Download Hypertension

Antihypertensives
or
How not to blow your cork
Background
 Cardiovascular pharmacology must always deal with two
problems
1. Treating the disease state (e.g. reducing elevated
blood pressure)
2. Accounting for the body’s homeostatic response to
the treatment
 Individual variation in response, and probable drug
interactions, will dictate the correct regimen of drugs to
be administered
 Goal is to develop regimen using fewest drugs at
lowest effective doses
 Reduces number and severity of side effects
 Increases patient compliance
Hypertension
 Defined as elevation of arterial blood pressure above a
normal value (120/80 mmHg).
 Highest risk factor associated with cardiovascular
disease  risk doubles with each 20 mm Hg increase
in systolic bp over 140 mm Hg
 Most cases of hypertension (90%) are due to unknown
etiology  called essential hypertension
 Normal increase in bp with age (most cases diagnosed
in middle age)
Note: for this class BP = AP
Hypertension is asymptomatic
but may increase risk of other
pathologies:
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Atherosclerosis
Coronary artery disease
Congestive heart failure
Diabetes
Insulin resistance
Stroke
Renal disease
Retinal disease (easiest condition to diagnose)
Recall: Regulation of blood
pressure due to combination
of
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Renin-angiotensin-aldosterone system
Sympathetic nervous system
Vasopressin (ADH) system
Fluid retention/excretion by the kidney
Note: the most effective antihypertensive
drug regimens will impair the function of
one or more of the above systems
Compensatory mechanisms counteracting
decreased blood pressure
Classes of Antihypertensive
Drugs
1.
2.
3.
4.
5.
6.
7.
β blockers
Peripherally acting sympatholytics
Centrally acting sympatholytics
(Diuretics)
Angiotensin inhibitors
Calcium channel blockers
Direct vasodilators
Figure 12-2 Summary of sites and mechanisms of action
antihypertensives
Stages of Hypertension
Heart failure
Angina
Post-myocardial infarction
Extensive coronary artery
disease
Diabetes
Chronic kidney failure
Recurrent stroke
prevention
Mechanisms of Action:
Diuretics
 Will talk about specifics later but
generally reduce blood volume by
decreasing electrolyte, and thus water,
reabsorption in the kidney (increase urine
excretion)
 Causes reduced plasma volume which
decreases CO, which lowers BP
Diuretics
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amiloride
Thiazides*
burnetanide
chlorthalidone
eplerenone
furosemide (also used in race horses, altitude sickness)
indapamide
metolazone
spironolactone
triamterene
Mechanisms of Action:
Angiotensin Inhibitors
 Angiotensin converting enzyme (ACE) inhibitor
 blocks conversion of angiotensin I to angiotensin II
 Angiotensin receptor blockers
 Reversibly bind to the Ang. I subtype of Ang. II
receptors in blood vessels  reduce physiological
effect of Ang. II
Note: both above have similar antihypertensive effect
Angiotensin Inhibitors
 ACEs
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captopril
enalapril
lisinopril
benazepril
ramipril
 Angiotensin receptor blockers
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losartan
valsartan
candesartan
telmisartan
Mechanisms of Action: Drugs
affecting the SNS – Adrenergic β, α
receptor antagonists
 Many types of β blockers
 All competitively antagonize the effects of
epinephrine and norepinephrine on β1 –adrenergic
receptors in the heart, and renin-secreting cells of
the kidney
 α receptor antagonists work only by blocking α1
receptors on vascular smooth muscle
Mechanisms of Action: Drugs
affecting the SNS – Sympatholytics
CNS active
 Work by reducing the firing rate of sympathetic nerves
 Mediated by activation of α2-adrenergic receptors in the
CNS but exact site is unclear
 Enter brain after absorption into bloodstream
Peripherally acting
 Interfere with norepinephrine release from sympathetic
nerve terminals
 May inhibit formation of catecholamines
Adrenergic receptor antagonists
 β-blockers
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propanolol
atenolol
sotalol
pindolol
labetalol
Carvedilol
 α1 receptor antagonists
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clonidine
α-methyldopa
guanfacine
guanabenz
Reserpine – 1st widely used antihypertensive
Mechanisms of Action:
Ca2+ Channel Blockers
 All excitable tissue contains voltage-dependent
Ca2+ channels
 Inhibit inward movement of Ca2+ through
specific (L-type) voltage-dependent Ca2+
channels
 This type of channel prevalent in cardiac and
vascular smooth muscle
 When Ca2+ channels are inactivated, Ca2+ is
pumped out of cell, actin dissociates from
myosin and muscle relaxes, opening vascular
lumen and decreasing resistance, which
decreases BP
 Major effect is on coronary and peripheral
arterioles
Ca2+ channel blockers
 Verapamil (1st one used to treat
hypertension)
 nifedipine
 diltiazem
Mechanisms of Action:
Direct vasodilators
 Most powerful antihypertensive drugs
 May cause strong compensatory reactions to
bring BP back up
 Fluid retention
 Increase in
 renin-release
 heart rate
 contractility
 Usually used only in severe hypertension or for
patients not responding to other
antihypertensives
Direct vasodilators
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Hydralazine
Minoxidil
Pinacidil
Diazoxide
Clinical considerations:
diuretics
 Usually well tolerated, relatively cheap,
and work as well as other methods
 They are especially effective in AfricanAmericans
 At initial treatment urinary excretion
increase significantly but after several
days returns close to normal, and BP
remains depressed
Clinical considerations:
angiotensin inhibitors
 Most effective in patients with elevated plasma
renin levels (but this condition is rare)
 Still effective in hypertensive patients with
normal or even low levels of renin
 Useful for treating hypertension associated
with other cardiovascular risk factors, like heart
failure, stroke, myocardial infarctions, diabetes,
and kidney disease
Clinical considerations:
SNS drugs
 The long-term decrease in CO is usually most
responsible for lowering BP
 For some patients CO returns to normal as TPR
decreases  decreased BP continues
 β–blockers also inhibit renin release which contributes
significantly to decreased BP, especially if renin levels
are elevated
 Effect on two different systems causes β–blockers to
often be used in combination with other
antihypertensives (direct vasodilators, α1 adrenergic
receptor blockers) because get three types of effects
with only two drugs
 β–blockers may also counteract reflex compensatory
responses (that increase CO) caused by these other
drugs
Clinical considerations:
SNS drugs (con’t)
 Peripheral α1 adrenergic receptor
blockers (prazosin, doxazosin) reduce
TPR  may cause fluid retention  may
then need to give diuretics to counteract
Clinical considerations:
2+
Ca channel blockers
 All excitable tissue contains receptors for Ca2+
channel blockers but not all tissue affected
equally
 Dependence of tissue on exogenous Ca2+ dictates
sensitivity to blockers
 High in cardiac tissue (especially AV node), lower in
skeletal muscle
 Some may be contraindicated due to other disease
states or if using specific drugs
 Example - do not use verapamil in cases of heart failure
associated with increased TPR  will slow down an
already poorly pumping heart
 Example - do not use certain β-blockers in combination
with Ca2+ channel blockers in heart failure
Drugs for hypertensive
emergencies
 May have to reduce BP quickly but temporarily
 Unexpected side effects of other drugs
 Side effects of illegal drugs
 Accidental poisoning
 Above may cause severe tachycardia  can
reduce BP (and HR) by i.v. infusion of
nitroprusside
 Full effect in seconds
 Recovery from effect within a few minutes
 Or repeated low-dose i.v. injections of
diazoxide
 Full effect in 1 to 5 minutes
 Recovery within a day
Treatment of Hypertension
and see Table 12-1