CV drugs and antihypertensives 53/54/55 Flashcards
anti-HTN:
Diuretics
Beta blockers
Calcium channel blockers
RAAS inhibitors
Antihyperlipidemics
Bile acid binding resins
HMG-CoA reductase inhibitors
Fibrates
Niacin
Antidiabetics
Insulin
Sulfonylureas
Biguanides
Thiazolidinediones
Antianginals
Nitrates
Calcium channel blockers
Beta blockers
Drugs for CHF
Cardiac glycosides Non-glycoside inotropes ACE inhibitors Diuretics Vasodilators Beta blockers
Antiarrhythmics
Sodium channel blockers
Potassium channel blockers
Calcium channel blockers
Beta blockers
Hydrochlorothiazide (Microzide)
thiazide Diuretic
Chlorthalidone (Thalitone)
thiazide Diuretic
Indapamide
thiazide Diuretic
direct dilator action on vascular smooth muscle
lesser propensity to raise serum cholesterol (even though it is longer acting)
Furosemide (Lasix)
loop diuretic
short-acting. Often given two or three times a day
Triamterene (Dyrenium)
K+ sparing diuretic
inhibitor of renal Na+ channels
Spironolactone (Aldactone)
K+ sparing diuretic
competitively block binding of aldosterone
interferes with sex-steroid receptors (non-sp)
Eplerenone (Inspra)
K+ sparing diuretic
competitively block binding of aldosterone
Reserpine
Peripheral Adrenergic Neuron Blocker
Depletes storage of the peripheral neurotransmitter: NE in vesicles of sympathetic nerve endings, thereby reducing amount of NE released with each nerve impulse
dec. both CO and TPR–>dec. BP
* irreversible*: persistent effect, need to make new vesicles
- do not get rebound HTN
used in standard HTN pt: cheap!
Methyldopa
Central Adrenergic Neuron Blocker
prodrug which is converted into methylnorepinephrine
alpha2 adrenergic AGONIST in the central vasomotor centers, dampening sympathetic neural outflow
- dec. in TPR*- main effect
dec. in renin
dec. in CO
HTN during pregnancy
not used as much anymore
Clonidine (Catapres)
Central Adrenergic Neuron Blocker
sim. to Methyldopa, influence CNS imidazoline rec
patch for transdermal absorption: moother BP control with fewer side effects although many show local skin reactions
primary HTN
Prazosin (Minipress)
α1-Adrenergic Receptor Blocker
3x day
more severe first-dose postural hypotension
Doxazosin (Cardura)
α1-Adrenergic Receptor Blocker
1x day
Terazosin (Hytrin)
α1-Adrenergic Receptor Blocker
1x day
important pgs to learn
skip pgs 5-7 (mostly pathology)
know pgs: 11-25
sections 13-23
after: sections 24-34 not as important
36-38: important tables
Propranolol (Inderal-LA)
β1 and 2-Adrenergic Receptor Blocker
Nadolol (Corgard)
β1 and 2-Adrenergic Receptor Blocker
Timolol
β1 and 2-Adrenergic Receptor Blocker
Pindolol
β1 and 2-Adrenergic Receptor Blocker (with ISA)
*partially stimulates B2, so contributes to vasodilation, lowering TPR–>lowering BP
Atenolol (Tenormin)
β1-Adrenergic Receptor Blocker
Metoprolol (Toprol-XL)
β1-Adrenergic Receptor Blocker
Acebutolol (Sectral)
β1-Adrenergic Receptor Blocker
Labetalol (Trandate)
α1/β1,2 Blocker
partial agonist @ B2
BP falls mainly from a decrease in peripheral resistance (due to the alpha block, partial vascular beta-2 stimulation and less renin release) but with some decrease in CO
severe primary HTN (oral) HTN emergency (IV)
Nebivolol (Bystolic)
NO-releasing β1 Blocker
“vasodilating powerhouse” (Also decreases NO degradation)
decrease in BP is due to vasodilator effect (dec. TPR) as well as dec. CO:
β 1 -blocking action decreases renin release, HR and contractility
Increase in endothelial NO dilates vascular smooth muscle
good for HTN pts w. imparied endothelial cell function
good for mild-mod primary HTN
Hydralazine
Direct Arteriolar Dilator
release NO from arteriole endothelium–>vasodilate–>dec. TPR
partly inactivated by acetylation in the liver: “rapid” acetylators in the population show much smaller drug effects than “slow” acetylators (adjust dosing)
added as 3rd drug if not responding to diuretic and 2nd drug (i.e. B-blocker), but being used less due to SEs
SE: lupus-like rxn (also edema described elsewhere)
Minoxidil
Direct Arteriolar Dilator
opens ATP-sensitive K+ channels in arteriolar smooth muscle cells (via active sulfate metabolite)
added as 3rd drug if not responding to diuretic and 2nd drug (i.e. B-blocker), but being used less due to SEs
use for severe HTN
esp. effective treating renal insufficiency (good renal arteriolar dilator)
SE: hair growth (also edema described elsewhere)
Verapamil (Calan)
Calcium Channel Blocker (CCB)
-block in heart
older: short acting (3x/day)
Diltiazem (Cardizem)
Calcium Channel Blocker (CCB)
-block in heart
older: short acting (3x/day)
SEs: nausea, headache
directly suppressed heart rate and A-V conduction
Nifedipine (Procardia - XL)
Calcium Channel Blocker (CCB)
-block in vasculature
older: short acting (3x/day), original prototype, pts were dying from rapid effects
* tx for primary pulmonary HTN*
Felodipine
Calcium Channel Blocker (CCB)
-block in vasculature
longer-acting with slow onset (safer)
Amlodipine (Norvasc)
Calcium Channel Blocker (CCB)
-block in vasculature
only “dipine” not effected/enhanced by grapefruit juice (metabolism in liver)
longer-acting with slow onset (safer)
Captopril (Capoten)
ACE Inhibitor
prototype ACE inhibitor (NOT prodrug)
SEs: sulfydryl group: rash, loss of taste, and possibly (though seldom) some renal abnormalities causing loss of protein in urine.
