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BLOOD PRESSURE
arterial blood pressure HYDRAULIC EQUATION ABP directly
proportionate to CO and PVR
BP= CO x PVR Systolic BP Diastolic BP
cardiac contraction affected by cardiac output (CO) CO= volume
of blood pumped by the left ventricle per contraction
blood filling of cardiac chambers affected by TPR/SVR/PVR -total
peripheral resistance/ systemic vascular resistance/ peripheral
vascular resistance TPR= resistance to passage of blood through
precapillary arterioles
MAJOR FACTORS INFLUENCING BP Cardiovascular System
-both normotensive and hypertensive indls -hypertensive set at
higher level Venous tone: degree of constriction; net capillary
filtration, TPR, BP NORMAL REGULATION OF BLOOD PRESSURE
Hydraulic equation (BP= CO x TPR) -3 anatomic sites where CO and
TPR are maintained (both normotensive and hypertensive): 1)
arterioles (resistance vessels) 2) postcapillary venules
(capacitance vessels) 3) heart 4) kidney contributes to maintenance
of blood pressure by regulating the volume of intravascular
fluid
Postural baroreflex - mediated by autonomic nerves
-responsible for rapid, moment-to-moment adjustments in blood
pressure, such as in transition from a reclining to an upright
posture vasomotor area of the medulla
Carotid baroreceptors: stimulated by the stretch of the
vessel
walls brought about by ABP
Baroreceptor activation inhibits central sympathetic
discharge
Transition to upright posture baroreceptors sense the
reduction in arterial pressure as reduced wall stretch
sympathetic discharge is disinhibited increase in
sympathetic
outflow PVR (constriction of arterioles) and CO (direct
stimulation of the heart and constriction of capacitance
vessels,
which increases venous return to the heart) normal BP
RAAS - humoral mechanism Vasoactive substances
- local release from vascular endothelium may also be involved
in the regulation of vascular resistance
- endothelin-1 constricts BVs -nitric oxide dilates blood
BVs
*Baroreflex + humoral mech (RAAS) = contribute to maintain
normal BP at the 4 anatomic sites
* Hypertensive px differs in that the baroreceptors and the
renal
blood volume-pressure control systems appear to be "set" at
a
higher level of blood pressure.
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Physiology
Blood flow: volume of blood that flows through any tissue in a
given time period (in mL/min) Cardiac output: volume of blood that
circulates through systemic (or pulmonary) blood vessels each
minute; SV x HR Stroke volume: volume of blood pumped by the
ventricles per contraction Vascular Resistance: opposition to blood
flow bet. Blood and the walls of the bvs Venous return: volume of
blood flowing back to the heart through systemic veins; due to
pressure generated by contraction of left ventricle Determinants of
arterial pressure: cardiac output- determined by SV and HR vascular
resistance- determined by functional and anatomic changes in small
arteries Cardiac Output Stroke volume Preload: degree of stretching
of heart muscles -proportional to EDV high heart rate, short vent.
diastole, low EDV, low SV -high venous return, high EDV high SV,
high CO, high BP
Myocardial contractility: positive inotropic agents (ANS
stimulation; E/NE; increased Ca2+; digitalis); negative inotropic
agents (inhibition of ANS; anoxia, acidosis, increased K+)
Afterload: higher pressure, lower stroke volume, low CO lower
BP
Heart Rate Autonomic Regulation -CV center in medulla
increase/decrease frequency of nerve impulses in sympathetic and
parasympathetic branches of ANS -proprioceptors; chemoreceptors;
baroreceptors
Chemical regulation -Hormones E/NE increase both heart rate and
contractility
-Cations Elevated blood levels of K+ or Na+ decrease heart rate
and contractility; Excess Na_ blocks Ca2+ inflow during cardiac
action potentials, thereby decreasing the force of contraction;
whereas excess K+ blocks generation of action potentials; moderate
increase in interstitial Ca2+ level speeds heart rate and
strengthens the heartbeat Age, gender, physical fitness, and body
temperature
Vascular Resistance size of the lumen- smaller lumen greater
