Hypertension Treatment Lecture Notes PDF

Lecture 2/3 Treatment of Hypertension Disease: Hypertension Hypertension: An elevation of systolic and/or diastolic blood pressure to the point where it increases the risk of cardiovascular disease (>140/90mmHg) Affects 30% of total population and ~65% of over 60s. Major risk factor for stroke, coro...

Lecture 2/3 Treatment of Hypertension Disease: Hypertension Hypertension: An elevation of systolic and/or diastolic blood pressure to the point where it increases the risk of cardiovascular disease (>140/90mmHg) Affects 30% of total population and ~65% of over 60s. Major risk factor for stroke, coronary artery disease, congestive heart failure, myocardial infarction, stroke. Damages cardiovascular system o High pressure damages endothelium of conduit arteries, promoting formation of atherosclerosis. o Increases afterload (force of LV to expel blood into aorta) – results in cardiac hypertrophy and ischaemia. o High pressure into low resistance vascular systems such as those in the brain and kidney can damage the microcirculation and result in renal failure and stroke. o Isolated systolic hypertension can compromise coronary blood flow in the LV as this only occurs during diastole. Types of hypertension: 1. Midlife hypertension: thought to occur because the mechanisms which regulate mean BP fail are dysfunctional. Mean, systolic and diastolic BP rise, associated with a rise in total peripheral resistance (TPR) o a. Due to a defect in Na+ excretion by the kidneys o b. Due to neurohormonal abnormalities 2. Old-age hypertension: age-related arterial stiffening leads to isolated systolic hypertension Systolic pressure rises, but diastolic BP typically falls, so there’s only a small increase in mean BP. o With age/developing hypertension the previously elastic aorta becomes stiffened Knowing cause of hypertension allows for better drug targeting. Primary HT = no identifiable cause, can be due to genetics, environmental e.g. stress and lifestyle changes e.g. high salt diet. Secondary HT: renal stenosis, hyperaldosteronism, birth control pill, rare monogenic syndromes. No obvious cause available = treat with drugs that act on body systems to reduce BP Systems to be changed: ANS/baroreceptor reflex: short term system mainly acts on the heart and blood vessels. o Regulate vascular tone and cardiac output Renin/angiotensin/aldosterone system (RAAS): long term system - acts on the kidneys and blood vessels o Regulate renal function and influence vascular tone. Pressure natriuresis: long term system – acts on the kidneys o Regulate renal function to stabilise blood volume Short term: Baroreceptor reflex: The BRR senses when the blood pressure changes from a set point determined in the brain and regulates it back to the set point. SNS activation increases arterial and venous tone. This raises BP by increasing TPR and CO. ANS also influences HR, SNS = increased heart rate, PSNS = decreased HR. SNS also increases cardiac contractility. Many people feel that the ANS is not involved in hypertension as it is a short-term control mechanism, whereas BP increases in the long term in hypertension. Long term: RAAS Renin, angiotensin, aldosterone system is the medium-long-term system involved in the control of blood pressure. Activation of the RAAS increases arterial constriction, venous tone and TPR. RAAS also acts to increase/restore blood volume. RAAS stimulated by SNS as kidneys are innervated sympathetically which releases NA which stimulates beta receptors on juxtaglomerular cells, which release renin, the first step in the RAAS cascade. Prorenin cleaved to form renin. Renin is an enzyme that converts angiontensinogen to angiotensin I. Angiotensin converting enzyme (ACE) converts angiotensin 1 to angiotensin 2. Angiotensin 2 is a horomone which binds to angiotensin 2 receptors to exert its effects. Effects of angiotensin 2: systemic vasoconstrictionin arterioles, promotes sodium reabsorption in proximal convoluted tubules, induces release of aldosterone from adrenal cortex, which also promotes sodium and and water in kidneys, induces hypothalamus to encourage thirst and water intake, induces posterior pituitary to release antidiuretic horomone which promotes water retention in kidneys. Reduces sensitivity of baroreceptor reflex to blood pressure. Pressure natriuresis: When the arterial BP goes up, this increases the blood pressure in the renal arteries and arterioles, and this causes the kidneys to excrete more Na+ and therefore more fluid. This means that the volume of the extracellular fluid compartment in the body goes down, and since the plasma is a part of that compartment, the blood