Enalapril (Vasotec)
ACE Inhibitor
prodrug that is activated by deesterification to enalaprilat (need adequate liver function)
Lisinopril (Prinivil, Zestril)
ACE Inhibitor
active derivative to enalaprilat (NOT prodrug)
Fosinopril (Monopril)
ACE Inhibitor
long-acting, prodrug activated primarily by *liver
“smartdrug”:
Active liver metabolite which has balanced route of elimination which shifts toward liver if the kidneys are damaged (useful in HTN pts with renal insufficiency)
Quinapril (Accupril)
ACE Inhibitor
long-acting, prodrug activated primarily by *liver
Ramipril (Altace)
ACE Inhibitor
long-acting, prodrug activated primarily by *liver
Losartan (Cozaar)
Angiotensin II Receptor Blocker (ARB)
Valsartan (Diovan)
Angiotensin II Receptor Blocker (ARB)
Candesartan (Atacand)
Angiotensin II Receptor Blocker (ARB)
Aliskiren (Tekturna)
Renin Inhibitor
HTN def
sustained systemic arterial blood pressure (BP) levels above 140/90 mmHg (systolic/diastolic)
>1 reading
Isolated systolic hypertension (ISH), usually seen over age 65, is defined by some as a systolic blood pressure (SBP) > 160.
(mostly concerned with large arteries, capillaries and veins also involved)
?? may be the most popular drugs for therapy of chronic primary hypertension
Thiazides and thiazide-like drugs (e.g. hydrochlorothiazide, chlorthalidone, indapamide)
indapamide with a lesser propensity to raise serum cholesterol
thiazide diuretic mechanism in HTN
In lowering BP, initially diuretics induce a natriuresis which shrinks blood volume thus reducing cardiac output (within 2-3 days).
[This activates mechanisms responsible for maintenance of fluid volume, particularly (RAAS) which may then limit the degree of volume reduction and the degree of ↓ BP]. –>tends to eventually return to normal
Continued diuretic use leads to a fall in TPR (and return of cardiac output toward normal, within 6-8 weeks), which is the reason for continued antiHTN effect. This may be due to an autoregulatory phenomenon and/or to direct relaxant actions of the drugs on vascular smooth muscle (indapamide may do the latter via calcium channel blockade)- direct dilator action (as well as inhib. Na+ retention)
autoregulatory phenomenon
decreased perfusion leading to vasodilation
thiazides have ??? on BP and blood chemistry
flat dose response curve
i. e. increasing dose does not significantly increase therapeutic response
- typically good enough for mild hypertensive pts
HTN pts may have
high-normal or
low-normal renin
why would it be low?
tx these pts with what ??
it is suppressed
makes sense to tx these high volume pts with diuretics (“volume dependent” HTN)
i.e. elderly, Afr. Americans
Resistance to thiazides
Overly vigorous diuretic therapy may activate the RAAS excessively–>pressure-raising mechs
-vasoconstrictive effect of angiotensin and aldosterone-mediated exchange of K for Na (tending to retain Na and waste more K)
overwhelming load of dietary Na or an intrinsically impaired renal capacity to excrete Na to begin with
the reduction in BP by direct vasodilation–>inc. hydrostatic press–>edema
may lead to intense Na retention, mandating use of additional diuretic
Thiazide SEs
Hypokalemia: K+ wasting
–>ventricular ectopic activity, sudden cardiac death
Hypercholesterolemia (be careful in high cholesterol pts)
Glucose Intolerance with hyperglycemia (be careful with DM pts)
how to minimized hypokalemia from thiazides
use of small doses and/or use of only moderately long-acting diuretics rather than very long-acting ones
combine K+ sparers with the diuretic and/or add drugs that suppress the RAAS.