resistance to blood flow BP increases (vasoconstriction) blood
viscosity- depends on ratio of RBCs to plasma volume (polycythemia,
dehydration); higher viscosity higher resistance higher BP -anemia,
hemorrhage low viscosity low BP total blood vessel length: longer
bv, higher resistance; obese have addl bvs in their adipose tissues
higher bv length higher BP Venous Return skeletal muscle pump:
contraction, pushes blood upward more blood returned to heart
higher BP respiratory pump: inhalation, blood pushed upward more
blood returned higher BP
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Total Blood Volume Renin-angiotensin-aldosterone system
Decrease in blood volume decreased blood pressure
juxtaglomerular cells secrete renin converts angiotensinogen, a
plasma protein produced by the liver, into angiotensin I (lungs)
the enzyme ACE converts angiotensin I into the hormone angiotensin
II Blood level of angiotensin II increases Ang II stimulates the
adrenal cortex to secrete aldosterone ( kidneys) aldosterone
increases reabsorption of Na and water so that less is lost in the
urine; Ald also stimulates the kidneys to increase secretion of K+
and H+ into the urine increased water reabsorption by the kidneys,
blood volume increases blood pressure increases to normal --Ang II
vasoconstriction of the arterioles increases blood pressure raise
blood pressure to normal
HYPERTENSION Most common CV disease Increasing prevalence with
advanced age Other factors: psychological stress, environmental and
dietary factors ( salt and potassium or calcium intake) as
contributing to the development of HTN Elevated arterial pressure,
pathological changes in vasculature and hypertrophy of LV Principal
cause of stroke Major risk factor for CAD and its attendant
complications, MI and sudden cardiac death Major contributor to
cardiac failure, renal insufficiency, and dissecting aneurysm of
the aorta ETIOLOGY OF HYPERTENSION Primary/ Essential/Idiopathic
HTN
- Familial and is likely to be the consequence of an interaction
between environmental and genetic factors -With unknown cause
(~90%)
Secondary HTN
-With known cause (~10-15%)
-e.g. renal artery constriction, coarctation of the aorta,
pheochromocytoma, Cushing's disease, and primary aldosteronism
GESTATIONAL HYPERTENSION during pregnancy predisposes a patient
to pre- eclampsia and eclampsia -Preeclampsia abnormal condition of
pregnancy characterized by sudden hypertension (140/90mmHg),
proteinuria (300mg/24hr) and generalized edema that typically
appears after the 20th week of pregnancy -Other signs and symptoms
are generalized edema, blurred vision, and headaches -Preeclampsia
might be related to an autoimmune or allergic reaction resulting
from the presence of a fetus (1st pregnancy) -Eclampsia: more life
threatening (with seizures) Drugs: methyldopa (DOC) hydralazine
labetalol
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Classification of Blood Pressure for Adults (Age >18)a JNC 7
(7th report of the Joint National Committee on the Detection,
Evaluation and Treatment of High Blood Pressure) -based on the
average of two or more properly measured, seated BP readings on
each of two or more office visits -if SBP and DBP values yield
different classifications, the highest category is used for the
purpose of determining a classification
BP Classification
SBP mmHg
DBP mmHg
Lifestyle Modification
Initial Drug Therapy
W/o compelling indication
With compelling indication
Normal 100 Yes Two-drug combinationc for most (thiazide and
ACEI/ARB/BB/CCB)
b for px w/ DM of CKD, values > 130/80mmHg are considered
above goal
c initial combined therapy should be used cautiously in those at
risk for orthostatic hypotension d Tx px w/ CKD or DM to BP goal of
130/80 mmHg
COMPELLING INDICATIONS are co-morbid conditions where specific
drug therapies have been shown in outcome trials to provide unique
long-term benefits
* A diagnosis cannot be made based on one elevated BP
measurement. An elevated value from the average of two or more
measurements on two or more clinical encounters is needed to
diagnose hypertension.
