James Stim, MD Clinical Assistant Professor of Medicine, UICOM-R Board Certified in Nephrology Specialist in Clinical Hypertension September 12, 2012.

James Stim, MD Clinical Assistant Professor of Medicine, UICOM-R Board Certified in Nephrology Specialist in Clinical Hypertension September 12, 2012

Hypertension: General Facts Most common cardiovascular disease About 1 in 3 Americans have hypertension Hypertension is a leading cause of stroke, heart attack, and kidney failure Hypertension is controllable by life style modification and/or medications

Antihypertensive amongst most prescribed drugs in top 10 for 2010  Lisinopril was 3 rd at 87 million Rxs  Amlodipine 5 th at 57 million  Hydrochlorothiazide 10 th at 48 million

Diagnosis of Hypertension Based on repeated reproducible measurement of elevated blood pressure Usually asymptomatic unless end organ damage occurs Normal < 120 Systolic & < 80 Diastolic Pre hypertension 120-139 or 80-89 Hypertension Stage 1 140-159 or 90-99 Stage 2 > 160 or > 100

What is Blood Pressure ?  Blood pressure is proportional to blood flow (cardiac output, CO) and resistance to the blood flowing through the vasculature (systemic vascular resistance, SVR)

Cardiac Output (CO)  CO equals stroke volume times the heart rate in beats per minute  CO increases with increasing heart rate, increasing contractility, and increasing stroke volume  Stroke volume increases with increased venous return which increases ventricular filling pressure

Systemic Vascular Resistance(SVR)  Resistance to blood flow through all of the systemic vasculature other than pulmonary  SVR determined by factors affecting vascular resistance in individual vascular beds Length and diameter of vessels Vascular network organization: parallel vs. series Physical characteristics of blood: viscosity Extra vascular mechanical forces: muscle contraction

What determines blood flow through vascular beds? Change in vessel diameter particularly of small arteries and arterioles Vascular tone or the degree of constriction by a blood vessel relative to its maximally dilated state It is controlled by extrinsic and intrinsic factors Intrinsic Myogenic (from vascular smooth muscle) Endothelial factors: nitric oxide decreases, endothelin increases tone Local hormonal/chemical factors: Arachidonic acid metabolites, histamine and bradykinins which may constrict or dilate Extrinsic Sympathetic nerves and circulating angiotensin II increases tone Atrial natriuretic peptide decreases tone

Vascular tone determinants

Physiologic basis of hypertension Increase in arterial blood pressure is caused by either an increase in CO or an increase in SVR Possible mechanisms for hypertension LV volume ejection too high Intravascular volume too high Elevated venous tone with excess venous return Arterial resistance too high or compliance too low  Forms the basis for pharmacologic treatment

Major Classes of Antihypertensive Medications  Diuretics  Vasodilators  Sympatholytics  Renin Angiotensin System (RAS) blockers

Definitions  Diuretic is an agent that increases urine volume  Natriuretic is an agent that causes increase in renal sodium excretion

Diuretics  Most commonly used anti hypertensive  Most inexpensive  Oldest drug class for anti hypertensive use  Recognized safety and tolerance by majority of users

Diuretics: Mechanism of Action  Decreases body sodium stores and water  Which reduces blood volume and venous pressure  Which reduces cardiac filling or preload  Which decreases ventricular stroke volume and cardiac output  After long term use (6-8 weeks) cardiac output reverts toward normal and peripheral vascular resistance declines through unknown mechanism  Sodium contributes to vascular resistance by increasing vessel stiffness and neural reactivity  Postulated to increase sodium-calcium exchange with increased intracellular calcium

Understanding diuretics  Understand how kidneys handle sodium and water  Be familiar with the nephron in particular tubular mechanisms of sodium transport

Normal renal regulation of blood volume  The kidneys maintain blood volume by adjusting sodium and water excretion to blood pressure levels  Pressure natriuresis: Increased blood volume reflected by increased arterial pressure increases glomerular filtration rate resulting in increased excretion of water and sodium  When blood volume subsequently decreases and arterial pressure decreases, the excretion of water and sodium decreases  What happens though to sodium and water downstream in the tubules of the nephron?

Renal handling of sodium and water

Sodium and water regulation by the nephron  Blood flows through the glomerular capillaries which are highly permeable to water and electrolytes  Hydrostatic pressure of the blood produces the ultrafiltrate that forms in Bowman’s space and flow into the proximal convoluted tubule (PCT)  65-70% of the filtered sodium, water and bicarbonate is reabsorbed from the PCT iso osmotically

Proximal tubular sodium reabsorption Sodium reabsorbed in the form of sodium bicarbonate and sodium chloride Na + /H + exchanger in the luminal membrane of the proximal tubule epithelial cell pulls Na + in, H + out The H + secreted into the lumen combines with bicarbonate to form carbonic acid which is rapidly dehydrated to CO2 and H2O by carbonic anhydrase

Proximal tubular sodium reabsorption The CO2 diffuses into the proximal tubule cell and rehydrated to H2CO3 by intracellular carbonic anhydrase The H2CO3 dissociates and the bicarbonate is transported out of the cell by a basolateral membrane transporter The proton is exchanged back out into the lumen by the Na/H exchanger

Proximal convoluted tubule (PCT)  Although a majority of the sodium in the urine is reabsorbed at the proximal tubule, the only diuretic agent that works here is the carbonic anhydrase inhibitor i.e. acetazolamide  The predominant location of carbonic anhydrase is the luminal membrane of the PCT

