James Stim, MDClinical Assistant Professor of Medicine, UICOM-R

Board Certified in NephrologySpecialist in Clinical Hypertension

September 12, 2012

Hypertension: General FactsMost common cardiovascular diseaseAbout 1 in 3 Americans have hypertensionHypertension is a leading cause of stroke,

heart attack, and kidney failureHypertension is controllable by life style

modification and/or medications

Antihypertensive amongst most prescribed drugs in top 10 for 2010

Lisinopril was 3rd at 87 million Rxs Amlodipine 5th at 57 million Hydrochlorothiazide 10th at 48 million

Diagnosis of HypertensionBased on repeated reproducible measurement

of elevated blood pressureUsually asymptomatic unless end organ

damage occursNormal < 120 Systolic & < 80 DiastolicPre hypertension 120-139 or 80-89Hypertension 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 bedsLength and diameter of vesselsVascular network organization: parallel vs.

seriesPhysical characteristics of blood: viscosityExtra 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

IntrinsicMyogenic (from vascular smooth muscle)Endothelial factors: nitric oxide decreases, endothelin

increases toneLocal hormonal/chemical factors: Arachidonic acid

metabolites, histamine and bradykinins which may constrict or dilate

ExtrinsicSympathetic nerves and circulating angiotensin II increases

toneAtrial natriuretic peptide decreases tone

Vascular tone determinants

Physiologic basis of hypertensionIncrease in arterial blood pressure is caused

by either an increase in CO or an increase in SVR

Possible mechanisms for hypertensionLV volume ejection too highIntravascular volume too highElevated venous tone with excess venous returnArterial 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 inhibitedCauses 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 wastingDrowsiness and paresthesiasContraindicated 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

Diuretic agents

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

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

ToxicityOtotoxicity 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

Diuretic agents

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

Sodium and water regulation by the nephron: distal convoluted tubule The urine flows into the distal

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 dailyThiazide-like in action, not structure

Chlorthalidone 25-50 mg dailyThiazide-like in action, not structure

Indapamide 2.5-10 mg dailyThiazide-like in action, not structure

Diuretic agents

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

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 aldosteroneActions depend on the renal prostaglandin

production and therefore inhibited by NSAIDsAmiloride 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 AntagonistsConivaptan, Lithium, and DemeclocyclineInhibits the effect of ADH in the collecting

tubuleReduces 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 coupledPhosphatidylinositol pathwayNitric 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 functionIncreasing 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 vasculatureThe 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 chemoreceptorsHypothalamus 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 vesselsSympathetic adrenergic nerves release

norepinephrine (NE)as neurotransmitterNE preferentially binds to alpha 1 receptors that

cause smooth muscle contraction and constrictionNE 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

MethyldopaEnters the brain using an aromatic amino acid transporterMaximal antihypertensive effect in 4-6 hoursEffects 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 sedationDepression, nightmares, vertigoLactation due to increased prolactin secretionPositive 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 toneBlood 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 maintainedDecreased 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 severeShould not be given for people at risk for depression

or are depressedThis may be reversed by tricyclic antidepressantsWithdrawal 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

GuanethidineVery powerful sympathoplegic. Old drug for

severe hypertensionBad effects of pharmacoligic sympathectomy:

postural hypotension, diarrhea, and impaired ejaculation

ReserpineAlkaloid extracted from an Indian plant Rauwolfia

serpentinaOne 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

ReserpineBlocks the ability of aminergic transmitter vesicles to take up

and store biogenic aminesThis 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 resistanceToxicity: 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

LDrug Selectivity Partial agonist

activityLipid solubility Elimination half

life

Acebutolol Beta 1 Yes Low 3-4 hrs

Atenolol Beta 1 No Low 6-9 hrs

Betaxolol Beta 1 No Low 14-22 hrs

Bisoprolol Beta 1 No Low 9-12 hrs

Carteolol None Yes Low 6 hrs

Carvedilol None No High 7-10 hrs

Esmolol Beta 1 No Low 10 min

Labetalol None Yes Moderate 5 hrs

Metoprolol Beta 1 No Moderate 3-4 hrs

Nadolol None No Low 14-24 hrs

Penbutolol None Yes High 5 hrs

Pindolol None Yes Moderate 3-4 hrs

Propranolol None No High 3.5-6 hrs

Sotalol None No Low 12 hrs

Timolol None No Moderate 4-5 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 pharmacokineticsHepatic metabolism (first pass) Metoprolol/propranololOral administration results in less bioavailability than

IV routeRapidly 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 BlockersLabetalol and Carvedilol (Combined beta and

alpha blockerLabetalol 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 IVUsed for hypertensive emergencies. Dosing 200

– 2400 mg/dayCarvedilol 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 StrategyBeta 1 selective (metoprolol) versus Non

selective (propranol)More effective in hyperkinetic hypertension

(tachycardia, excess sympathetic activity)Add to vasodilators to block reflex tachycardiaResults in minimal fluid retentionTakes 2 weeks to see dose effectRegression of Left Ventricular Hypertrophy (LVH)Reduce mortality after myocardial infarctionUse 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: MechanismSelective 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?

Major Classes of Antihypertensive

Medications Diuretics Vasodilators Sympathoplegics Renin Angiotensin System (RAS)

blockers

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 resistanceSodium Niroprusside also relaxes veinsCompensatory responses mediated by

baroreceptors and the sympathetic nervous system and renin-angiotensin-aldosterone system cause tachycardian and salt/water retention

HydralazineHydrazine derivativeDilates arterioles but not veinsMechanism unknown, multipleWell 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 dailyOral and IVLupus 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

MinoxidilVery strong oral vasodilatorOpens potassium channels in smooth muscle

membranes by minoxidil sulfateHyperpolarizes the cell making smooth muscle cell

more difficult to activateDilates arterioles, not veinsSide effects:

Tachycardia and anginaFluid retentionHair growthPericardial effusionPostural hypotension

Use in severe hypertensionUse 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 interactionsBeta blockers with diltiazem or verapamilDigitalis: Diltiazem and verapamil may raise

levelsMonotherapy Combine with ACE inhibitor and diureticLVH reversedLipid neutralGood in peripheral vascular diseaseCerebral blood flow preservedGFR 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

Major Classes of Antihypertensive

Medications Diuretics Vasodilators Sympathoplegics Renin Angiotensin System (RAS)

blockers

Renin Angiotensin System

Angiotensin Inhibition20% 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 releaseAngiotensin 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 NorepinephrineStimulates 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 cortexCauses renal vasoconstriction, increased proximal

tubule sodium reabsorption, inhibit renin releaseStimulates thirst and increased secretion of vasopressin

and ACTHMitogenic 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 InhibitorsCaptopril, Enalapril, Lisinopril

Angiotensin Receptor BlockersLosartan, Valsartan, Candesartan

Renin AntagonistAliskiren

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 contractedRenal failure due to release of efferent glomerular

arteriolar constrictionHyperkalemia 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 pharmacologicSodium restriction of 70-100 mEq Sodium per

dayDiet rich in fruits, vegetables, low fat dairy,

reduced saturated fats, moderation in alcoholWeight reduction may normalize 75% of

overweight patients with mild hypertensionExercise

PharmacologicOne drug approach: Thiazides, Dihydropyridine

Calcium channel blocker, or ACE Inhibitors/ARBAdditional 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

References

Uptodate 2012 cvphysiology.com/Blood%20Pressure/

BP001htm Cardiovascular Physiology Concepts

2nd Edition Lippincott Williams & Wilkens 2011