reduce dietary Na+ intake and increase dietary K+ intake
loop diuretic: Furosemide
loop diuretics may exert a natriuretic effect near 25 percent of the filtered Na load (much more than thiazide diuretics) by blocking NaCl reabsorption in the thick ascending limb of the loop of Henle
better for v. low GFR and severe edema
indicated for patients with reduced renal Na excretory function
Reserpine SEs
sedation, migraine and mental depression: depletes NT; deplete serotonin (does get into brain!)
postural hypotensive symptoms (deplete NE in vasc. smooth musc)
bradycardia (deplete NE in SA node)
systemic fluid retention
nasal congestion
GI: PUD, diarrhea (unopp. parasymps)
Methyldopa SEs
peripheral fluid retention
and centrally-mediated sedation and dry mouth.
"autoimmune" disorders and may cause parkinsonian signs (possibly due to accumulation of methyldopamine in CNS dopamine neurons) not seen with the other central alpha2 drugs.
surprisingly not much postural hypotension
not much rebound HTN as it is a pro-drug, so active form takes time to disappear
clonidine SEs
patch may cause local skin reactions
rebound hypertension may occur (though less with patch vs. oral drug)
a1-adrenergic receptor blockers:
doxazosin, prazosin and terazosin
Blockade of arterial vascular alpha1- receptors competitively inhibits binding of sympathetically-released NE–>dec. vasoconstriction–>dec. TPR–>dec. BP
primary HTN
affects vv as well as aa (some dec. in CO as well)
may improve glucose tolerance (but don’t want to use in pts with autonomic neuropathy–>impaired postural reflex)
lower cholesterol and triglyceride levels, increase HDL
a1-adrenergic receptor blocker SEs
severe first-dose postural hypotension
postural dizziness
stress-induced urinary incontinence (esp. old ladies)
Reflex tachycardia and systemic fluid retention (less than other vasodilating drugs)
B-blockers reduce BP how ??
B1 action:
reduce CO (↓ contractility and possibly by ↓ HR)
inhibit the release of renin from the renal JG cells
non-selective (B1 and B2) blockers
remove the normal physiologic level of beta2-mediated vasodilation
tends to offset the decrease in total peripheral vascular resistance expected from the inhibition of renin release, thus limiting the overall antihypertensive effectiveness
but work well, so still used
metabolism of B-blockers
more lipid soluble–>metabolized by liver and more enters brain
less lipid soluble–>excreted thru kidney, less enters brain (less CNS effects, better pt compliance)
B blockers won’t work as well in ??
useful in pts with ??
elderly and African- American patients
pts with lower plasma renin
Chinese pts are MORE sensitive
HTN associated with tachycardia and high CO
HTN accompanied by other cardiovascular conditions which can also be tx with B-blockers: e.g. angina, arrhythmia
B-blocker CV SEs
less SEs with partial agonist activity (ISA)
bradycardia (if little/no ISA) -20% lower!
reduced exercise ability and easier fatigue
slow A-V conduction and suppress ventricular contractility too much
Rebound HTN
B-blocker pulmonary SEs
less SEs with partial agonist activity (ISA) and with selective B1 blockers
Bronchoconstriction
inhibition of airway β2 receptors (Especially a problem in patients who need to inhale beta2-agonists to maintain open airways) (try to chose a more selective B1 blocker for these pts)
B-blocker metabolic SEs
less SEs with partial agonist activity (ISA) and selective B1 blockers
insulin-induced hypoglycemia may be longer in duration and/or more severe in the presence of especially nonselective beta-blockers without ISA
ALL B-blockers mask an important warning sign of such hypoglycemia, i.e. tachycardia (sweating still occurs)
aggravate insulin resistance with glucose intolerance
Hypertriglyceridemia and a fall in HDL-cholesterol
B-blocker central SEs
Bad dreams, even hallucinations
-much less likely with lipid insoluble agents
combined a1/B adrenergic receptor blocker (Labetalol) SEs
a-blockade:
postural dizziness which B- blockade can not correct
B-blockage:
bradycardia
A-V block at high doses Obviously, little chance of reflex tachycardia otherwise expected with regular alpha-1 blockers!
