Hypertension PJ2311 for Blackboard - Tagged PDF

HYPERTENSION Elaine Court  LEARNING OUTCOMES On completion of this set of lectures you should be able to: Describe a number of parameters which will can contribute to increasing the blood pressure. Outline what processes are normally involved in the control of blood pressure. Summarise the...

HYPERTENSION Elaine Court  LEARNING OUTCOMES On completion of this set of lectures you should be able to: Describe a number of parameters which will can contribute to increasing the blood pressure. Outline what processes are normally involved in the control of blood pressure. Summarise the renin-angiotensin-aldosterone (RAA) system. Discuss the importance of the RAA system and the implications of this for extracellular fluid volume and blood pressure.  LEARNING OUTCOMES On completion of this set of lectures you should be able to: Explain the mechanism of action of ACE inhibitors and why this results in both beneficial effects and why some of the characteristic side effects occur. Provide a named example of a drug from each of the various classes of agent used to treat hypertension. Give a detailed description of the mechanism of action of each of the different types of agent and provide an explanation as to why this action results in a decrease in the blood pressure.  A QUICK REMINDER  WHICH VESSEL TYPE IS NOT CORRECTLY MATCHED WITH ONE OF ITS FUNCTIONS? a. arteries – conduct blood away from the heart b. arterioles – return blood from the tissues to the atria c. capillaries – site of exchange of substances between the blood and tissue fluid d. veins – serve as a blood reservoir WHEN SOMEONE IS NOT EXERCISING, WHERE IS MOST OF THEIR TOTAL BLOOD VOLUME LOCATED? a. heart b. arteries c. capillaries d. veins  WHAT CAUSES BLOOD TO MOVE THROUGH THE VASCULAR SYSTEM? a. Valves in the wall of the blood vessels b. Peristalsis caused by the smooth muscle in the blood vessel walls c. Pressure gradients created by the heart d. Osmotic pressure WHAT ADDS PRESSURE TO THE BLOOD IN THE ARTERIES FOLLOWING VENTRICULAR SYSTOLE AND HELPS TO MAINTAIN ARTERIAL BLOOD PRESSURE DURING VENTRICULAR DIASTOLE? a. anastomoses b. precapillary sphincters c. venous valves d. elastic recoil  PHYSIOLOGY OF BLOOD PRESSURE Blood Pressure = Cardiac Output (CO) X Peripheral Vascular Resistance Components of Blood Pressure oSystolic Pressure oDiastolic Pressure oPulse Pressure oMean Arterial Pressure BLOOD PRESSURE PHYSIOLOGY Normal blood pressure is 120 mm Hg. 80 Pulse pressure (PP) = Systolic bp – Diastolic bp 120 mm Hg - 80 mm Hg = 40 mm Hg Pulse pressure is increased with age and atherosclerosis. Mean arterial blood pressure (MABP) MABP = diastolic bp + ⅓ pulse pressure 80 +⅓ x 40 = 93 mm Hg  PRESSURE CHANGE IN SYSTEMIC CIRCULATION Arteries 120 mm Hg 80 Arterioles 80-90 mm Hg 70 Capillaries 35 mm Hg 16 Vein < 16 mm Hg, no diastolic pressure DIAMETER AND CROSS-SECTIONAL AREA RELATIONSHIP Why is the cross-sectional area of capillary beds greatest? diameter of an individual capillary is significantly smaller there are vastly more capillaries in the body than any other types of blood vessels. BLOOD PRESSURE AND BLOOD VELOCITY RELATIONSHIP Greatest pressure drop is in arterioles – greatest resistance Blood flow decreases from arteries to arterioles to capillaries Allows time for exchange processes. Blood flow increases through veins as blood is returned to the heart. IF VENOUS PRESSURE IS SO LOW, HOW IS BLOOD RETURNED TO THE HEART? Vein - (90 % of the extracellular fluids (ECF’s) osmotic activity. Normal sodium Increased Normal sodium concentration sodium concentration (140 mmol/L) concentration (140 mmol/L)  WHAT CONTRIBUTES TO INCREASED BLOOD PRESSURE? Increased Heart Increased Rate Increased Blood Volume Stroke Volume Increased Blood Pressure Increased Increased Peripheral Blood Viscosity Resistance  WHAT CONTRIBUTES TO INCREASED BLOOD PRESSURE? Increased Heart Increased Rate Increased Blood Volume Stroke Volume Increased Blood Pressure Increased Increased Peripheral Blood Viscosity Resistance HOW IS THE NEED TO RETAIN SODIUM DETECTED? Decreased circulating volume stimulates renin release via the juxtaglomerular apparatus The juxtaglomerular apparatus releases renin in response to: o Sympathetic nervous system stimulation o Decreased filtrate osmolality o Decreased stretch (due to decreased blood