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
[email protected] with any questions
References
Uptodate 2012 cvphysiology.com/Blood%20Pressure/
BP001htm Cardiovascular Physiology Concepts
2nd Edition Lippincott Williams & Wilkens 2011
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