalis 2- Kcl 3- Ca2+-ion chelating agents e.g.EDTA 4- Atropine 5- Specific antiarrhythmic drugs 6- Digoxin –specific Fab fragments Dr. Mahmoud H. Taleb 10 Long- term digoxin treatment during pregnancy may shorten the duration of pregnancy and retard intrauterine growth, resulting in low birth weight and shorter labor. Nevertheless, digoxin is the drug of choice for fetal supraventricular tachycardia, it is generally considered a safe drug during pregnancy, with no risk of teratoginicity, but overdose cab be detrimental to the mother and lethal to the fetus. Drug interactions Digitalis action may be enhanced by substances that 1- Slow GI motility and thereby increase gastrointestinal absorption 2- Disrupt body electrolytes by lowering plasma potassium levels, eliciting hypokalemia and hypomagnesia and hypercalcemia e.g. diuretics, amphotericin B, oral and parental glucose. 3-Change renal clearance and or alter plasma protein binding 4-Stimulate ß- adrenoreceoptor and cause cardiac dysrhythmias Digitalis action may be reduced by substances that Reduce gastrointestinal absorption e.g. kaolin-pectin, antihyperlipidemic agents, antacids. Increase gastrointestinal motility e.g. metoclopramide Stimulate hepatic microsomal enzymes e.g. phenytoin, ASA, barbiturate. Spironolactone, phenylbutazone Dr. Mahmoud H. Taleb 11 Other positive inotropic agents *** ß - adrenergic agonist : ß - adrenergic stimulation improve cardiac performance by positive inotropic effects and vasodilation. Bobutamine is the most commonoly used , where it leads tob an increase in the intracellular concentration of cAMP. This results in an increase in intracellular calcium, which results in the activation of protein kinase. Slow calcium channels are one important site of phosphorylation by protein kinas. When phosphorylated, the entry of calcium ions into the myocardium increases thus enhances contraction. Dobutamine must be given by IV infusion. ** Phosphodiasteras inhibitors Amrinone and milrinone are phosphodiasteras inhibitors that increase the intracellular concentration of cAMP. This results in an increase in intracellular calcium, and thus cardiac contractility and improvement of myocardial function., they increase mortality in heart failure. Dr. Mahmoud H. Taleb 12 II. Vasodilators Vasodilatation may be produced by various types of pharmacological agents. Nitroglycerine and various nitrates have been used in treatment of cardiac diseases. Other drugs used for the same purpose include postganglionic blockers of sympathetic nervous system, α-adrenergic blockers, β2 - adrenorenoreceptor agonists, histaminergic or dopaminergic receptor agonists, blockers of calcium channels in the muscle cell membrane, angiotensin- converting enzyme(ACE) inhibitors, and drugs that relax vascular smooth muscle directly without acting on any specific receptors. . The three clinical indications for the use of vasodilators are angina pectoris, hypertension, and refractory heart failure. Nitrites are used primarily for angina pectoris; hydralazine, diazoxide, sodium nitroprusside, and minoxidil are used chiefly for treatment of hypertensions; calcium channel blockers are used for both purpose and various other agents are useful in the treatment of refractory heart failure. Dr. Mahmoud H. Taleb 13 therapeutic application of these drugs. * Nitrates and nitrites have effects on the veins. * Sodium nitroprusside acts on both arterioles and on veins. * Hydralazine and diazoxide act mainly on arteries. In addition, vasodilators can differ in their action in various vascular areas; i.e., some will increase blood flow mainly in the coronary arteries while others act chiefly in the renal, mesenteric, or skin vessels. Blood flow in all tissues depends on the balance between vascular resistance and cardiac output. The relative contribution of cardiac and local factors to the regulation of blood flow is quite different in various tissues. Hence, it's easy to understand that a vasodilator that increases cardiac output may increase blood flow more in a particular vascular area in which perfusion depends mainly on the cardiac output, than another vasodilator that is without such cardiac effect. The extent of vasodilation depends