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Diastolic BP
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
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
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%)
Normal
Prehypertension
SBP
mmHg
DBP
mmHg
Lifestyle
Modification
<120
120-139
and <80
or 80-89
Encourage
Yes
Stage 1
Hypertension
140-159
or 90-99
Yes
Stage 2
Hypertension
> 160
or >100
Yes
With compelling
indication
No antihypertensive
drug indicated
Drug(s) for
compelling
indicationd
Drug(s) for
compelling
indicationsd
Other hypertensive
drugs (diuretics,
ACEI, ARB, BB, CCB
as needed)
Thiazide-type
diuretics; consider
ACEI, ARB, BB, CCB,
or combination
Two-drug
combinationc for
most (thiazide and
ACEI/ARB/BB/CCB)
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.
Hypertensive Crises
180/120 mm Hg
2 categories:
Hypertensive emergencies
with acute target-organ
damage
immediate treatment with IV
drugs
goal: DBP < 110
Hypertensive urgencies
without damage
managed with oral drugs for
hours or days
ANTI-HYPERTENSIVES
Primary
Diuretics
ACE inhibitors
Angiotensin-receptor
blockers (ARBs)
-blockers
Calcium-channel blockers
Secondary
1-blockers
Central 2-agonists
Peripheral adrenergic
antagonists
Direct arterial vasodilators
Classification of Anti-HTN
*based on principal regulatory site or mechanism on which they
act
A. Diuretics
- lower blood pressure by depleting sodium and
other electrolytes in the body and reducing
blood volume
1. Carbonic anhydrase inhibitors
2. Loop diuretics
3. Thiazide diuretics
4. Potassium-sparing diuretics
5. Osmotic diuretics
B. Sympathoplegics
act on the sympathetic system
reduce PVR
inhibit cardiac function
increase venous pooling
subtypes:
1. Centrally-acting
Methyldopa, Clonidine, Guanfacine,
Guanabenz
2 . Peripherally-acting
Trimethaphan, Reserpine, Guanethidine,
Guanadrel
2. Alpha blockers
Phentolamine, Phenoxybenzamine
3. Beta blockers (-olol)
C.
Direct vasodilators
-reduce pressure by relaxing vascular smooth
muscle dilating resistance vessels andto
varying degreesincreasing capacitance as well
Oral (Hydralazine, Minoxidil)
D.
Angiotensin antagonists
-reduce peripheral vascular resistance and (potentially)
blood volume
1. ACE inhibitors (-pril)
2. Angiotensin II receptor blockers/ ARBs (-sartan)
E. Aliskiren selective rennin inhibitor
Monotherapy vs. Polypharmacy
Monotherapy
Polypharmacy
Better compliance
Most
patients
with
Lower cost
hypertension require two or
Fewer adverse effects(in more
some cases
drugs, each acting by a
different mechanism
Each of the drugs acts on
one of a set of interacting,
mutually
compensatory
regulatory mechanisms for
maintaining blood pressure
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
Dosage/Administration/
Side effects
Effect/ Mechanism
Pharmacodynamics
of Action
Methyldopa
PRODRUG
Agonist at
Maximal anti HTN effect in
overt sedation at onset of
(Aldomet)
presynaptic
46 hours
tx
Analog of L-dopa;
a2receptors in the
Persists for up to 24 hours
chronic use: persistent
converted to brainstem
mental lassitude (slow)
methyldopamine and REDUCES TPR
SAFE FOR PREGNANT
and impaired mental
methylnorepinephrine
WOMEN
concentration
inhibits
lactation
dopaminergic
positive Coombs test
mechanism in the
-presence of antigens in the
hypothalamus
RBC hemolytic anemia
prolactin
lactation
Clonidine
Lipid-soluble and rapidly Agonist at a2 Relatively short half-life
WITHDRAWAL-INDUCED
(Catapres)
enters the brain from
receptors
Effect is directly related
REBOUND HYPERTENSION
the circulation
to blood concentration =
Tx:
75mcg / 150mcg
2-imidazoline derivative Partial agonist at
PO bid (or as a patch) to