pressure) HOW DOES THIS GIVE INCREASED SODIUM REABSORPTION? How does Angiotensin influence blood pressure? How Does Aldosterone Affect the Distal Nephron? How Does Aldosterone Affect the Distal Nephron? Increases sodium reabsorption  WATER REABSORPTON IN THE DISTAL NEPHRON H2O does not automatically follow Na+ reabsorption vasopressin must be present to make the epithelium of the distal nephron permeable to H2O vasopressin ≡ antidiuretic hormone (ADH)  WATER REABSORPTION With maximal vasopressin, the collecting duct is freely permeable to water. Water leaves by osmosis and is carried away by the vasa recta capillaries The urine is concentrated In the absence of vasopressin the - collecting duct is impermeable to H2O Factors Affecting the Release of Vasopressin  EFFECTS OF ACE INHIBITOR Angiotensinogen renin Angiotensin I ACE ACE inhibitor Angiotensin II Aldosterone Vasoconstriction secretion ADH secretion ↑d Na+ & H2O ↑d peripheral vasc reabsorption resistance ↑d blood pressure  SIDE EFFECTS Cough – dry and and non-productive Angioedema. Can induce hyperkalemia –WHY?  EFFECTS OF ACE INHIBITOR Angiotensinogen kininogen renin kalikrein Angiotensin I Bradykinin / Substance P ACE ACE inhibitor kininase II Angiotensin II Cough Inactive Aldosterone Vasoconstriction Vasodilation secretion ADH ↑d vascular secretion permeability ↑d Na+ & H2O ↑d peripheral vasc ↓d peripheral vasc reabsorption resistance resistance oedema ↓d blood pressure ↑d blood pressure  COUGH RECEPTORS Cough receptors are located in the larynx, trachea, and larger bronchi. Bradykinin and Substance P o stimulate C afferents in the airways Leads to cough  EFFECTS OF ACE INHIBITOR Angiotensinogen kininogen renin kalikrein Angiotensin I Bradykinin / Substance P ACE ACE inhibitor kininase II Angiotensin II Cough Inactive AT receptor antagonist Aldosterone Vasoconstriction Vasodilation secretion ADH ↑d vascular secretion permeability ↑d Na+ & H2O ↑d peripheral vasc ↓d peripheral vasc reabsorption resistance resistance oedema ↓d blood pressure ↑d blood pressure  ANGIOTENSIN II RECEPTOR ANTAGONISTS (AIIRA) losartan, valsartan Act on AT1 receptors May allow more complete inhibition of AT II’s actions o (as it can be produced by routes other than ACE) Has no effect on bradykinin metabolism o minimises cough and angioedema side effects May provide mortality benefit in severe heart failure  EFFECTS OF AT RECEPTOR ANTAGONISTS (ARB’S) Angiotensinogen renin Angiotensin I ACE Angiotensin II Does not affect AT antagonist breakdown of bradykinin or Aldosterone Vasoconstriction substance P secretion ADH secretion ↑d Na+ & H2O ↑d peripheral vasc reabsorption resistance ↑d blood pressure CALCIUM CHANNEL BLOCKERS Mechanism of action is based on the role of calcium in maintaining smooth muscle tone and in the contraction of myocardium.  CONTRACTION OF VASCULAR SMOOTH MUSCLE Ca2+ enters and binds to calmodulin(CM) Once active CM activates myosin light-chain kinase (MLCK) Activated MLCK phosphorylates the light chains within the head of the myosin molecule The activated head cross-bridges with actin Results in contraction  CALCIUM CHANNEL BLOCKERS Blocking the entry of calcium through cell surface L-type channels relaxes smooth muscle cells. Selective block of arteriole smooth muscle cells is most desirable for reduction of peripheral vascular resistance. Dihydropyridines – amlodipine, nifedipine, felodipine, isradipine, nicardipine, and nisoldipine. o Have higher affinity for vascular calcium channels than for cardiac calcium channels DIURETICS  NORMAL CONTROL OF BLOOD PRESSURE Normally kidney and cardiovascular system modify blood volume and pressure. Compensation not effective, so induce it with a diuretic  WHAT HORMONE WOULD INCREASE SODIUM AND WATER EXCRETION? a. aldosterone b. angiotensin I c. atrial natriuretic peptide d. cortisol e. erythropoietin f. renin g. vasopressin CONTROL OF NA+ & H2O EXCRETION IS REGULATED BY ATRIAL NATRIURETIC PEPTIDE (ANP)  DIURETICS Are used to decrease extracellular fluid volume. For a mild effect o a thiazide can be used e.g. bendroflumethiazide o a thiazide-like diuretic e.g. indapamide If a greater effect is required then a loop diuretic is given eg furosemide Could additionally give a collecting duct diuretic o aldosterone antagonist eg spironolactone o sodium channel blockers  THIAZIDES Cause a modest reduction in intravascular