Diuretic agents  Carbonic anhydrase inhibitor  Osmotic agents  Loop agents  Thiazides  Aldosterone antagonists  ADH antagonists

Carbonic Anhydrase Inhibitors  Sulfanilamide—unsubstituted sulfonamide moiety  Diuretic properties discovered when sulfanamide antibiotics caused alkaline diuresis  Mechanism of action: Inhibition of membrane bound and cytoplasmic carbonic anhydrase  Pharmacokinetics: Well absorbed orally. Urine pH increases within 30 minutes and lasts for 12 hours after single dose. Secreted in the proximal tubule S2 segment

Carbonic Anhydrase Inhibitors: Pharmacodynamics and Toxicity 85% of PCT bicarbonate reabsorption inhibited Causes hyperchloremic metabolic acidosis and limits the diuretic efficacy to 2-3 days. Renal stones may occur due to hypercalciuria and phosphaturia and calcium salts being insoluble at alkaline pH Renal potassium wasting Drowsiness and paresthesias Contraindicated in Na and K depletion

Carbonic Anhydrase Inhibitors: Clinical Indications Glaucoma: Reduces aqueous humor formation decreases the intraocular pressure Urinary Alkalinizaton: Enhanced urinary excretion of uric acid, cystine and other weak acids which can also be achieved by bicarbonate administration Metabolic Alkalosis: Correction of alkalosis produced by excessive diuresis in severe heart failure by loop diuretics or by respiratory acidosis Acute Mountain Sickness: Decreases the pH of cerebrospinal fluid and brain, ventilation is increased which reduces symptoms

Carbonic Anhydrase Inhibitors:  Acetazolamide 250 mg 1-4 times daily  Dichlorphenamide 50 mg 1-3 times daily  Methazolamide 50-100 mg 2-3 times daily  Not used for hypertension or heart failure

Sodium and water regulation by the nephron: Loop of Henle  Water is reabsorbed into the interstitium across the loop of Henle which is more permeable to water and moves across a concentration gradient  The urine becomes more concentrated as it reaches the thick ascending limb (TAL) of the loop of Henle  The sodium potassium chloride co transporter at the TAL reabsorbs 25% of the original sodium load of the urine  Loop diuretics (furosemide, bumetanide) inhibit this co transporter

Loop Diuretics  Selectively inhibits NaCl reabsorption in the thick ascending loop by blocking the Na/K/2 Cl cotransporter  Furosemide, bumetanide and torsemide are sulfonamides  Ethacrynic acid is not a sulfonamide  Similar efficacy

Loop Diuretics: Pharmacokinetics  Rapidly absorbed and bound to plasma proteins  Eliminated in the kidney by secretion by the organic acid (anionic) transport system  Torsemide oral absorption rapid and similar to IV  Furosemide duration 2-3 hours, torsemide 4-6 hours  Loop agents act on the luminal side of the tubule  Loop agents are secreted in the proximal tubule as weak acid, there may be reduction in secretion when NSAIDs or probenecid compete for the same site

Loop diuretics  Marked increase in the excretion of Ca and Mg, due to reduction in the lumen positive potential that comes from K recycling  Profound increase in the urinary excretion of Na and Cl (25% of the filtered load)  Excretion of bicarbonate and phosphate increased  Blocks formation of a hypertonic medulla so unable to concentrate urine

Loop diuretics: Renal hemodynamics  Increases total renal blood flow (RBF) and redistributes RBF to the midcortex inducing synthesis of renal prostaglandins  NSAIDs (Ibuprofen) can reduce loop diuretic efficacy by inhibiting renal prostaglandins hence causing renal vasoconstriction  Powerful stimulators of renin release directly via the macula densa, stimulates sympathetic nervous system and prostaglandins

Loop diuretics: Other actions/toxicity  Increase systemic venous capacitance and thus decrease left ventricular filling pressure which is useful in heart failure  Toxicity Ototoxicity due to alteration in the electrolyte composition of endolymph: tinnitus, deafness,vertigo  Hypokalemia

Loop diuretics: Toxicity  Lipids: Increases LDL cholesterol and triglycerides, decreases HDL cholesterol  Skin rashes and gastrointestinal disturbances  Hyperuricemia precipitating acute gout attack  Hypomagnesemia  Allergic reactions: Skin rash, eosinophilia  Contraindicated if allergic to sulfonamides: Use ethacrynic acid instead

Loop diuretics: Clinical Uses  Acute pulmonary edema  Treatment of hypertension in reduced renal function states  Edema of nephrotic syndrome  Edema and ascites of cirrhosis  Drug overdose to force more excretion of certain drugs

Loop diuretics: Clinical Uses  Hypercalcemia to force calcium excretion  Treat hyponatremia by diuresis  Edema associated with chronic renal insufficiency  Acute Renal Failure (ARF) changing oliguric to nonoliguric ARF  Enhance excretion of toxic ingestion of bromide, fluoride, and iodide

Loop diuretics: Dosage  Bumetanide 0.5 – 2 mg/day  Ethacrynic acid 50-200 mg/day  Furosemide 20-80 mg/day  Torsemide 5-20 mg/day

Sodium and water regulation by the nephron: distal convoluted tubule  The urine flows into the dista l convoluted tubule (DCT) where another 5% of the sodium is reabsorbed by the sodium chloride co transporter  Thiazide diuretics (hydrochorothiazide) inhibit this co transporter

Thiazide Diuretics  Developed to be more potent carbonic anhydrase inhibitor  Orally absorbed well. Chlorothiazide is the only parenteral form. Indapamide is excreted by the biliary system  Inhibits NaCl symport at the DCT  Contain unsubstituted sulfonamide group

