CHAPT 11: ANTIHYPERTENSIVE AGENTS Flashcards
the most common cardiovascular disease
hypertension
sustained arterial hypertension damages blood vessels in what organs?
kidney heart and brain
sustained arterial hypertension damages blood vessels in kidney heart and brain leads to an increased incidence of ___ __ __ __ _
renal failure
coronary disease
heart failure
stroke
dementia
Epidemiologic studies indicate that the risks of damage to
kidney, heart, and brain are directly related to the extent of ?
blood pressure elevation
normal blood pressure
< 120 / 80 mm Hg
BP of hypertension
≥ 140 / 90 mm Hg
Both systolic hypertension and diastolic hypertension are associated with end-organ damage; so-called ___
isolated systolic
hypertension
Patients in whom no specific cause of hypertension can
be found are said to have?
essential or primary hypertension
Patients with a specific etiology are said to have
secondary hypertension
In most cases, elevated blood pressure is associated with an
overall ___ through arterioles,
whereas ___ is usually normal.
increase blood flow, cardiac output
normal regulation of BP
BP = CP X PVR
physiologically, how does BP is maintained by the body?
moment-to-moment regulation of cardiac output and peripheral vascular resistance
book figure 11-1
1. resistance arterioles
2. capacitance venules
3. pump output heart
A fourth anatomic control
site to maintain BP in the body is, __, contributes to ___ by regulating the volume of intravascular fluid.
kidney, maintenance of blood pressure
a reflex mediated by autonomic nerves act in combination with humoral
mechanisms, including the renin-angiotensin-aldosterone system, to coordinate function at these four control sites and to maintain normal blood pressure.
baroreflex
responsible for rapid, moment-to-moment adjustments in blood pressure, such as in transition from a reclining to
an upright posture
baroreflexes
are stimulated by the stretch of the vessel walls brought about by the internal pressure (arterial blood pressure).
carotid baroreceptors
An organ that is primarily responsible
for long-term blood pressure control.
kidney
what happens when there is a reduction in renal perfusion?
it causes intrarenal redistribution of BF and increased reabsorption of salt and water.
decreased pressure in renal arterioles as well as sympathetic neural activity (via β adrenoceptors) stimulates production of ___ which increases production of ___
renin, angiotensin II
angiotensin II causes?
- direct constriction of resistance vessels
- stimulates aldosterone synthesis in adrenal cortex, which increases renal sodium absorption and intravascular BV.
a hormone released by the posterior pituitary gland that has the ability to regulate water reabsorption in the kidney
vasopressin
site of action of reserptine, guanethidine, guanadrel?
sympathetic nerve terminals
site of action of methyldopa, clonidine, guanabenz, guanfacine
vasomotor center
site of action of trimethaphan?
sympathetic ganglia
site of action of aliskiren
inhibits production of renin from angiotensinogen
antihypertensive agents which lower blood pressure by depleting the body of
sodium and reducing blood volume and perhaps by other
mechanisms.
diuretics
antihypertensive agents which lower blood pressure by reducing peripheral vascular resistance, inhibiting cardiac function, and increasing venous pooling in capacitance vessels.
sympathoplegic agents
antihypertensive agents which reduce pressure by relaxing vascular smooth muscle, thus dilating resistance vessels and—to varying degrees—increasing capacitance as well.
direct vasodilators
antihypertensive agents reduce peripheral vascular resistance and (potentially) blood volume.
agents that block production or action of angiotensin
most common adverse effect of diuretics
potassium depletion
drugs that are most effective when used concomitantly with a diuretic
sympathoplagic antihypertensive drugs
an analog of L-dopa and is converted to a-methyldopamine and a-methylepinephrine
methyldopa
where are a-methylnorepinephrine stored?
adrenergic nerve vesicles where is stoichiometrically replaces norepinephrine and is released by nerve
stimulation to interact with postsynaptic adrenoceptors
clonidine binds to a nonadrenoceptor site where this receptor also mediate antihypertensive effects
imidazoline receptor
centrally active antihypertensive drugs that share the central α adrenoceptor-stimulating
effects of clonidine.
guanabenz and guanfacine
was widely used in the past but is now used primarily for hypertension during pregnancy
decreases peripheral vascular resistance, decrease HR and CO
methyldopa
methyldopa enters the brain via what transporter
aromatic amino acid transporter
usual oral dose of methyldopa produces its
maximal antihypertensive effect in what hour
4-6 hours, and the effect can persist for up to 24 hours
most common adverse effect of methyldopa
sedation, particularly at the onset of treatment.
another toxic effect of methyldopa that is mediated by inhibition of dopaminergic mechanism in the hypothalamus, resulting with an increased prolactin secretion that can occur in men and women
lactation
how do you reduce the toxicity of methyldopa
Discontinuation of the drug
drug that reduces blood pressure in the supine position and only rarely causes postural hypotension
clonidine
characteristics of clonidine
- it is lipid soluble (can easily enter the brain from the circulation)
- short half life
- orally, twice a day to maintain smooth BP level
toxicity of clonidine
dry mouth and sedation are common
patients who are at risk for mental depression.