volume o 90 % of Na+ reabsorption has already taken place prior to the distal tubule bendroflumethiazide o diuresis starts in about 2 hours after a dose, peaks after about 3 to 6 hours, and lasts for 12 to 18 hours or longer. bendroflumethiazide  THIAZIDE-LIKE DIURETICS These have the same mechanism of action as thiazides, but are not structurally the same. Inhibit the Na+-Cl- symporter in the distal convoluted tubule o Eg chlortalidone, indapamide  NA Na ++ ABSORPTION AND K+ SECRETION IN DCT K+ secretion is largely passive, through leak channels on the luminal membrane. tubular lumen thiazide Cl- diuretics Cl + - Na Na+ Na+ Na+ K+ K+ K+ filtrate interstitial fluid plasma The thiazide diuretics act from the apical side as competitive antagonists of the Na+-Cl- cotransporter.  REABSORPTION OF Na NA++ IN COLLECTING DUCTS More Na+ entering the collecting ducts will result in more reabsorption there. tubular lumen Na+ 3Na+ Na+ 2K+ K+ filtrate interstitial fluid plasma Leads to a loss of K+  LOOP DIURETICS : HIGH CEILING furosemide sulfonamide bumetanide } derivatives ethacrynic acid is not a furosemide sulfonamide, so in cases of allergies it can be useful. Produce an intense, dose- dependent diuresis of relatively short duration A front line therapy for the relief of pulmonary oedema in the treatment of heart failure  LOOP DIURETICS: MECHANISM OF ACTION Acts on the thick ascending limb of the Loop of Henle Reversibly and competitively inhibits the Na+-K+-2Cl- cotransporter on the luminal surface. lumen interstitium plasma Na+ K+ Na+ 2Cl- K + Cl- K+ Cl- K+ Vasa apical basolateral recta membrane membrane  LOOP DIURETICS: MECHANISM OF ACTION Loop diuretics have higher affinity than Cl- for the Na+-K+- 2Cl- cotransporter. Binding is reversible and competitive lumen interstitium plasma furosemide Na+ K+ X Na+ 2Cl- K + Cl- K+ Cl- K+ Vasa apical basolateral recta membrane membrane  FUROSEMIDE WILL THEREFORE: Decrease NaCl reabsorption Decrease Mg2+ and Ca 2+ absorption Prevents the effective generation of the o counter current multiplier o hyperosmotic region within the medulla  Effect of hypertonic medulla colIecting duct In the presence of H20 aquaporins Allows concentrated urine to be produced  Less hypertonic medulla colIecting duct In the H20 presence of aquaporins Does not allow concentrated urine to be produced WHY CAN HYPOKALEMIA ARISE? More Na+ therefore enters the latter part of the distal tubule and collecting ducts. The re-absorption of Na+ drives water reabsorption. So more water remains in the tubule. This Na+ is then reabsorbed, causing the loss of K+ Can lead to o hypokalemia Why are they called high ceiling diuretics?  CONSIDER ABSORPTION PER DAY. Approx 180 L/day enters the Bowmans capsule. Volume of fluid reabsorbed L/day Bowmans capsule -- Proximal tubule 126 Loop of Henle 36 Distal tubule & Collecting duct 16.5 These are average values and will be influenced by fluid intake etc. COLLECTING DUCT DIURETICS Suppress Na+ reabsorption by one of two mechanisms E.g. Spironolactone, epleronone an aldosterone antagonist o Binds to the receptor and prevents nuclear translocation What does this normally cause to happen? Why is suppressing the action going to affect Na+ reabsorption? COLLECTING DUCT DIURETICS Suppress Na+ reabsorption by one of two mechanisms Spironolactone an aldosterone antagonist o Binds to the receptor and prevents nuclear translocation What does this spironolactone normally cause to happen? Why is suppressing the action going to affect Na+ reabsorption?  Amiloride and triamterene – Competitive inhibitors of the epithelial Na+ channel Na+ is not re-absorbed, o so the driving force for water reabsorption is reduced spironolactone Amiloride Why are they called K+ sparing diuretics?  CONCOMITANT USE OF DIURETICS K+ sparing diuretics are mild diuretics They can, however, be used to potentiate the actions of o Loop diuretics o Thiazides Particularly if hypokalemia is a problem  ALTERNATIVE DRUGS Used less frequently, but can be used if hypertension is not controlled.  VASCULAR SMOOTH MUSCLE EFFECTS OFΑLPHA- ADRENOCEPTOR STIMULATION Stimulation of both o α1-adrenoceptors o α2-adrenoceptors Causes contraction of vascular smooth muscle. By preventing the action of noradrenaline (or adrenaline) on these receptors contraction is prevented, hence relaxation.  