Thiazide diuretics  Secreted by the organic acid secretory system in the proximal tubule and competes with uric acid secretion  Enhances Ca2+ reabsorption at both the PCT and DCT  Action may depend in part on prostaglandins  Mg2+ excretion increased  Blocks formation of dilute urine

Thiazide diuretics: Uses  Edema  Ineffective when GFR less than 30-40 ml/min except metolazone  Hypertension  Nephrolithiasis due to idiopathic hypercalciuria  Osteoporosis  Nephrogenic diabetes insipidus

Thiazide diuretics: Toxicity  Decreased glucose tolerance  Hyperlipidemia: Increased LDL, triglyceride  Hyponatremia: Due to combination of hypovolemia induced elevation of ADH, reduction in diluting capacity of the kidney, and increased thirst  Allergic reactions Skin rash. Sulfonamide sensitivity  Rare weakness, fatigability, and impotence

Thiazide diuretics: Dosage  Hydrochlorothiazide 12.5-50 mg daily\ Prototypical  Metolazone 2.5-10 mg daily Thiazide-like in action, not structure  Chlorthalidone 25-50 mg daily Thiazide-like in action, not structure  Indapamide 2.5-10 mg daily Thiazide-like in action, not structure

Sodium and water regulation by the nephron: distal nephron  The distal segment of the DCT and the upper collecting duct has a sodium potassium hydrogen antiporter which reabsorbs 1-2 % of the sodium  The activity of this transporter is dependent on the tubular concentration of sodium  The more sodium delivered to this segment of the nephron, the more sodium absorbed  Aldosterone stimulates the reabsorption of sodium with increase in urinary losses of potassium and hydrogen ions through this transporter

Sodium and water regulation by the nephron: distal nephron  Water is reabsorbed in the collecting duct through pores regulated by antidiuretic hormone (ADH) or vasopressin released by the posterior pituitary  This leads to a more concentrated urine and reduced urine outflow (anti diuresis)  In the final urine, less than 1% of the original filtered sodium remains

Potassium Sparing Diuretics Reduces Na absorption in the collecting tubules and ducts This site is regulated by aldosterone Actions depend on the renal prostaglandin production and therefore inhibited by NSAIDs Amiloride and Triamterene interfere with Na entry through the epithelial sodium ion channels in the apical membrane of the collecting tubule Spironolactone and eplerenone bind to aldosterone receptors and reduce the intracellular formation of active metabolites of aldosterone

Potassium Sparing Diuretics  Amiloride and triamterene are both organic bases and transported by the organic base secretory mechanism in the proximal tubule  NaCl excretion is modestly increased  May be contraindicated if renal failure present, hyperkalemia, or in combination with other K sparing diuretics, angiotensin converting enzyme inhibitors  Must be cautious if K supplements taken  Triamterene may cause drug containing renal stones

Potassium Sparing Diuretics: Uses  Combined with other diuretics to prevent hypokalemia, in particular thiazide diuretics  States of mineralocorticoid excess or hyperaldosteronism due to either primary hyperaldosteroneism or secondary hyperaldosteronism by heart failure, hepatic cirrhosis, or nephrotic syndrome  Spironolactone the diuretic of choice for hepatic cirrhosis

Aldosterone Antagonists: Toxicity  Eplerenone less toxicity  Life threatening hyperkalemia  May induce metabolic acidosis in cirrhotic patients  Gynecomastia, impotence, decreased libido, hirsutism, deepening of voice, and menstrual irregularities  Peptic ulcers

Potassium Sparing Diuretics: Combinations/Dosage  Maxzide (Triamterene 75 mg/HCTZ 50 mg)  Midamor (Amiloride 5 mg)  Moduretic (Amiloride 5 mg/HCTZ 50 mg)  Dyazide (Triamterene 37.5 mg/HCTZ 25 mg)  Aldactone (Spironolactone 25, 50, 100 mg  Aldactazide (Spironolactone 25 mg/HCTZ 50 mg)

Diuretic agents  Carbonic anhydrase inhibitor  Osmotic agents  Loop agents  Thiazides  Aldosterone antagonists  ADH antagonists  Osmotic diuretics

Agents that alter water excretion  Antidiuretic Hormone Agonists Vasopressin and desmopressin used for central diabetes insipidus  Antidiuretic Hormone Antagonists Conivaptan, Lithium, and Demeclocycline Inhibits the effect of ADH in the collecting tubule Reduces the formation of cyclic AMP in response to ADH  Osmotic diuretics

Osmotic Diuretics  Freely filtered at the glomerulus with limited reabsorption by the renal tubule  Causes water retention in the proximal tubule and descending limb of Henle’s loop which are freely permeable to water  Relatively inert pharmacologically  Increases the osmolality of the plasma and tubular fluid  Mannitol is the prototype, Glycerin

Osmotic diuretics: Clinical Indications  Increase urine volume where water excretion is preferred over sodium excretion  To prevent anuria that may arise when large pigment load comes to the kidney (hemolysis or rhabdomyolysis)  Reduction of intracranial and intraocular pressure (glycerin) by inducing water to leave cells and reduce intracellular volume  Cerebral edema, Glaucoma

Osmotic Diuretics: Toxicity  Extracellular Volume Expansion: Precipitate heart failure, pulmonary edema  Dehydration and Hypernatremia due sodium and water wasting  Hyponatremia by dilution of plasma  Glycerin metabolized causing hyperglycemia

Diuretics: Conclusions  The only class of drugs that directly deals with the fundamental cause of hypertension: Sodium retention  Longstanding history of use, efficacy and tolerance  Inexpensive  Considered first line therapy for most forms of hypertension as a standard of care  Often necessary in combination therapy with other classes of anti hypertensives that may cause salt and water retention as compensatory response

Clinical problem  A 70 y/o man with heart failure has been aggressively diuresed with furosemide with a 10 pound weight loss over several days, decrease in edema from 4+ to 1+, and now has a bicarbonate level of 40 (24 normal) with potassium of 3  He still needs to be on furosemide since he has JVD, and bibasilar rales, and edema  What should be done next and what could be done to reduce the bicarbonate level?