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Hypertensive Crises 180/120 mm Hg 2 categories: Hypertensive
emergencies Hypertensive urgencies
with acute target-organ damage immediate treatment with IV drugs
goal: DBP < 110
without damage managed with oral drugs for hours or days
Overall Goal of Therapy to reduce hypertension-related morbidity
& mortality goal BP values based on JNC 7: most patients:
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A. DIURETICS
B. SYMPATHOPLEGICS I. Centrally-acting Sympathoplegics
sympathetic outflow from vasopressor centers in the brainstem but
retain or increase sensitivity to baroreceptor control
Antihypertensive and toxic actions are generally less dependent on
posture
Drug Properties Pharmacologic Effect/ Mechanism
of Action
Dosage/Administration/ Pharmacodynamics
Side effects
Methyldopa (Aldomet)
PRODRUG Analog of L-dopa; converted to - methyldopamine and -
methylnorepinephrine
Agonist at presynaptic a2receptors in the brainstem REDUCES TPR
inhibits dopaminergic mechanism in the hypothalamus prolactin
lactation
Maximal anti HTN effect in 46 hours Persists for up to 24 hours
SAFE FOR PREGNANT WOMEN
overt sedation at onset of tx chronic use: persistent
mental lassitude (slow) and impaired mental concentration
lactation positive Coombs test -presence of antigens in the
RBC hemolytic anemia
Clonidine (Catapres) 75mcg / 150mcg
Lipid-soluble and rapidly enters the brain from the circulation
2-imidazoline derivative (originally tested as nasal
decongestant)
Agonist at a2-receptors Partial agonist at a- receptors inhibits
pressor effects of other a-agonists Direct stimulation of
a-adrenoceptors in arterioles sympathetic and parasympathetic tone
BP , TPR and bradycardia renal vascular resistance Produces a brief
rise in blood pressure followed by more prolonged hypotension
(IV)
Relatively short half-life Effect is directly related to blood
concentration = PO bid (or as a patch) to maintain smooth blood
pressure control Transdermal: reduces blood pressure for 7 days
after a single application Increasing doses are more effective (but
also more toxic) Tapering of dose with simultaneous administration
of alternative anti-HTN drug
WITHDRAWAL-INDUCED REBOUND HYPERTENSION Tx:
phentolamine+propranolol Dry mouth and sedation -->
centrally-acting and dose-dependent coincide temporally w/ the
drugs anti-HTN effect Hypertensive crisis (>1mg/day)
nervousness, tachycardia, headache, sweating after omitting 1 or 2
doses
TX: reinstitute clonidine OR admin of mixed
/-adrenoceptor-blockers
CI: mental depression DI: Tricyclic antidepressants (TCAs)
a-adrenoceptor-blocking action
Guanfacine (Tenex) Guanabenz (Wytensin)
adjunct drugs avoided unless unresponsive to other meds
share the central adrenoceptor-stimulating effects of clonidine
do not appear to offer any advantages over clonidine
II.Peripherally-acting sympathoplegics Trimethaphan Ganglionic
receptor
blocker -competitively blocks nicotinic cholinoceptors on
postganglionic
IV infusion for hypertensive emergencies
adverse effects of ganglion blockers: -sympathoplegia (excessive
orthostatic hypotension and sexual dysfunction)
-parasympathoplegia
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neurons in both sympathetic and parasympathetic ganglia
(constipation, urinary retention, precipitation of glaucoma,
blurred vision, dry mouth)
Reserpine Alkaloid from Rauwolfia serpentina
Inhibits catecholamine storage by blocking the ability of
aminergic transmitter vesicles to take up and store biogenic amines
(VMAT) Parkinsonism dopamine depletion in the corpus striatum
CNS: sedation, mental depression, and parkinsonism symptoms
readily enters the brain GI: mild diarrhea, GI cramps and increased
gastric acid secretion CI: peptic ulcer, mental depression
Guanethidine Very polar drug Inhibits NE release at nerve
endings
-concentrated in transmitter vesicles where it replaces
norepinephrine causes a gradual depletion of norepinephrine stores
in the nerve ending
Long half-life (5 days) Gradual onset of sympathoplegia (maximal
effect in 12 weeks) and persists for a comparable period after