a great deal on the preexisting state of the vessels. Drug-induced relaxation can be best demonstrated in vessels that have been previously contracted. Dr. Mahmoud H. Taleb 14 Clinical indications for the use of vasodilators Hypertension This is the main indication for the use of vascular smooth-muscle relaxants other than the nitrates. Diastolic hypertension is consequent to increased peripheral resistance, and therefore the rationale for lowering arterial pressure by using drugs that relax vascular smooth muscle is obvious. Previously, their use was limited because they tended to case tachycardia and increased cardiac contractility by activation of baroreceptor reflexes. These compensatory changes counterbalance the antihypertensive effect of vasodilators. Today, vasodilators are used together with β-blockers to treat hypertension, to counteract the reflex tachycardia and increased cardiac output. The antihypertensive effect can be balances by the concomitant use of diuretics. In more severe hypertension, diuretics are used in combination with β-blocking drugs, vasodilators or other drugs acting on the sympathetic nervous system. Diuretics decrease extracellular and plasma volume; this action and their vascular effects enhance the lowering of blood pressure caused by vasodilators. In addition, diuretics prevent retention of salt and water, which is a frequent consequence of the excessive capillary permeability to Na+ that is caused by vasodilators. Dr. Mahmoud H. Taleb 15 . Baroreceptors and the sympathetic nervous system Baroreflexes involving the sympathetic nervous system are responsible for rapid moment regulation of blood pressure. A fall in blood pressure causes pressure- sensitive neurons ( baroreceptors in the aortic arch and carotid sinuses) to send fewer impulses to cardiovascular centers in the spinal cord. This prompts a reflex response of increased sympathetic and decreased parasympathetic output to the heart and vascular, resulting in vasoconstriction and increased cardiac output. These changes result in a compensatory rise in blood pressure Dr. Mahmoud H. Taleb 16 Figure (4) Baroreceptor reflex mechanism Dr. Mahmoud H. Taleb 17 3- Renin- angiotensin- aldosterone system. The kidney provides for the long-term control of blood pressure by altering the blood volume .Baroreceptors in the kidney respond to reduced arterial pressure (and to sympathetic stimulation of B-adrenoceptors) by releasing the enzyme renin (see Figure )This peptidase converts angiotensinogen to angiotensin I, which is in turn converted to angiotensin II in the presence of angiotensin converting enzyme (ACE) Dr. Mahmoud H. Taleb 18 Figure (5) Renin- angiotensin- aldosterone system reflex mechanism. Dr. Mahmoud H. Taleb 19 2- Hypertension Hypertension is the most common cardiovascular disease. Thus, the third National Health and Nutrition Examination Survey (NHANES III), conducted from 1992 to 1994, found that 27% of the USA adult population had hypertension. The prevalence varies with age, race, education, and many other variables. Sustained arterial hypertension damages blood vessels in kidney, heart, and brain and leads to an increased incidence of renal failure, coronary disease, cardiac failure, and stroke. Dr. Mahmoud H. Taleb 20 Diagnosis The diagnosis of hypertension is based on repeated reproducible measurements of elevated blood pressure. In fact, hypertension is usually asymptomatic until overt end organ damage is imminent or has already occurred. Etiology 1- Primary, idiopathic or essential hypertension: due to unknown cause. 2- Secondary hypertension: may be due to : Renal disease e.g. Glomerulonephritis. Endocrinal disorders e.g. Acromegaly, Cushing syndrome. Renovascular disease e.g. Renal artery stenosis Catecholamine- producing tumor. Toxemia of pregnancy Use of certain drugs e.g. oral contraceptive, adrenal steroids. Predisposing factors to the occurrence of hypertension as environmental factors, stressful lifestyle, high dietary intake of sodium, obesity, and smoking. Dr. Mahmoud H. Taleb 21 Basic Pharmacology of Antihypertensive agents All antihypertensive agents act at one or more of the four anatomic control sites depicted in Figure( 6) and produce their effects by interfering with normal mechanisms of blood pressure regulation. Figure . Sites of action of the major classes of antihypertensive Dr. Mahmoud H. Taleb drugs. 