Transcript STIM Antihypertensives

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
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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
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Diagnosis of Hypertension
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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
Stage 2
140-159
> 160
or
or
90-99
> 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
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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
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 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?
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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
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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
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Definitions
Diuretic is an agent that increases urine
volume
 Natriuretic is an agent that causes
increase in renal sodium excretion
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Diuretics
Most commonly used anti hypertensive
 Most inexpensive
 Oldest drug class for anti hypertensive
use
 Recognized safety and tolerance by
majority of users
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Diuretics: Mechanism of Action
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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
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Normal renal regulation of blood
volume
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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
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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
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Diuretic agents
Carbonic anhydrase inhibitor
 Osmotic agents
 Loop agents
 Thiazides
 Aldosterone antagonists
 ADH antagonists
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Carbonic Anhydrase Inhibitors
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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
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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
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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
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Diuretic agents
Carbonic anhydrase inhibitor
 Osmotic agents
 Loop agents
 Thiazides
 Aldosterone antagonists
 ADH antagonists
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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
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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
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Loop Diuretics: Pharmacokinetics
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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
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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
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Loop diuretics: Other actions/toxicity
Increase systemic venous capacitance and
thus decrease left ventricular filling pressure
which is useful in heart failure
 Toxicity
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 Ototoxicity due to alteration in the electrolyte
composition of endolymph: tinnitus,
deafness,vertigo
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Hypokalemia
Loop diuretics: Toxicity
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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
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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
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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
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Diuretic agents
Carbonic anhydrase inhibitor
 Osmotic agents
 Loop agents
 Thiazides
 Aldosterone antagonists
 ADH antagonists
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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
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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
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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
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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
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Thiazide diuretics: Toxicity
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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
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Hydrochlorothiazide 12.5-50 mg daily\
 Prototypical
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Metolazone 2.5-10 mg daily
 Thiazide-like in action, not structure
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Chlorthalidone 25-50 mg daily
 Thiazide-like in action, not structure
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Indapamide 2.5-10 mg daily
 Thiazide-like in action, not structure
Diuretic agents
Carbonic anhydrase inhibitor
 Osmotic agents
 Loop agents
 Thiazides
 Aldosterone antagonists
 ADH antagonists
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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
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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
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Potassium Sparing Diuretics
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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
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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
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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
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Potassium Sparing Diuretics:
Combinations/Dosage
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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
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Agents that alter water excretion
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Antidiuretic Hormone Agonists
 Vasopressin and desmopressin used for
central diabetes insipidus
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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
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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
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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
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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
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Diuretics: Conclusions
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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
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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?
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Vascular signal transduction mechanisms
Modulation of intracellular calcium
controls vascular tone
 Three signal transduction mechanisms
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 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
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Sympathoplegics: Drugs that alter
sympathetic nervous system function
Reduces peripheral vascular resistance
 Reduces cardiac output by
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 Inhibiting cardiac function
 Increasing venous pooling in capacitance vessels
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Can be classified according to whether it is
centrally acting or peripherally acting in the
sympathetic reflex arc
Autonomic innervation of heart and
vasculature
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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)
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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)
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Baroreceptor reflex arc
Adrenergic and cholinergic receptors
in blood vessels
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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
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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
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Methyldopa
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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
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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
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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
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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
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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
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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
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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
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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
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Reserpine
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
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

Drug
Selectivity
Partial agonist
activity
Lipid 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
L
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?

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 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

Major Classes of
Antihypertensive Medications
Diuretics
 Vasodilators
 Sympathoplegics
 Renin Angiotensin System (RAS)
blockers

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

[email protected] with any
questions
References
Uptodate 2012
 cvphysiology.com/Blood%20Pressure/B
P001htm
 Cardiovascular Physiology Concepts
2nd Edition Lippincott Williams & Wilkens
2011