volume falls. And since the blood volume is a determinant of the blood pressure, a fall in the blood volume lowers the BP. Mechanisms of pressure natriuresis: Increased pressure in afferent arterioles = greater glomerular filtration = more NA+ and fluid filtered and excreted. Pressure in capillaries increases, inhibiting their reabsorption of fluid, so more fluid and Na+ is excreted. Increased BP = increased pressure natriuresis. Activated RAAS/decreased BP = decreased pressure natriuresis. Drugs to treat hypertension Drug class and example Mechanisms of action Side effects ACE inhibitors (e.g. ramipril) Inhibit ACE, therefore blocking the production and effects of angiotensin II. Leads to a reduction in blood volume. Leads to chronic dry cough in 5-10% of patients and angiodema as bradykinin is not broken down by ACE. Deterioration of renal function. Angiotensin receptor blockers (e.g. losartan) Blocks angiotensin 2 receptors (AT1) and therefore the effects of angiotensin 2. Renin inhibitor (e.g. aliskiren) Prevents angiotensinogen from binding to renin. Very effective renin antagonist blocking ang1 synthesis by 98-99%. Ca2+ channel blockers (e.g. amlodipine, diltiazem, verapamil) Release of calcium is responsible for contraction of blood vessels as calcium ions bind to troponin. Vascular selective CCBS block calcium channels, therefore they block constriction and reduce TPR. Non-selective CCBs also cause negative inotropy (power of heartbeat) and negative chronotropy (heart rate) Block the NA+/Cl- cotransporter in the distal tubule, therefore increasing salt and water excretion. This reduces blood volume and cardiac output. Also reduces TPR through an unknown mechanism Thiazide-like diuretics (e.g. chlortalidone, metolazone, bendroflumethiazide) K+ sparing diuretics (e.g. spironolactone) AKA mineralocorticoid receptor antagonists. Aldosterone is blocked by these drugs, which reduces Na+ Other points First line treatment in white people 55 bradycardia and excessively negative or black any age. Not for diabetics. inotropy. Effects due to vasodilation. Amlodipine = vascular selective. Don’t use for heart failure and Verapamil and diltiazem nonpregnancy. selective. Can cause hypokalemia because Contraindicated in gout. blocking sodium reabsorption in DCT can increase sodium reabsorption in collecting tubule which causes excretion of K+ as there is a Na+-Kantiporter reabsorption in the collecting tubule. May also reduce vascular stiffness. -blockers (e.g. propranolol, bisoprolol, pindolol, carvedilol) 1-adrenoceptor antagonists (e.g. prazosin) Methyl-dopa imidazoline receptor agonists K+ channel agonist (minoxidil) Prescribing algorithm: Reduce BP by blocking beta 1 receptors. Propranol = non selective beta blocker, bisoprolol = beta 1 selective beta blocker, pindolol = b1 blocker, b2 agonist, carvedilol = beta 1 and alpha 1 blocker. Beta 1 = heart rate and force of contraction of cardiac muscle, beta 1 = smooth muscle relaxation, vasodilation, bronchodilation. Alpha 1 = smooth muscle contraction and vasoconstriction. Alpha 2 = presynaptic inhibition of noradrenaline release. May also inhibit renin secretion so causes vasodilation indirectly by lowering plasma levels of Ang2. Noradrenaline causes vasoconstriction in vascualar smooth muscle cells – therefore increasing vascular tone and TPR. Blocking this therefore causes vasodilation and decreases TPR. Metabolised to alpha methyl noradrenaline in the brain. Stimulates imidazoline and alpha 2 receptors to reduce rate of firing in sympathetic neurons. Opens calcium channels in vascular smooth muscle cells – results in hyperpolarisation and reduces vasoconstrictor mediated depolarisation and contraction. Bronchospasm – don’t use in asthma. Cardiac depression. Fatigue. Tingling and coldness in fingers and toes. Sleep disturbances. Hypoglycaemia as some processes during hepatic glucose production require sympathetic nervous stimulation. Found to reduce mortality after MI and in chronic heart failure. No longer in favour as first line drugs as calcium channel blockers and thiazide diuretics were shown to be more effective at improving survival in the ASCOT trial in 2005. Orthostatic hypotension, ankle oedema, drowsiness. Highest incidence of side effects in antihypertensive drugs. Rarely used – only in combination with other antihypertrnsive agents. Headache, nausea, sleep disturbance Not commonly used but has no effects on fetus so can be used for pregnancy induced hypertension. Tachycardia and oedema Used with a dieuretic and beta blocker to avoid tachycardia and oedema. Used for malignant hypertension over 180/120 – emergency that can damage kidney heart and eyes.