Clinical problem  He continues to have problems with low potassium. What alternative diuretic could be used?  The next day he breaks out in a severe rash and is suspected of having allergy to sulfa, yet still needs aggressive diuresis for CHF. He is on 8 other drugs but what drug would you suspect is he allergic to? What alternative could he use as a strong diuretic?

Vascular signal transduction mechanisms  Modulation of intracellular calcium controls vascular tone  Three signal transduction mechanisms Gs-Protein coupled Phosphatidylinositol pathway Nitric oxide-cGMP pathway

Gs Protein Coupled Signal Transduction

IP3 coupled Signal Transduction

Nitric Oxide-cGMP System

Major Classes of Antihypertensive Medications  Diuretics  Vasodilators  Sympathoplegics  Renin Angiotensin System (RAS) blockers

Sympathoplegics: Drugs that alter sympathetic nervous system function  Reduces peripheral vascular resistance  Reduces cardiac output by Inhibiting cardiac function Increasing venous pooling in capacitance vessels  Can be classified according to whether it is centrally acting or peripherally acting in the sympathetic reflex arc

Autonomic innervation of heart and vasculature The medulla in the brainstem regulates the sympathetic and parasympathetic (vagal) outflow to the heart and blood vessels The nucleus tractus solitarius of the medulla receives sensory input from systemic and central receptors Baroreceptor and chemoreceptors Hypothalamus and higher centers (stress) The heart is innervated by vagal and sympathetic fibers that affect rate and strength of contraction mediated by beta adrenoreceptors and muscarinic receptors respectively

Autonomic innervation of heart and vessels

Autonomic innervation in vessels  Sympathetic adrenergic nerves course along arteries and nerves and found in the adventitia of blood vessels  Capillaries receive no innervation  Vasoconstriction of arteries and veins mediated by alpha adrenoreceptors (alpha 1 and 2)

Baroreceptor reflex arc

Adrenergic and cholinergic receptors in blood vessels Sympathetic adrenergic nerves release norepinephrine (NE)as neurotransmitter NE preferentially binds to alpha 1 receptors that cause smooth muscle contraction and constriction NE may bind weakly to post junctional beta 2 receptors causing vasodilation(minor effect) Circulating epinephrine (EPI) at higher concentrations bind to alpha 1 and 2 receptors to produce vasoconstriction Some vessels (coronary) innervated by parasympathetic cholinergic fibers which release acetyl choline that bind to muscarinic receptors that couple to nitric oxide formation causing vasodilation

Centrally Acting Sympathoplegic Drugs  Reduces sympathetic outflow from vasopressor centers in the brainstem while allowing it to be sensitive to baroreceptor control (no postural changes)  Methyldopa produces false neurotransmitter  Clonidine,Guanabenz, Guanfacine all structurally similar alpha 2 agonists

Baroreceptor reflex arc

Autonomic nervous system and circulatory system

Methyldopa  Analog of L-dopa  Converted to alpha methyldopamine and alpha methylnorepinephrine thus producing false neurotransmitters  Anti hypertensive action due to stimulation of central alpha adrenoceptors by the above metabolites  Lowers peripheral vascular resistance with some reduction in heart rate and cardiac output  Reduces renal vascular resistance

Methyldopa Enters the brain using an aromatic amino acid transporter Maximal antihypertensive effect in 4-6 hours Effects persist for 24 hours because the effects depend upon accumulation and storage of metabolite in vesicles of nerve endings Toxicity: Most common side effect is sedation Depression, nightmares, vertigo Lactation due to increased prolactin secretion Positive Coombs test in 10-20% of patients on therapy for more than 12 months. May cause rarely hemolytic anemia, hepatitis, drug fever which reverses once drug is stopped Most commonly used now for treating hypertension in pregnancy due to its known safety with fetus Dosing is 250, 500 mg every 6-8 hours

Clonidine Partial agonist at alpha receptors and may produce pressor response due to direct stimulation of alpha adrenoceptor in arterioles Agonist at alpha 2 adrenoceptors in the medulla of the brain Reduces both sympathetic and parasympathetic tone Blood pressure lowered by reduction of cardiac output due to decreased heart rate and relaxation of capacitance vessels with reduction in peripheral vascular resistance Renal blood flow maintained Decreased circulating levels of catecholamines

Clonidine  Severe hypertension may complicate massive overdose  Binds more tightly to alpha2 than to alpha1 receptors  May act at pre and post synaptic sites to inhibit norepinephrine release  Lipid soluble and rapidly enters brain  Rapid half life, so oral dose is at least twice a day  Patch or transdermal form available(once every 7days)  Dose:.1 mg to.2 mg every 8-12 hours

Clonidine: Toxicity Dry mouth and sedation frequent and may be severe Should not be given for people at risk for depression or are depressed This may be reversed by tricyclic antidepressants Withdrawal abruptly after prolonged use with high doses may result in life threatening hypertensive crisis due to increased sympathetic nervous activity Manifests as tachycardia, nervousness, headaches, sweating Treat this with alpha or beta blocking agents