cessation of therapy
Profound sympathoplegia Marked postural hypotension, diarrhea,
and impaired Ejaculation No CNS effects vs. other anti-HTN drugs
too polar! Diarrhea parasympathetic dominance DI: cocaine,
amphetamine, TCS, phenothiazines, phenoxybenzamine (block CA uptake
or displaces amines) -nasal decongestant CI: pheochromocytoma
Guanadrel guanethidine-like drug
Orthostatic hypotension Impaired sexual function in males
III. Alpha-1 blockers reduce arteriolar resistance increase
venous capacitance cause vasodilation
Prazosin (Minipress) Terazosin (Hytrin) Doxazosin (Cardura)
essential hypertension CHF BPH
FIRST-DOSE PHENOMENON (highest in prazosin) -sudden fall in BP
when abruptly changing from lying to standing position Postural
hypotension related to first dose or when drug is resumed after
several months off Syncope in 1% with prazosin > 2 mg
Self-limiting Best started on a low dose and taken at night
(hs)
Nonselective Alpha-Adrenoceptor Receptor Blockers
Phentolamine Phenoxybenzamine
Diagnosis and treatment of pheochromocytoma and in other
clinical situations associated with exaggerated release of
catecholamines
IV. Beta-blockers
competitive inhibitors of catecholamines at beta-adrenoreceptor
sites (B1, B2, B3)
B2- bronchial & peripheral BVs (brocho & vasodilation)
B3- adipose tissues (CA-induced thermogenesis, cardiac
contractility) act to reduce the effect of the catecholamine
agonist on
sensitive tissues heart contractility heart rate cardiac output
renin secretion Cardiac Effects
Decrease contractility negative inotropy)
mask hypoglycemia CI: COPD, bronchial asthma SI: withdrawal
syndrome severe bradycardia and heartblock Cardioselectivity:
ability of a drug to preferentially bind to one type of B-receptor
Tx for angina but higher doses lowers cardioselectivity
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Decrease relaxation rate (negative lusitropy) Decrease heart
rate (negative chronotropy) Decrease conduction velocity (negative
dromotropy)
Vascular Effects Smooth muscle contraction (mild
vasoconstriction)
Nonselective
Propranolol (Inderal) Nadolol (Corgard)
Timolol (Blocadren) Pindolol (Visken)
Selective Betaxolol (Betaoptic)
Bisoprolol (Zebeta) Esmolol (Brevibloc) Acebutolol (Sectral)
Atenolol (Tenormin)
Metoprolol (Lopressor)
Mixed a-& -blockers Labetalol (Normodyne)
Carvedilol (Coreg)
With intrinsic sympathomimetic activity (ISA) Acebutolol
Pindolol Penbutolol
With membrane-stabilizing activity Pindolol
Acebutolol
For chronic open-angle glaucoma Carteolol (Ocupress) Betaxolol
(Betaoptic)
Levobunolol (Betagan) Metipranolol (Optipranolol)
Timolol (Timoptic) Levobetaxolol (Betaxon)
Class/Drug HTN Angina Arrhy MI CHF Comments
Non-selective B1/B2
Carteolol X ISA; long-acting; also for glaucoma
Carvedilol X x a-blocking acitivity
Labetalol X X ISA; a-blocking acitivity
Nadolol X X X X long-acting
Penbutolol X X ISA
Pindolol X X ISA; MSA
Propranolol X X X X MSA; prototype
Sotalol X Several other significant mech
Timolol X X X X Primarily for glaucoma
B1 selective
Acebutolol X X X ISA
Atenolol X X X X
Betaxolol X X X MSA
Bisoprolol X X X
Esmolol X X Ultra short acting; intra/ postoperative HTN
Metoprolol X x X x X MSA Nebivolol x Rel. selective in most pxl
vasodilationg (NO rel)
C. VASODILATORS relax smooth muscles of blood vessels TPR and
mean ABP compensatory responses mediated by baroreceptors and the
sympathetic nervous system, as well as renin, angiotensin, and
aldosterone because sympathetic reflexes are intact, vasodilator
therapy does not cause orthostatic hypotension or sexual
dysfunction (kaya dapat polypharmacy)
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Oral (long-term outpx therapy)
Parenteral (hypertensive emergencies)
Calcium channel blockers (both)
Hydralazine Minoxidil
Sodium nitroprusside Diazoxide
Fenoldopam
Drug Indication Pharmacologic Effect/
Mechanism of Action
Dosage/Administration/ Pharmacodynamics
Side effects
Hydralazine (Apresoline)
Treatment of gestational HTN Combination of hydralazine with
nitrates is effective in heart failure
