HTN-2 Flashcards
Type 4: L-type calcium channels are sensitive to what
dihydropyridine (vascular)
phenylalkylamine (heart)
benzothiazepine (heart and vascular)
Diphydropyrid”INE” medicines
Amlodipine
Nifedipine
Felodipine
Phenylalkyl”AMI”ne
Verapamil
Benzoth”IAZE”pine
Diltiazem
An increase in cytosolic Ca2+ in vascular tissue causes what to smooth muscle
sustained contraction
In cardiac cells Ca2+ bind to what to cause contraction
troponin C
Voltage-gated calcium channels excite what
skeletal, smooth, and cardiac muscle
What do voltage-gated calcium channels regulate
Aldosterone in the adrenal cortex
What do voltage-gated calcium channels conduct
pacemaker signals
dihydropyridine, phenylalkylamine, benzothiazepine have a greater frequency of achieving blood pressure control with Ca2+ channel blockers as monotherapy in what patients
african americans
elderly
What are the adverse effects of dihydropyridine, phenylalkylamine, and benzothiazepine
-invoke baroreceptor reflex-mediated sympathetic discharge, dihydropyridines causing tachycardia
-bradycardia and sinoatrial arrest
-peripheral edema
What does hydralazine cause
tachycardia and tachyphylaxis
Combination therapy with arteriolar vasodilators
beta receptor antagonist, diuretic, vasodiltor
MOA of hydralazine
directly relaxes arteriolar smooth muscle
Reflexes of hydralazine
NE (increase HR and contractility)
Increased plasma renin activity and fluid retention
Pharmacological effects of hydralazine
decrease in vascular resistance in arterioles
Arteriolar vasodilators have low bioavailability ___ in fast acetylators and ___ in slow acetylators
16%
35%
The acetylated compound of arteriolar vasodilators is inactive meaning the dose necessary to produce a systemic effect is ______ in fast acetylators
larger
In what hypertensive emergency do you use hydralazine
pregnant women (preeclampsia)
What are two main adverse effects of hydralazine
Extensions of the pharmacological effects of the drug (palpitations, tachycardia, angina pectoris, myocardial ischemia)
Immunological Reactions: drug-induced lupus syndrome
Is minoxidil a pro-drug
yes
MOA of minoxidil
K+ channel permitting K+ efflux
Pharmacological effects of minoxidil
arteriolar vasodilation
myocardial contractility and in cardiac output
vasodilate renal artery
Treatment uses for minoxidil
severe hypertension
renal insufficienct
children
Major adverse effects of minoxidil
retention of salt and water
cardiovascular effects
myocardial ischemia
beta-adrenergic blocker
hypertrichosis
What is a rare side effect of minoxidil
stevens-johnson syndrome
The influx of calcium can occur through what 4 sites
receptor-operated channels
Na/Ca exchange
Leak pathways
potential dependent channels
Arterial smooth muscle is more or less sensitive to ca2+ channels than venous smooth muscle
more
1,4-DHP are usually hydrophobic or hydrophilic
hydrophobic
What is essential for 1,4-DHP activity
pharmacophoric ring
What is at position 1 of 1,4-DHPs and has to be unsubstituted
nitrogen
What is at position 4 of 1,4-DHPs
aryl substituent (ortho or meta position)
What is the difference between nifedipine and felodipine compared to amlodipine
amlodipine is basic because it has an amine
At physiologic pH verapamil and diltiazem are primarily __________ whereas 1,4-DHPs are primarily ____________
ionized
unionzied
Rapid ester hydrolysis inactivates what drug
clevidipine (inactive metabolite is charge and not lipophilic anymore)
What drug is the only one in its class and is well absorbed from the GI tract and is metabolized in the GI mucosa and in the liver
hydralazine
Minoxidil is not an active hypotensive drug until it is metabolized by hepatic thermolabile _________ _______________ (SULT1A1) to minoxidil N-O-sulfate
phenol sulfotransferase
Hyperglycemic agents work by preventing release of ______ from the pancreas
insulin
What are the medicine indications for African Americans
increased need for combo treatment
lower renin
thiazide and CCB first line option
Geriatric (>75) medicine indications
often isolated SBP
mat need to be more conservative with tx goals especially if orthostatic hypotension, high fall risk, or ADEs
Children medicine indications
lifestyle interventions is key