Ganglionic Blocking Agents Lowers blood pressure by preventing release of norepinephrine from postsynaptic gangionic sympathetic neurons, not used due to side effects Guanethidine Very powerful sympathoplegic. Old drug for severe hypertension Bad effects of pharmacoligic sympathectomy: postural hypotension, diarrhea, and impaired ejaculation Reserpine Alkaloid extracted from an Indian plant Rauwolfia serpentina One of the first effective used

Guanethidine  Inhibits release of norepinephrine from sympathetic nerve endings  Upon entering the nerve, it is concentrated in transmitter vesicles and replaces norepinephrine  Drugs that block the catecholamine uptake process or displace amines from the nerve terminal block the effects: Cocaine, amphetamine, tricyclic antidepressants, phenothiazines, and phenoxybenzamine

Guanethidine Hypotensive action occurs by lowering cardiac output due to bradycardia and relaxation of capacitance vessels Peripheral vascular resistance reduced with long term use Long half life of 5 days, so onset of effects gradual but persists after stopping Essentially not used presently

Guanethidine: toxicity/side effects  Severe compensatory sodium and water retention Toxicity: Symptomatic postural hypotension, diarrhea, delayed or retrograde ejaculation Interactions: Sympathomimetics in cold preps, tricyclics, patients with pheochromocytoma all will cause severe HTN

Reserpine Blocks the ability of aminergic transmitter vesicles to take up and store biogenic amines This occurs throughout the body, resulting in depletion of norepi, dopamine, and serotonin in central and peripheral neurons; also adrenal medulla Hypotensive effects due mostly from depletion of peripheral amines and as a result may cause sedation, mental depression, and parkinsonism symptoms Decreases cardiac output and peripheral vascular resistance Toxicity: Minimal postural hypotension, diarrhea, mental effects

Sympathetic Ganglia Blocker  Trimethopram  Selectively blocks the nicotinic receptor in the sympathetic ganglia  IV infusion, short acting  Does not cross the blood brain barrier  Used in hypertensive emergencies, dissecting aortic aneurysm  Side effects: hypotension, tachycardia, decreased GI motility, cycloplegia, urinary retention

Clinical Problems  A 35 year old man who is a truck driver has hypertension and is establishing care with you. He is on an antihypertensive with decent control but has complaints of side effects including drowsiness which is a difficult problem due to his driving. He also notes dry mouth. What medication might he be on?

Adrenoreceptor Antagonists: Beta Blockers  Binds to Beta adrenoreceptors and competitively competes with norepinephrine and epinephrine at these sites  Some are partial agonists; partially activating the beta receptor while blocking norepinephrine; full agonists being isoproterenol  First generation are non selective meaning blocks both beta 1 and beta 2 adrenoreceptors  Second generation are relatively selective for beta 1 adrenoreceptors or cardioselective  Third generation possess vasodilator activity by blockade of vascular alpha adrenoreceptors

Adrenoreceptor Antagonists: Beta Blockers  Differences in lipid solubility  Clinical uses encompass not only hypertension but treatment of ischemic heart disease, congestive heart failure, and cardiac arrhythmias

Sympathetic nerve terminal to cardiac myocyte

Sympathetic nerve terminal to vascular smooth muscle

Beta Adrenergic Blockers  Beta 1 receptors in the heart upon stimulation increase HR, contractility, AV conduction, and decrease AV node refractoriness  Beta 2 receptors, some in heart but mostly in bronchial muscle and peripheral vascular muscle that result in constriction  Beta 3 receptors in heart and adipose tissue, mediate thermogenesis and decrease heart contractility  Selectivity for Beta 1 versus non selective

L DrugSelectivityPartial agonist activity Lipid solubilityElimination half life AcebutololBeta 1YesLow3-4 hrs AtenololBeta 1NoLow6-9 hrs BetaxololBeta 1NoLow14-22 hrs BisoprololBeta 1NoLow9-12 hrs CarteololNoneYesLow6 hrs CarvedilolNoneNoHigh7-10 hrs EsmololBeta 1NoLow10 min LabetalolNoneYesModerate5 hrs MetoprololBeta 1NoModerate3-4 hrs NadololNoneNoLow14-24 hrs PenbutololNoneYesHigh5 hrs PindololNoneYesModerate3-4 hrs PropranololNoneNoHigh3.5-6 hrs SotalolNoneNoLow12 hrs TimololNoneNoModerate4-5 hrs

Beta Blockers: Propranolol  Propranolol: Prototypical first generation and first one to be effective for hypertension and ischemic heart disease  Non selective Beta blocker  Decreases cardiac output  Inhibits the stimulation of renin production by cathecholamines (mediated by beta1 receptors)  Resting bradycardia with reduction in heart rate during exercise are responses seen and guide therapy

Beta Blockers: Metoprolol Equipotent to propranolol in beta 1 blockade (in the heart) but 50 to 100 times less potent in beta 2 blockade. More cardioselective Causes much less bronchial constriction in asthmatics than propranolol Beta blocker pharmacokinetics Hepatic metabolism (first pass) Metoprolol/propranolol Oral administration results in less bioavailability than IV route Rapidly distributed with large volume of distribution