Direct relaxation of arteriolar (but not veins) smooth muscle =
SVR
Well absorbed Rapid first-pass metabolism (~25% bioavailability)
rapid acetylators have first-pass metabolism, blood levels, and
antiHTN benefit from a given dose than do slow acetylators t1/2 =
1.5-3 h bid-tid for smooth BP control SLE-like syndrome
(=400mg/day)
SLE-like effects: myalgia, arthralgia, rashes, fever (>
400mg/d) not assoc. w/ renal damage; reversible IHD: reflex
tachycardia & sympathetic stimulation angina tachyphylaxis to
its antihypertensive effects developed rapidly Toxicity: headache,
nausea, anorexia, palpitations, sweating, and flushing
Minoxidil (Loniten) Topical: Rogaine stimulant to hair
growth for correction of baldness
PRODRUG AM: Minoxidil sulfate Very efficacious orally active
vasodilator Must be used in combination with a a-blocker and a loop
diuretic Should replace hydralazine when maximal doses of the
latter are not effective or in patients with renal failure and
severe hypertension, who do not respond well to hydralazine
Opening of K+ channels in smooth muscle membranes by minoxidil
sulfate stabilizes membrane at resting potential no contraction
Dilates arterioles but not veins
t1/2 = 4h 90% bioavailability 40 mg/d
Associated with reflex sympathetic stimulation and sodium and
fluid retention (compensatory mechanism) Hypertrichosis, headache,
sweating
Sodium nitroprusside (Nitropress) Complex of iron, cyanide(CN)
groups, and a nitroso moiety Na2[Fe(CN)5NO)]
Useful in hypertensive emergencies and severe HF Rapidly lowers
BP; effects disappear within 1-10 mins after discontinuation
Activation of guanylyl cyclase (either via release of NO or by
direct stimulation of the enzyme) intracellular cGMP relaxation of
vascular smooth muscle Dilates BOTH arteries & veins = PVR,
venous return
Parenterally administered (IV infusion) Freshly prepared,
covered w/ opaque foil (light sensitive) Begins at 0.5 mcg/kg /min
and may be increased up to 10 mcg/kg/min as necessary Rapidly
metabolized by uptake into RBCs w/ liberation of CN CN metabolized
by mitochondrial enzyme, rhodanase, in the presence of a sulfur
donor, to the less toxic thiocyanate CN- + sulfur (rhodanase)
SCN-
CN toxicity: metabolic acidosis, arrhythmias, excessive
hypotension, death Low dose toxicity: defect in CN metabolism
ANTIDOTE: Sodium thiosulfate (sulfur donor) and hydroxocobalamin
(combine w/ CN0 to form cyanocobalamin/B12 Accumulation of
thiocyanate in renal insufficiency SCN- toxicity: weakness,
disorientation, psychosis, muscle spasms, and convulsions (> 10
mg/dL)
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Thiocyanate is distributed in ECF Slowly eliminated by the
kidney
Delayed hypothyroidism - inhibition of I- uptake by the thyroid
(rare)
Diazoxide (Hyperstat IV)
Long-acting arteriolar dilator Occasionally used to treat HTN
emergencies PO Proglycem: used to manage hypoglycemia secondary to
insulinoma
Prevents vascular smooth muscle contractions by opening K+
channels and stabilizing membrane potential at resting level
Inhibits insulin release from the pancreas (probably by opening K+
channels in the -cell membrane)
Dose gradually increase (50 150mg) Effect post rapid injection
(within 5 mins) and lasts for 4-12 h Bound extensively to serum
albumin and to vascular tissue reduce dose in renal px Partially
metabolized
Rapid fall in TPR and mean ABP associated with substantial
tachycardia and increased CO hypotensive effects when patients are
pretreated with a-blockers to prevent the reflex tachycardia and
associated increase in CO
Fenoldopam (Corlopam)
Peripheral arteriolar dilator used for hypertensive emergencies
and postoperative hypertension
Agonist of dopamine D1 receptors dilation of peripheral arteries
+ natriuresis
Rapidly metabolized by conjugation t1/2 = 10 minutes
Administered by continuous IV infusion Initiated at a low dosage
(0.1 mcg/kg/ min) titrated upward every 15 or 20 minutes to a
maximum dose of 1.6 mcg/kg/min
Reflex tachycardia, headache, and flushing; increased IOP (CI:
glaucoma)
Calcium Channel Blockers Anti-anginal & anti-arrhythmic
effects Reduce PVR and BP by inhibiting Ca+2influx into arterial