phentolamine+propranolol
(originally tested as nasal a- receptors
maintain smooth blood
decongestant)
inhibits pressor
pressure control
Dry mouth and sedation -->
effects of other acentrally-acting and doseagonists
Transdermal: reduces blood dependent coincide
pressure for 7 days after a
temporally w/ the drugs anti Direct stimulation
single application
HTN effect
of a-adrenoceptors
in arterioles
Increasing doses are more
Hypertensive crisis
effective (but also
(>1mg/day) nervousness,
sympathetic and
more toxic)
tachycardia, headache,
parasympathetic
sweating after omitting 1 or 2
tone
Tapering of dose with
doses
BP , TPR and
simultaneous administration
TX: reinstitute clonidine OR
bradycardia
of alternative anti-HTN drug
admin of mixed /adrenoceptor-blockers
renal vascular
resistance
CI: mental depression
DI: Tricyclic antidepressants
Produces a brief
(TCAs) a-adrenoceptorrise in blood
blocking action
pressure followed
by more prolonged
hypotension (IV)
Guanfacine (Tenex)
adjunct drugs
share the central
avoided unless
adrenoceptorGuanabenz (Wytensin)
unresponsive to other
stimulating
meds
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
Reserpine
Guanethidine
Guanadrel
Alkaloid from
Rauwolfia serpentina
neurons in both
sympathetic and
parasympathetic
ganglia
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
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
(constipation, urinary
retention, precipitation of
glaucoma, blurred vision, dry
mouth)
CNS: sedation, mental
depression, and parkinsonism
symptoms readily enters
the brain
GI: mild diarrhea, GI cramps
and increased gastric acid
secretion
guanethidine-like
drug
Diagnosis and treatment of pheochromocytoma and in other clinical situations associated with exaggerated
release of catecholamines
IV. Beta-blockers
competitive inhibitors of catecholamines at betaadrenoreceptor 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
Nonselective
Selective
Propranolol (Inderal)
Nadolol (Corgard)
Timolol (Blocadren)
Pindolol (Visken)
Betaxolol (Betaoptic)
Bisoprolol (Zebeta)
Esmolol (Brevibloc)
Acebutolol (Sectral)
Atenolol (Tenormin)
Metoprolol (Lopressor)
Labetalol (Normodyne)
Carvedilol (Coreg)
Pindolol
Acebutolol
Carteolol (Ocupress)
Betaxolol (Betaoptic)
Levobunolol (Betagan)
Metipranolol (Optipranolol)
Timolol (Timoptic)
Levobetaxolol (Betaxon)
Acebutolol
Pindolol
Penbutolol
Class/Drug
HTN
Non-selective B1/B2
Carteolol
X
Carvedilol
X
Labetalol
X
Nadolol
X
Penbutolol
X
Pindolol
X
Propranolol
X
Sotalol
Timolol
X
B1 selective
Acebutolol
X
Atenolol
X
Betaxolol
X
Bisoprolol
X
Esmolol
X
Metoprolol
X
Nebivolol
x
Angina
Arrhy
MI
CHF
x
X
X
X
X
X
X
X
X
X
X
x
X
X
X
X
X
X
X
X
X
Comments
ISA; long-acting; also for glaucoma
a-blocking acitivity
ISA; a-blocking acitivity
long-acting
ISA
ISA; MSA
MSA; prototype
Several other significant mech
Primarily for glaucoma
ISA
X
MSA
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)
Oral
(long-term outpx therapy)
Hydralazine
Minoxidil
Drug
Hydralazine
(Apresoline)
Indication
Treatment of
gestational HTN
Combination of
hydralazine with nitrates
is effective in heart
failure
Minoxidil
(Loniten)
PRODRUG
AM: Minoxidil sulfate
Topical: Rogaine
stimulant to hair
growth for
correction of
baldness
Sodium nitroprusside
(Nitropress)
Complex of iron,
cyanide(CN) groups,
and a
nitroso moiety
Na2[Fe(CN)5NO)]
Must be used in
combination with a ablocker 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
Useful in hypertensive
emergencies and severe
HF
Rapidly lowers BP;
effects disappear within
1-10 mins after
discontinuation
Parenteral
Calcium channel blockers
(hypertensive emergencies)