Other Beta blockers  Nadolol, carteolol, and atenolol (Beta 1 selective) are excreted in the urine and not metabolized  Dosing reduced in renal failure  Betaxolol and bisoprolol metabolized in the liver with long half lives, dosed once daily  Pindolol, Acebutolol, and Penbutolol are partial agonists (with intrinsic sympathomimetic activity)  Lowers vascular resistance but much less decrease in cardiac output due to agonist effects at Beta 2 receptors

Other Beta Blockers Labetalol and Carvedilol (Combined beta and alpha blocker Labetalol is a mixture of 4 isomers with 3:1 ratio of Beta:Alpha antagonism. The beta blocking isomer is selective Beta 2 agonist and nonselective Beta antagonist Reduces systemic vascular resistance without any change in cardiac output or heart rate Labetalol may be given IV Used for hypertensive emergencies. Dosing 200 – 2400 mg/day Carvedilol use for heart failure also. Dosing 6.25 mg twice a day to start

Esmolol  Beta 1 selective blocker rapidly metabolized by hydrolysis by red blood cell esterases. Half life 9-10 minutes. IV infusion.  Used for intraoperative and postoperative hypertension and hypertensive emergency especially with tachycardia.

Beta blocker side effects  Reduced CO and worsening of CHF (beta1)  Worsening of heart block (beta 1)  Bradycardia (beta 1)  Reduced exercise tolerance (beta 1)  Bronchospasm (beta 2)  Worsening of hypoglycemia (beta 1 and 2)  Hyperkalemia during exercise (beta 2)  Worsening of peripheral vascular disease (beta 2) due to unopposed alpha activity

Beta blocker side effects  CNS depression (beta 2)  Lipids decreased HDL, increase TG (beta 1)  Sexual dysfunction in men and women  Occasional postural hypotension (beta 1)

Beta Blockers: Treatment Strategy Beta 1 selective (metoprolol) versus Non selective (propranol) More effective in hyperkinetic hypertension (tachycardia, excess sympathetic activity) Add to vasodilators to block reflex tachycardia Results in minimal fluid retention Takes 2 weeks to see dose effect Regression of Left Ventricular Hypertrophy (LVH) Reduce mortality after myocardial infarction Use with caution in asthma, diabetes, COPD, PVD, depression, sinus bradycardia

Beta blockers hints  Know selectivity  Know if it has partial agonist activity  Know if lipid soluble  Be aware of multiple uses other than hypertension  Know whether hepatic versus renal metabolism

Alpha Adrenergic Blocker: Mechanism Selective blocker of the peripheral postsynaptic alpha 1 receptors in arterioles and venules Allows Norepinephrine to exert unopposed negative feedback to presynaptic receptors Dilates both resistance (arterial) and capacitance (venous) vessels since both are innervated with sympathetic nerves There is some sympathetic tone under basal conditions, even more so under stress and pheochromocytoma

Alpha adrenoreceptor effects

Alpha blockers  Prazosin, terazosin, and doxazosin  More effective when used with beta blocker and a diuretic  May be used for benign prostatic hypertrophy  Non selective alpha blockers phentolamine and phenoxybenzamine block both post junctional alpha 1 and 2 adrenoreceptors and used for treatment of hypertensive emergency caused by pheochromocytoma  Phenoxybenxamine is a non competitive blocker some action is prolonged

Alpha blockers: side effects/toxicity  First dose phenomenon: Precipitous fall in blood pressure upon standing in some patients after first dose, so start with lowest dose at bedtime with warning. More common if salt or volume depleted  Postural hypotension causing dizziness  Salt and water retention  Nasal congestion due to dilation of mucosal arterioles  Headaches  May improve lipid profiles

Clinical Problem  A 52 year old man who has a BMI 32, hypertension, and hyperlipidemia sees you in the office. His family history is significant for his father having a heart attack at age 55. His blood pressure is 160/95 pulse 90 and trace edema  What class of drug would be the best one to start monotherapy of hypertension and why?

Vasodilators Hydralazine and minoxidil (oral) Nitroprusside, diazoxide, and fenoldopam (IV) Calcium Channel Blockers (oral and IV) Vasodilators relax smooth muscles of arterioles and decrease peripheral vascular resistance Sodium Niroprusside also relaxes veins Compensatory responses mediated by baroreceptors and the sympathetic nervous system and renin-angiotensin-aldosterone system cause tachycardian and salt/water retention

Hydralazine Hydrazine derivative Dilates arterioles but not veins Mechanism unknown, multiple Well absorbed, rapidly metabolized by the liver during first pass, bioavailability low (25%) Metabolized by acetylation and some variation occurs amongst individuals with rapid acetylators having less anti hypertensive effect Dosage 40 – 200 mg/day two to three times daily Oral and IV Lupus erythematosus like syndrome more likely above 200 mg

Hydralazine: Toxicity  Most common: headache, nausea, anorexia, palpitations, sweating and flushing, edema  Angina due to tachycardia in patients with ischemic heart disease  Lupus like syndrome with skin rash, myalgia, arthralgia, fever, more likely in slow acetylators, high doses

Minoxidil Very strong oral vasodilator Opens potassium channels in smooth muscle membranes by minoxidil sulfate Hyperpolarizes the cell making smooth muscle cell more difficult to activate Dilates arterioles, not veins Side effects: Tachycardia and angina Fluid retention Hair growth Pericardial effusion Postural hypotension Use in severe hypertension Use with loop diuretic and beta blocker

Activation of ATP sensitive potassium channels results in hyperpolarization which closes voltage gated calcium channels