smooth muscle cells
Pharmacologic Effects peripheral edema reflex tachycardia (DHP)
bradycardia (Non-DHP) heart block (Non-DHP + Beta Blocker)
Dihydropyridine type block Ca+2channel in blood vessels
- cardiac depressant effect, more selective vs non-DHP
Non-dihydropyridine type -depresses both heart and BVs
Amlodipine (Norvasc) Felodipine (Plendil)
Isradipine (DynaCirc) Nicardipine (Cardene)
Nifedipine (Adalat) Nisoldipine (Sular)
Verapamil (Isoptin) Greatest depressant effect on heart HR and
CO
Diltiazem (Cardizem) Intermediate actions block Ca+2channels in
heart & blood vessels
D. Angiotensin Antagonists ACE inhibitors Angiotensin II
Receptor blockers
ACE inhibitors Angiotensin II Receptor blockers Inhibit
Angiotensin Converting Enzyme (ACE), thereby preventing the
conversion of Angiotensin I (decapeptide) into the active
Angiotensin II (octapeptide) ACE inhibits:
Peptidyl dipeptidase converting enzyme peptidyl dipeptidase that
hydrolyzes angiotensin I to angiotensin II
Plasma kininase: inactivates bradykinin (potent vasodilator) w/c
works by stimulating release of nitric oxide and prostacyclin
Angiotensin II Receptor Blockers provide similar benefits as
with ACEIs less occurrence of angioedema & dry cough
ACE Inhibitors
BP principally by TPR CO and HR are not significantly
changed
-
Do not result in reflex sympathetic activation and can be used
safely in persons with ischemic heart disease vs vasodilators
-absence of reflex tachycardia may be due to downward resetting of
the baroreceptors or to enhanced parasympathetic activity
Drug Indication Mechanism of Action
Dosage/Administration/ Pharmacodynamics
Side effects
Captopril (Capoten) CKD: diminish proteinuria and stabilize
renal function (even in the absence of lowering of blood pressure)
Probably result from improved intrarenal hemodynamics, with
decreased glomerular efferent arteriolar resistance and a resulting
reduction of intraglomerular capillary pressure HF and MI Reduce
incidence of diabetes in patients with high cardiovascular risk
Inhibit peptidyl dipeptidase & plasma kininase
Short-acting BID/TID
Idiosyncratic dry cough (accompanied by wheezing) Angioedema
Hyperkalemia more likely in px assoc. w/ DM or renal insufficiency
Cough + Angioedema due to bradykinin and substance P DI: potassium
supplements or potassium-sparing diuretics, which can result in
hyperkalemia CI: second and third trimesters of pregnancy because
of the risk of fetal hypotension, anuria, and renal failure,
sometimes associated with fetal malformations or death
Enalapril (Vasotec) IV only
oral prodrug that is converted by hydrolysis to a converting
enzyme inhibitor, enalaprilat, with effects similar to those of
captopril
Peak concn of enalaprilat occurs after 3-4 hrs BID/TID
Lisinopril (Prinivil) lysine derivative of enalaprilat
1080 mg once daily
Perindopril (Aceon) Quinapril (Accupril) Ramipril (Altace)
Benazepril, fosinopril, moexipril trandolapril
All are prodrugs Converted to the active agents by hydrolysis,
primarily in the liver All ACEIs except fosinopril and moexipril
are eliminated via the kidney (lower dose)
Angiotensin II Receptor blockers
Candesartan (Atacand) Irbesartan (Avapro) Losartan (Cozaar)
Telmisartan (Micardis) Valdesartan (Diovan)
no effect on bradykinin metabolism more selective blockers of
angiotensin effects than ACE inhibitors have the potential for more
complete inhibition of angiotensin action vs ACEIs because there
are enzymes other than ACE that are capable of generating
angiotensin II provide benefits similar to those of ACEIs in px w/
HF or CKD SI: similar to ACEIs including the hazard of use during
pregnancy Cough and angioedema can less common
Aliskiren
Selective rennin inhibitor Directly inhibits renin(acts earlier
in RAAS vs. ACEIs or ARBs)
Same effectiveness in lowering BP as ACEIs, ARBs, and thiazides
Metabolized by CYP 3A4 Available as a FDC (fixed dose concn.) with
valsartanas well as HCTZ
SE: diarrhea (higher doses), cough and angioedema (less than
ACEIs) CI in pregnancy Hyperkalemia significantly more common with
aliskiren+valsartan