NO-releasing B1 receptor blocker (Nebivolol) SEs
Similar to other β 1 -blockers though less rebound HTN upon sudden complete withdrawal
headache and fatigue (FYI- due to inc. NO in cerebral blood vessels (paradoxical?))
selective arteriolar vasodilators:
(Hydralazine, Minoxidil) major SE
if taken ALONE: markedly dilate resistance arterioles leading to ↑ capillary hydrostatic pressure with ↑ filtration of fluid into the interstitial spaces (edema) plus renal retention of Na and H2O
fall in arterial BP markedly activates sympathetic and renal compensatory reactions causing considerable release of catecholamines and renin resulting in stimulation of the heart and much more retention of Na and water
use with B-blocker and diuretic to inhibit compensatory reactions
don’t effect vv as much, so little postural hypotension
CCBs that end in “dipine” block Ca2+ channels in the ??
vasculature
*not pure distinction, some crossover at high doses
dihydropyridine (“dipines”) CCB actions
reduce calcium entry into arterial vascular smooth muscle cells through arterial L-type calcium channels
–>decrease in free intracellular calcium –>reduces arterial vascular tone–>dec. TPR and BP
(little suppressive effect upon ventricular contractility at
standard therapeutic doses)
intrinsic natriuretic capability (not as much edema)
Diltiazem and verapamil actions
↓ calcium entry through ventricular L-type calcium channels–>reduces ventricular contractility–>suppresses CO
May be some ↓ in HR and some ↓
arterial tone, via inhibition of similar channels in cardiac SA node and arterial smooth
muscle
CCBs are used for ??
particularly useful for ??
virtually all types of primary systemic hypertension (versatile)
elderly and African-American hypertensive patients
also work well in the face of high Na intake, irrespective of the degree of Na sensitivity.
dihydropyridine CCB SEs
reflexively (indirectly) increased heart rate due to peripheral vasodilation–>increased risk MI (incr. sympathetic activity)
nausea, headache, tachycardia, slight postural dizziness, ankle edema
Verapamil SEs
nausea, headache, constipation
directly suppressed heart rate and A-V conduction
(verapamil > diltiazem)
serious myocardial depression like excessive bradycardia and excessive A-V nodal dysfunction
ACE inhibitors end in ??
action ??
“pril”
inhibit production of the active form of angiotensin (angiotensin II)
inactivates the vasodepressor hormone bradykinin
–>increase availability of bradykinin and related PG vasodilators which can further ↓ BP by ↓ TPR
ACE inhibitors are eliminated primarily by the ??; dose should be reduced in patients with ??
kidneys
renal insufficiency
(also note the prodrugs are metabolized/activated by the liver)
MOA of RAAS inhibitors:
Renin inhibitors (prevent angiontensinogen–>AngI)
ACE inhibitors
ARBs
Ang-II mediated vasoconstriction is obviously overcome and TPR and BP then falls
A-II mediated synthesis of aldosterone is inhibited, thereby Na and H2O retention potentially reduced
also inhibits positive feedback of RAAS
good candidates for of RAAS inhibitors
“normal renin” as well as in “high renin” patients with primary HTN and/or with diuretic-induced renin-related resistance
HTN secondary to diabetic nephropathy
pts who should not get RAAS inhibitors
patients with fully established bilateral (efferent and afferent) renovascular hypertension (GFR is very low) , wherein abnormally “super” high levels of A-II keep renal GFR from falling too low beyond the stenoses by constricting the efferent arterioles; these patients may experience more loss of GFR with these drugs
(still sometimes used in these pts because of v. high systemic HTN)
AngII is more effective at vasoconstricting the ?? arterioles
efferent (vs. afferent)
therefore RAAS inhibitors decrease GFR by preventing efferent vasoconstriction
RAAS inhibitor SEs:
higher bradykinin levels with ACE inhibitors (less with ARBs or the renin inhibitor), may cause ??
nonproductive cough
Angioedema: localized, potentially fatal (asphyxiation)
RAAS inhibitor SEs
hyperkalemia (may become worse with addition of a K-sparing diuretic or K supplements)
too much hypotension
teratogenic!!
hepatotoxicity
??These drugs?? may impair the antihypertensive effects of ACE inhibitors by blocking ??
NSAIDs
bradykinin-mediated vasodilation because it is, at least in part, prostaglandin mediated
CASE: middle-aged male, HTN, start on diuretic hydrochlorothiazide (25mg: intermediate dose)
- adequately maintained
- comes in few mos later with severe hypokalemia, what is next most appropriate step??
a. lowering dose of hydrochlorothiazide
b. add on captopril (ACE inhib)
c. add on K+ sparing diuretic
d. add on other powerful diuretic
a. NO: would increase BP
b. NO: while it would raise the K+, it would lower BP too much (he is currently adequately controlled)
c. YES: would raise K+ without affecting BP much (these are weak diuretics, less effect on BP)
d. NO: would lower BP too much (remember: he is adequately controlled)