ALPHA1-ADRENOCEPTOR ANTAGONISTS prazosin, tetrazosin, doxazosin, trimozosin - selective competitive antagonists of α1-adrenoceptors Phentolamine, phenoxybenzamine - non-selective antagonists. (Used in the treatment of hypertensive emergencies) Relaxation of arterial and venous smooth muscles o most vessels have some degree of tone α1- adrenoceptor antagonists cause dilation. efffect more pronounced in arteries reduces peripheral vascular resistance lowers blood pressure  ΒETA-ADRENOCEPTOR ANTAGONISTS Reduces cardiac output; Inhibits renin release, angiotensin II and aldosterone production, and lowers peripheral resistance; May decrease adrenergic outflow from the CNS. Combined use with diuretics are common. Especially useful in treating hypertension with pre- existing conditions such as o previous myocardial infarction, angina pectoris, migraine headache.  EFFECT OF ΒETA ADRENOCEPTOR STIMULATION β1 adrenoceptors will increases o inotropy o chronotropy o dromotropy Have a greater effect when sympathetic activity is high.  CARDIAC CONTRACTILITY AND NORADRENALINE Sympathetic β antagonist/blocker stimulation releases X noradrenaline and initiates a cyclic AMP second-messenger system This results in actin and myosin interacting so causing the contraction of the heart. EFFECTS OF CATECHOLAMINES ON SA NODE CELLS. (Positive chronotropic effect) Noradrenaline increases the slope of pacemaker potential o Reduces time to reach threshold potential. β1 antagonist prevents this so slows heart rate  EFFECT OF ΒETA ADRENOCEPTOR STIMULATION β2 adrenoceptors relax vascular smooth muscle  ΒETA-ADRENOCEPTOR ANTAGONISTS bisoprolol, metoprolol, atenolol o selective β1 antagonist heart juxtaglomerular cells reduced renin release nebivolol o selective β1 antagonist o stimulates nitric oxide synthase causes production of nitric oxide vasodilation  ΒETA-ADRENOCEPTOR ANTAGONISTS carvedilol: o non-selective β-adrenoceptor antagonist. o antagonist at 1 adrenoceptors. vasodilating properties propranolol o Non selective β-adrenoceptor antagonist Choice usually depends on the person's comorbidities, local recommendations, and cost.  ALPHA2 ADRENOCEPTOR STIMULATION Administration of an α2-adrenoceptor agonist will cause a reduction in blood pressure. E.g. clonidine Central effect (on the medullary cardiovascular centre). o Reduced sympathetic outflow Less renin released Less constriction of blood vessels  CONSIDER THE USUAL SITUATION Ca2+ gate Action potential Ca2+ Ca2+ cAMP adenylate cyclase NA ATP exocytosis α2-receptor NA Post-synaptic receptors  AN AUTO-INHIBITORY FEEDBACK MECHANISM Ca2+ gate Ca2+ Ca Ca 2+ 2+ cAMP cAMP adenylate cyclase NA ATP ATP exocytosis α2-receptor NANA Post-synaptic receptors  METHYLDOPA methyldopa is a prodrug. tyrosine tyrosine hydrolase Dihydroxyphenylalanine (DOPA) DOPA decarboxylase dopamine dopamine β-hydroxylase noradrenaline  METHYLDOPA It enters into adrenergic neurons and is converted to α-methylnoradrenaline α-methylnoradrenaline, is stored in the neurosecretory vessicles in place of noradrenaline. When released, α-methyl-NA is a potent α- adrenoceptor agonist (more effective on α2 than α1) - in the periphery it is a vasoconstrictor. In the CNS the effects are mediated by α2- adrenoceptors , o results in reduced adrenergic outflow from the CNS and an overall reduced total peripheral resistance.  METHYLDOPA Does not alter most of the cardiovascular reflexes. Cardiac output and blood flow to vital organs are maintained. It reduces renal vascular resistance and can be used in patients with renal insufficiency. Not used as first drug in monotherapy, but effective when used with diuretics.  MONOXIDINE Binds to imidazoline I1 receptors Located in rostral ventrolateral medulla (RVLM) of the brain (cardiovascular control centre) This increases release of catecholamines. The catecholamines then activate α2-adrenoceptors (α2-ARs), which inhibit presynaptic RVLM neurons. Leads to lowering of blood pressure  DIRECT VASODILATORS Relax smooth muscle of arterioles and some also work on veins. Stabilize membrane potential at resting level by o opening K+ channel (hydralazine, minoxidil, diazoxide), o increase intracellular cyclic GMP levels which leads to smooth muscle relaxation (sodium nitroprusside). The side effects of these agents restricts their use in outpatient treatment. They are effective for difficult to control hypertension