22 Treatment Strategy Mild hypertension can often be controlled with a single drug. More severe hypertension may require treatment with several drugs that are selected to minimize adverse effects of the combined regimen. Treatment is initiated with any of four drugs, depending on the individual patient: a diuretic, α-blocker, an ACE inhibitor, a calcium channel blocker. If blood pressure is inadequately controlled, a second drug is added. α -blocker is usually added if the initial drug was a diuretic, or a diuretic is added if the first drug was α -blocker. A vasodilator can be added as a third step for those patients who still fail to respond Dr. Mahmoud H. Taleb 23 Dr. Mahmoud H. Taleb 24 Depressant of sympathetic activity 1- α- adrenergic blockers The mechanism of hypotensive action is α- blockade → peripheral peripheralresistance vasodilatation resulting in reduction of blood pressure. α- blockers, except prazocin are not used here, they cause tachycardia & increase in C.O.P due to - reflex sympathetic stimulation of heart - blockade of presynaptic α2 receptors resulting in an increase of NE release. They are mainly used in peripheral vascular diseases. Prazocin ( RX Minipress) G.I.T disturbances. Dry mouth, blurred vision, rash and pruritis. Dr. Mahmoud H. Taleb 25 Mode of action: Prazocin is a vascular smooth muscle relaxant affecting arterioles more than venules. Blocking of the postsynaptic α-adrenergic receptor→ fall in peripheral resistance and blood pressure. Prazocin is a phosphodiasterase inhibitor→ accumulation of cAMP in vascular smooth muscle, leads to vasodilatation. Side effects: Postural hypotension and tachycardia with the first dose .This initial syncope can be avoided by: Giving the first dose at bed time or the patient in relaxed position. Angina pectoris. Fluid retention, oedema. Drowsness, headache. Dr. Mahmoud H. Taleb 26 β -drenoceptor Antagonists Propranolol) Rx Inderal, Deralin, Propol), Atenolol( Tenormin, Normetin, Cortenol, Atenol), pindolol (Rx Viskin), Acebutolol (Rx Sectral) , Nadolol (Rx Corgard), Timolol (Rx Blocardan ) , Metaprolol (Rx Lopressor), Labetolol (Rx Trandate ), Carvedilol (Rx Coreg) Bisoprolol (Rx Zebeta, Concor ,Cardioloc) Actions ii- Figure . Action of β- adrenergic blockers Dr. Mahmoud H. Taleb 27 B. Therapeutic uses D. Adverse effects Common effects: The β -blockers may cause CNS side effects such as fatigue, lethargy, insomnia, and hallucinations; these drugs can also cause hypotension. The β blockers may decrease libido and cause impotence; druginduced sexual dysfunction can severely reduce patient compliance Alterations in serum lipid patterns: The β -blockers may disturb lipid metabolism, decreasing high-density lipoproteins (HDL) and increasing plasma triacylglycerol. Drug withdrawal: Abrupt withdrawal may cause rebound hypertension, probably as a result of up-regulation of β -receptors. Patients should be tapered off of β blocker therapy in order to avoid precipitation of arrhythmias. The β blockers should be avoided in treating patients with asthma, congestive heart failure, and peripheral vascular disease. Dr. Mahmoud H. Taleb 28 iii- α2- adrenergic agonist Clonidine (Rx Catapress, Dikkinet, Clonirit) Clonidine is given orally or I.M, resulting in a fall of blood pressure, and this is due to decrease of C.O.P and PR. Mechanism of action: Central action Clonidine has been claimed to stimulate the central presynaptic α2 receptors , which are inhibitory to NE release → inhibition of sympathetic outflow. Peripheral action Clonidine prevents release of NE from adrenergic nerves→ prevent cardiac response to postganglionic adrenergic nerves stimulation. It has a weak direct peripheral vasodilator action. It produces bradycardia , which is due to decreases of sympathetic and increases vagal tone. It decreases renin secretion. Therapeutic uses control of moderate hypertension. Prophylactic for migraine. Side effects Mainly due to vagal tone stimulation Sedation. Bradycardia, dryness of the mouth, nausea, impotence. Dr. Mahmoud H. Taleb 29