drugs that lower blood pressure by preventing normal physiologic release of norepinephrine from postganglionic sympathetic
neurons.
adrenergic neuron blocking agents
a polar drug that can produce profound sympathoplegia effects in high enough doses that inhibits the release of norepinephrine from sympathetic nerve endings
guanethidine
is transported across the sympathetic nerve membrane by NET and uptake its essential for drugs action. It is concentrated in the transmitter vesicles, where it replaces norepinephrine and causes a gradual depletion of norepinephrine stores in the nerve ending.
guanethidine
half life of guanethidine
5 days
this toxicity is often associated with sympatomatic postural hypotension and hypotension following exercise.
in men, it may be associated with delayed retrograde ejaculation (into the bladder)
commonly causes diarrhea results from increased gastrointestinal motility
can produce hypertensive crisis by releasing catecholamines in patients with pheochromocytoma
Guanethidine
an alkaloid extracted from rauwolfa serpentina and was the first effective drugs used in treatment for hypertension.
reserpine
MOA that blocks VMAT transporter which causes a depletion of norepinephrine, epinephrine, dopamine and serotonin in CNS and PNS
reserpine
is reserpine reversible or irreversible?
irreversible; trace amounts of the drug remain bound to vesicular membranes for many days.
reserpine readily enters the ___ and depletion of cerebral amine causes sedation, mental depression and parkinsonism symptoms
brain
At lower doses used for treatment of mild hypertension, ___ lowers blood pressure by a combination of decreased cardiac
output and decreased peripheral vascular resistance.
reserpine
low dose effect and high dose effect of reserpine
low dose - produces little postural hypotension
high dose - produce sedation, lassitude, nightmares and severe mental depression
some toxic effects of reserpine
patient wish history of depression should not take reserpine
often produces mild diarrhea and GI cramps and increases gastric acid secretion
the prototypical B blocking drug
propranolol
was the first B blocker to be effective in hypertension and ischemic heart disease
propranolol
is propranolol selective or non selective?
nonselective B blockade
metoprolol is extensively metabolized by?
by CYP2D6 with high first pass elimination
Resting bradycardia and a reduction in the heart
rate during exercise are indicators of what drug effect
propranolol’s B-blocking effect
very widely used B blockers that is not extensively metabolized and is excreted primarily in the urine with a half-life of 6 hours
atenolol
toxic effect of propranolol
since it is nonselective, it has effects on both B receptors
B1 - bradycardia, cardiac conduction disease
B2 - patients with asthma, peripheral vascular insufficiency and diabetes
can receive withdrawal syndrome after prolonged regular use ( B blockers should not be discontinued abruptly)
drugs that are cardioselective and the most widely used B blockers in the treatment of hypertension
metoprolol and atenolol
is approximately equipotent to propranolol in inhibiting stimulation of β1 adrenoceptors such as those in the heart but 50- to 100-fold less potent than propranolol in blocking β2 receptors.
metoprolol
nonselective β-receptor antagonists, are not appreciably metabolized and are excreted to a considerable extent
in the urine.
nadolol and carteolol
are β1-selective blockers that are primarily metabolized in the liver but have long half lives.
betaxolol and bisoprolol
are partial agonist B blockers with some intrinsic sympathomimetic activity. they lower BP but are rarely used in hypertension
pindolol, acebutolol and penbutolol
has both B blocking and vasodilating effects.
formulated as a racemix mixture of four isomers
S,S and R,S - inactive isomers
S,R - potent a blocker
R,R - potent B blockers
labetalol
has a 3:1 ratio of β:α antagonism after oral dosing. Blood pressure is lowered by reduction of systemic vascular resistance (via
α blockade)
labetalol
useful in treating the hypertension of pheochromocytoma and hypertensive emergencies
labetalol
similar to labetalol, has a racemix mixture but has different isomers
S- - nonselective B adrenoceptor blocker
S- and R+ - equal a blocking potency
carvedilol
a non selective B adrenoceptor blocker that reduces mortality in patients with heart failure and is
therefore particularly useful in patients with both heart failure and
hypertension.
carvedilol
a β1-selective blocker with vasodilating properties
that are not mediated by α blockade.
Nebivolol
β1-selective blocker that is rapidly metabolized
via hydrolysis by red blood cell esterases. and is administered by intravenous infusion.
Esmolol
3 drugs that produce most of their antihypertensive effects by selectively blocking α1 receptors in arterioles
and venules.
These agents produce less reflex tachycardia when
lowering blood pressure than do nonselective α antagonists such
as phentolamine.