(both)
Sodium nitroprusside
Diazoxide
Fenoldopam
Pharmacologic
Dosage/Administration/
Side effects
Effect/
Pharmacodynamics
Mechanism of
Action
Direct
Well absorbed
SLE-like effects: myalgia,
relaxation of
Rapid first-pass
arthralgia, rashes, fever (>
arteriolar (but
metabolism
400mg/d) not assoc. w/ renal
not veins)
(~25% bioavailability)
damage; reversible
smooth muscle
rapid acetylators have
= SVR
first-pass metabolism,
IHD: reflex tachycardia &
blood levels, and antiHTN
sympathetic stimulation
benefit from a given dose
angina
than do slow acetylators
tachyphylaxis to its
t1/2 = 1.5-3 h
antihypertensive effects
bid-tid for smooth BP
developed rapidly
control
SLE-like syndrome
Toxicity: headache, nausea,
(=400mg/day)
anorexia, palpitations, sweating,
and flushing
Opening of K+
t1/2 = 4h
Associated with reflex
channels in
90% bioavailability
sympathetic stimulation
smooth muscle
40 mg/d
and sodium and fluid retention
membranes by
(compensatory mechanism)
minoxidil sulfate
stabilizes
Hypertrichosis, headache,
membrane at
sweating
resting potential
no contraction
Dilates
arterioles but not
veins
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-
Diazoxide
(Hyperstat IV)
Long-acting arteriolar
dilator
Occasionally used to
treat HTN emergencies
PO Proglycem: used
to manage hypoglycemia
secondary to insulinoma
Fenoldopam
(Corlopam)
Peripheral arteriolar
dilator used for
hypertensive
emergencies and
postoperative
hypertension
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)
Agonist of
dopamine D1
receptors
dilation of
peripheral
arteries +
natriuresis
Thiocyanate is distributed
in ECF
Slowly eliminated by the
kidney
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
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
Dihydropyridine type
block Ca+2channel in blood vessels
- cardiac depressant effect, more selective vs non-DHP
Amlodipine (Norvasc)
Felodipine (Plendil)
Isradipine (DynaCirc)
Nicardipine (Cardene)
Nifedipine (Adalat)
Nisoldipine (Sular)
Pharmacologic Effects
peripheral edema
reflex tachycardia (DHP)
bradycardia (Non-DHP)
heart block (Non-DHP + Beta Blocker)
Non-dihydropyridine type
-depresses both heart and BVs
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
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
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
Captopril (Capoten)
Enalapril (Vasotec)
Indication
CKD: diminish proteinuria
and stabilize renal function
(even in the absence of
lowering of
blood pressure)
IV only
Probably result from
improved intrarenal
hemodynamics, with
decreased glomerular
efferent arteriolar resistance
and a resulting reduction of
intraglomerular capillary
pressure
Mechanism of
Action
Inhibit peptidyl
dipeptidase &
plasma kininase
oral prodrug
that is
converted by
hydrolysis to a
converting
enzyme
inhibitor,
enalaprilat, with
effects similar to
those of
captopril
Lisinopril (Prinivil)
lysine derivative of
enalaprilat
Perindopril (Aceon)
Dosage/Administration/
Pharmacodynamics
Short-acting
BID/TID
Peak concn of
enalaprilat occurs after 34 hrs
BID/TID
HF and MI
Quinapril (Accupril)
Ramipril (Altace)
Reduce incidence of
diabetes in patients with
high cardiovascular risk
Side effects
Benazepril, fosinopril,
moexipril trandolapril
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
Losartan (Cozaar)
provide benefits similar to those of ACEIs in px w/ HF or CKD
Telmisartan (Micardis)
Valdesartan (Diovan)
Aliskiren
Directly inhibits
renin(acts earlier in
RAAS vs.
ACEIs or ARBs)
Same effectiveness in
lowering BP as ACEIs, ARBs,
and thiazides
CI in pregnancy
Hyperkalemia significantly
more common with
aliskiren+valsartan