Sodium Nitroprusside  Strong parenteral vasodilator used for treating hypertensive emergencies and severe heart failure  Dilates both arterioles and venules  Reduced peripheral vascular resistance and venous return  Guanylyl cyclase activated by release of nitric oxide or direct stimulation of the enzyme resulting in increase cGMP intracellular and relaxing of vascular smooth muscle  Cardiac output does not change

Mechanism for Nitroprusside and Nitrates

Nitroprusside  Complex of iron, cyanide groups and nitroso moiety  Rapid metabolism by uptake into red blood cells, release of cyanide which is metabolized into thiocyanate and slowly eliminated by the kidney  In renal insufficiency, thiocyanate may accumulate over several days causing weakness, disorientation, psychosis, spasms, and convulsions  Rapid effects IV given as pump infusion  In hypertensive emergencies, start oral meds at same time so time on nitroprusside minimized

Diazoxide  Similar chemically to thiazide diuretics but no diuretic activity  Mode of action through ATP sensitive K channels and opens the channel to increase K entry into vascular smooth muscle cells leading to vasodilation  Half life 28 hours  Parenteral, renally excreted  Hypertensive emergencies  Causes salt and water retention

Fenoldopam mesylate  Selective dopamine 1 receptor agonist  Produces peripheral, renal, mesenteric, and coronary arterial dilation  Hypertensive emergencies and postop hypertension  Causes natriuresis  Reflex tachycardia, headache, flushing  Increases intraocular pressure so avoid in patients with glaucoma

Calcium Channel Blockers  Retards the inward flux of calcium from extracellular to intracellular cytosol  There is normally a very large gradient from extracellular to intracellular, so that the flux of calcium into the cell is regulated by calcium channels of various types  Voltage gated calcium channels sub types L,N,T, and P  All opened by depolarization of the transmembrane voltage as happens when a vasoconstrictor triggers activation of vascular smooth muscle cell

Calcium Channel Blockers: Efficacy as vasodilator  Specifically blocks L type channels which are most abundant in cardiovascular tissue  The more active the channel, the more susceptible to blockade, and L type channels are most active in the vascular smooth muscle  The strength of vascular smooth muscle contraction is reduced by blocking the L type channels. Thus more effective with higher blood pressures that simulate more vigorous smooth muscle contraction of blood vessels (use dependence)

L type Calcium Channel Blockade

Calcium Channel Blockers  Three different types  Differentiated by degree of vascular vasodilator effects versus cardiac depressant effects  Dihydropyridines: Nifedipine, amlodipine, felodipine, isradipine, nicardipine, and nisoldipine (most vascular effects)  Phenylalkylamine: Verapamil (least vascular effects)  Benzothiazepine: Diltiazem (intermediate)  Clinically use for hypertension and angina

Calcium Channel Blockers  Cardiac depression: Slow AV conduction, negative inotropic, slow SA node  Inappropriate cardiac effects: cardiac arrest (SA), heart block (AV), and CHF (neg inotropic)  Concomitant beta blockers may worsen this  Inappropriate vasodilation causing headache, flushing, and edema  Postural hypotension  Constipation (verapamil) due to effects on non vascular smooth muscles  Reflex tachycardia and gum hypertrophy (Nifedipine)

Calcium Channel Blockers Drug interactions Beta blockers with diltiazem or verapamil Digitalis: Diltiazem and verapamil may raise levels Monotherapy Combine with ACE inhibitor and diuretic LVH reversed Lipid neutral Good in peripheral vascular disease Cerebral blood flow preserved GFR preserved

Clinical Problems  64 year old woman has moderate hypertension (170/95) and sees you in clinic.  What combination of drugs would work the best?  Hydralazine and Amlodipine  Hydralazine and Metoprolol  Metoprolol and Verapamil  HCTZ and Amlodipine

Renin Angiotensin System

Angiotensin Inhibition 20% of patients with essential hypertension have inappropriately low and inappropriately high plasma renin activity In high renin patients Beta blockers which lower plasma renin activity and angiotensin inhibitors both are effective in lowering blood pressure Angiotensin II is the octapeptide vasoconstrictor and promote sodium retention Angiotensin II stimulates aldosterone release Angiotensin may cause high vascular resistance in high renin states such as renal artery stenosis, intrinsic renal disease, and malignant hypertension Also, essential hypertension after sodium restriction, diuretics, or vasodilators

Actions of Angiotensin II Very potent pressor (40 times more than Norepinephrine Stimulates autonomic ganglia, increasing the release of epi and norepi from the adrenal medulla, facilitates sympathetic nerve transmission at the nerve terminal Stimulates aldosterone biosynthesis in adrenal cortex Causes renal vasoconstriction, increased proximal tubule sodium reabsorption, inhibit renin release Stimulates thirst and increased secretion of vasopressin and ACTH Mitogenic for vascular and cardiac muscle cells, may contribute to LVH, arteriolar hypertrophy

Angiotensin Converting Enzyme Inhibitor  Blocks the conversion of angiotensin I to angiotensin II and inhibits the degradation of bradykinin (a potent vasodilator)  Inhibiting bradykinin breakdown may cause cough and angioedema but contributes to hypotensive effects  Effective in hypertension, reduces morbidity and mortality in heart failure and LV dysfunction after MI, and delays progression of diabetic nephropathy  Decreases systemic vascular resistance, without increase in heart rate, and promotes natriuresis

Inhibitors of Angiotensin  Angiotensin Converting Enzyme Inhibitors Captopril, Enalapril, Lisinopril  Angiotensin Receptor Blockers Losartan, Valsartan, Candesartan  Renin Antagonist Aliskiren