Prazosin, Terazosin and doxazosin
are useful in diagnosis and treatment of pheochromocytoma and in other clinical situations associated with exaggerated release of catecholamines
phentolamine and phenoxybenzamine
oral vasodilators that are used for long term outpatient therapy of hypertension
hydralazine and minoxidil
parenteral vasodilatory which are used to treat hypertensive emergencies: the calcium channel blockers
nitroprusside and fenoldopam
where are nitrates used?
mainly in ischemic heart disease
a hydrazine derivative, dilates arterioles but not
veins. it is more effective when combined with nitrates in heart failure and with both hypertension and heart failure
hydralazine
is hydralazine absorbed and rapidly metabolized by the liver during the first pass?
yes, so that its bioavailability is low (averaging 25%)
characteristics of rapid acetylators
have greater first pass metabolism
lowers BP
less antihypertensive efefct
mechanism of action of vasodilators
release of nitric oxide from drug or endothelium
nitroprusside, hydralazine, nitrates, histamine, acetylcholine
mechanism of action of vasodilators
reduction of calcium influx
verapamil, diltiazem, nifedipine
mechanism of action of vasodilators
hyperpolarization of cell membrane through opening of potassium channels
minoxidil and diazoxide
mechanism of action of vasodilators
activation of dopamine receptors
fenoldopam
common adverse effect of hydralazine
headache, nausea, anorexia, palpitations, sweating and flushing
very efficacious orally active vasodilator. results from the opening of potassium channels in smooth muscle
membranes by minoxidil sulfate, the active metabolite.
minoxidil
active metabolite of minoxidil
minoxidil sulfate
causes rebound hypertension
clonidine
releases NO from endothelial cells to dilate BV
hydralazine
like hydralazine, ____ dilates arterioles but not veins
minoxidil
use of topical minoxidil
to correct baldness
a powerful parenterally administered
vasodilator that is used in treating hypertensive emergencies as
well as severe heart failure.
dilates both arterial and venous vessels. Activates guanylyl cyclase.
sodium nitroprusside
an effective and relatively long-acting potassium channel opener that causes hyperpolarization in smooth muscle
and pancreatic β cells.
diazoxide
a peripheral arteriolar dilator used for hypertensive
emergencies and postoperative hypertension. It acts primarily as an
agonist of dopamine D1 receptors, resulting in dilation of peripheral arteries and natriuresis
fenoldopam
what is natriuresis
secretion of sodium in urine
has the greatest depressant effect on the heart and may
decrease heart rate and cardiac output.
verapamil
family of dihydropyridine
amlodipine, felodipine, isradipine, nicardipine, nifedipine, nisoldipine and nitridipine
agents that are more selective as vasodilators and have less cardiac depressant effect than verapamil and diltiazem
difedipine and other dihydropyridine agents
what acts on angiotensinogen to yield the inactive precursor decapeptide angiotensin I?
Renin
Angiotensin I is primarily converted by ____ to the arterial vasoconstrictor ___
endothelial ACE (kininase II) , Angiotensin II
where does angiotensin III being converted?
in the adrenal gland
what activity does angiotensin II has?
vasoconstrictor and sodium-retention activity
Three classes of drugs that act specifically on the renin-angiotensin system?
ACE inhibitors
Losartan and other non-peptide antagonist
Aliskiren
Drugs that are aldosterone receptor inhibitors
Spironolactone, eplerenone
This class of drugs inhibbit the converting enzyme peptidyl dipeptidase that hydrolyzes angiotensin I to angiotensin II and inactivates bradykinin
Angiotensin-converting enzyme (ACE) inhibitors
a bradykinin B2 receptor antagonist that blunts the blood pressure lowering effect of captopril
Icatibant
An ACE inhibitor oral prodrug that is converted by hydrolysis to converting enzyme inhibitor, enalaprilat
Enalapril
Cleaves kininogen to release bradykinin (a potent vasodilator)
Kallikrein
what inhibits the breakdown of bradykinin to inactive metabolites
ACE inhibitors
Why ACE inhibitors are useful in treating patients with chronic kidney disease?
They diminish proteinuria and stabilize renal function.
Toxicity of ACE inhibitors
Severe hypotension in patients who are taking diuretics
Risk of fetal hypotension, anuria and renal failure for pregnant females during second and third trimester
First marketed blockers of the angiotensin II type (AT1) receptor.
Losartan and valsartan
A more selective blockers of angiotensin effects than ACE inhibitors . And also why?
Angiotensin receptor blocking agents. Because there are enzymes other than ACE that are capable of generating angiotensin II
Are commonly used in patients who have had adverse reaction to ACE inhibitors
Angiotensin receptor blocking agents
Why does combining ACE inhibitor and ARB or aliskiren inhibited?
Though they are useful for complete inhibition of renin-angiotensin system, they are not recommended due to toxicity levels
What is proteinuria
Abnormal amounts of protein in the urine
3 Initial step in treating hypertension may be nonpharmacologic.
Sodium restriction.
Weight reduction
Regular exercise
Reasonable dietary goal (sodium intake) in treating hypotension
70-100 mEq of sodium per day
Underlying pathologic process in malignant hypertension
Progressive arteriopathy with inflammation and necrosis of arterioles
Summary: MOA
Activates a2 adrenoceptors
Clonidine and methyldopa
Summary: MOA
Blocks aldosterone receptor in renal collecting tubule
Spironolactone and eplerenone
Summary: MOA
Selectively blocks a1 adrenoceptors
Prazosin, terazosin, doxazosin
Widely used B1 selective blockers
Metoprolol and atenolol
nonselective prototype B blocker
Propranolol
Summary: MOA
Blocks AT1angiotensin receptors
Losartan
Summary: MOA
Inhibits enzyme activity of renin
Aliskiren