ACE Inhibitors  Captopril first in the class, short acting  Enalapril, lisinopril, benazepril are all prodrugs converted to the active agent by hydrolysis in the liver  Active form is enalaprilat which can be given IV  Side effects Hypotension especially if volume contracted Renal failure due to release of efferent glomerular arteriolar constriction Hyperkalemia due to decreased aldosterone production which may be complicated by reduced GFR  Contraindicated in pregnancy

ACE Inhibitors  Macular papular rash and fever from sulfhydral group  Taste problem (dysgeusia)  Marrow suppression in CRF and SLE  Generally tolerated well  Enhanced by diuretic  Captopril and lisinopril active without conversion in liver  Reduce dose in renal failure

Angiotensin Receptor Blockers  Mechanism: Competitive antagonists highly specific to the AT1 angiotensin receptor isoform. This receptor mediates vasoconstiction and stimulation of aldosterone secretion  Provides more complete block of angiotensin II effects since ACE Inhibitors block only one possible route of Angiotensin II formation  Side effects similar to ACE Inhibitors except cough and angioedema occurs much less frequently. Contraindicated in pregnancy.

Renin Inhibitor  Aliskiren is an orally active nonapeptide with a half life of 24 hours  Metabolized by the liver, excreted by the kidneys  Plasma renin activity is reduced by 50-80% at normal therapeutic levels  Angiotensin I and II, and aldosterone levels are reduced  May cause cough, angioedema in less than 1% of patients  Contraindicated in diabetics who are taking ARB or ACE inhibitor due to increased incidence of renal failure, hypotension, or hyperkalemia

Renin inhibitors: cardiorenal effects  Arterial and venous vasodilation  Decreases blood volume by blocking the angiotensin II effects on the kidneys and inhibiting aldosterone secretion  Depress sympathetic activity by inhibiting the effects of angiotensin II on sympathetic nerve release and reuptake of norepinephrine  Inhibit cardiac and vascular hypertrophy

Other drugs that inhibit renin  Clonidine inhibits renin secretion by reduction in renal sympathetic nerve activity centrally mediated  Propranolol blocks the intra and extrarenal beta receptors involved in the control of renin secretion

Hypertension: Therapy Non pharmacologic Sodium restriction of 70-100 mEq Sodium per day Diet rich in fruits, vegetables, low fat dairy, reduced saturated fats, moderation in alcohol Weight reduction may normalize 75% of overweight patients with mild hypertension Exercise Pharmacologic One drug approach: Thiazides, Dihydropyridine Calcium channel blocker, or ACE Inhibitors/ARB Additional drug if inadequate control

Consider Comorbid Conditions/ethnicity  ACE Inhibitors with diabetes mellitus and proteinuria  Beta blockers or calcium channel blockers with angina  Alpha 1 blockers in men who have benign prostatic hypertrophy  Diuretics, ACE Inhibitors, ARB, or beta blocker for heart failure  African Americans tend to respond better to diuretics and calcium channel blockers

Clinical Problems  27 year old man comes to the ER with anxiety, headaches, blurry vision, and shortness of breath. His BP is 260/120 with HR 100, has papilledema, S4 gallop, and mild ankle edema. The best choice of antihypertensive is:  Propranolol because he is anxious  Lisinopril because there is less side effects and well tolerated  Lasix because he has edema  Clonidine po because it is fast acting  Nitroprusside because it is fast acting and has a short half life

Clinical Problems  27 year old man comes to the ER with anxiety, agitative, headaches, blurry vision, and shortness of breath. His BP is 260/120 with HR 90, no edema, has papilledema, S4 gallop, and mild ankle edema. The best choice of antihypertensive is:  Propranolol because he is anxious  Lisinopril because there is less side effects and well tolerated  Lasix because he has edema  Clonidine po because it is fast acting and sedating  Nitroprusside because it is fast acting and has a short half life

Clinical Problem  His labs return with a creatinine of 4  Is there any need to change drugs? Why?  If so what alternative drug may be useful?  What oral meds should be considered in order to control his blood pressure in the next several days and to wean off parenteral drugs?

Clinical Problem  His creatinine decreases to 1.5 over several days, and his glucoses are elevated, and he has 1+ proteinuria s  His BP has been around 130/80 and pulse 60 on metoprolol, amlodipine, and chlorthalidone  Is there any better choice of anti hypertensive or combination?

Clinical Problem  Several hours later you are asked to see a 32 year old woman 26 weeks pregnant who was sent because of BP 180/100 HR 88. She has 1+ ankle edema, clear lungs, and 2+ protein on urinalysis.  What is the best choice of antihypertensive for her?  Lisinopril or losartan because of proteinuria?  Aliskiren because it is better tolerated in pregnancy  Lasix because of edema  If none of the above what drugs could be used?

Contact information  jstim@rockfordnephrology.org with any questions jstim@rockfordnephrology.org

References  Uptodate 2012  cvphysiology.com/Blood%20Pressure/B P001htm  Cardiovascular Physiology Concepts 2 nd Edition Lippincott Williams & Wilkens 2011

James Stim, MD Clinical Assistant Professor of Medicine, UICOM-R Board Certified in Nephrology Specialist in Clinical Hypertension September 12, 2012.

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James Stim, MD Clinical Assistant Professor of Medicine, UICOM-R Board Certified in Nephrology Specialist in Clinical Hypertension September 12, 2012.

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Presentation on theme: "James Stim, MD Clinical Assistant Professor of Medicine, UICOM-R Board Certified in Nephrology Specialist in Clinical Hypertension September 12, 2012."— Presentation transcript:

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