Goal to reduce BP below <95th percentile (<90 if comorbidities are present)
Indications of orthostatic/postural hypotension
laying or sitting to standing
BP drop in >10 mmHg with dizziness
Titrate slow and avoid volume depletion
Pregnancy chronic hypertension (early onset)
present before pregnancy or within 20 weeks of pregnancy
Gestational hypertension or pregnancy induced hypertension (PIH): early onset
hypertension onset (>140/90)
goes away after delivery
no previous hypertension
Pregnancy late onset HTN: preeclampsia
BP >140/80 with proteinuria after 20 wks gestation
(bed rest , use hydralazine or labetalol in BP >105)
Could use ASA in high risk patients
Pregnancy late onset HTN: eclampsia
Onset of convulsions in preeclampsia
medical emergency
delivery indicated
What are the typical treatments of pregnancy HTN
methyldopa, labetolol, metoprolol, carvedilol
Resistant HTN is difficult to treat. We should max the _________ and then add an aldosterone antagonist as first option
trifecta
Resistant hypertension indications
-failure to achieve BP goal despite adherence to full doses of 3 drug regimen
-volume overload
-use aldosterone antagonists as next option
What is the steps of managing resistant HTN
-Max trifecta
-Add mineralcoricoid receptor antagonist (MRA) spironolactone
-Add beta blocker
-Add hydralazine (vasodilator)
-Sub minoxidil for hydralazine
MOA of beta adrenergic receptor antagonists
reduction in myocardial contractility and heart rate to reduce renin secretion and RAS activity
What does the efficacy of beta-blockers depend on
-lipid solubility and membrane-stabilizing properties
-selectivity for the beta 1 adrenergic receptor subtype
-presence of partial agonist or intrinsic sympathomimetic activity (ISA)
What are the classification of these drugs: nadolol, propranolol, pindolol
1st generation non-selective
What are the classification of these drugs: acebutolol, esmolol, atenolol, metoprolol, bisoprolol
2nd generation beta 1 selective
What are the classification of these drugs: carvedilol and lavetalol
3rd generation non-selective
What are the classification of these drugs: nebivolol
3rd generation beta 1 selective
______ blockers are preferred drugs for patients with myocardial infarction, ischemic heart disease, congestive heart failure
beta
(less response in elderly and african americans)
Contraindications for beta-adrenergic receptor antagonists
contraindication for asthma, SA or AV nodal dysfunction, insulin-dependent diabetes
Sudden discontinuation of beta blockers produce what
rebound hypertension (needs to be slowly backed off)
What are the classification of these drugs: prazosin, doxazosin, terazosin
alpha 1 adrenergic receptor antagonists
What kind of therapy are alpha 1 adrenergic receptor antagonists not used for
monotherapy (need diuretic, beta blocker, etc with it)
alpha 1 adrenergic receptor antagonists are good for hypertensive patients with what but are not used for what
for: benign prostatic hyperplasia
not: pheochromocytoma
major adverse effects of alpha 1 adrenergic receptor antagonists
orthostatic hypotenstion
doxazosin increase risk of CHF if monotherapy (retention of salt and water)
Labetalol has how many isomers
4
Labetalol is _____ antagonist and nonselective _______ antagonist with partial agonist activity
alpha 1
beta
Disadvantage of labetalol
fixed-dose combination products: alpha receptor antagonism is unpredictable and varies
What is labetalol FDA approved for
Eclampsia, preeclampsia, hypertension, hypertensive emergencies (pregnancy)
Carvedilol is a ____ blocker but has ________ receptor antagonist activity
beta
alpha 1
(a1 to B is 1:10)
What is carvedilol used for
hypertension and symptomatic heart failure
MOA of alpha 2 adrenergic receptor agonists (-clonidine catapres)
stimulate a2A receptors in the brainstem and decrease plasma concentrations of NE
What can alpha 2 adrenergic receptor agonists cause
lower arterial pressure
postural hypotension
reduction in HR and SV (cause congestive heart failure)
What are the major adverse effects of alpha 2 adrenergic receptor agonists
symptomatic bradycardia and sinus arrest
sedation and xerostomia
postural hypotension and erectile dysfunction
What kind of sympatholytic agent is methyldopa
centrally acting activator
Methyldopa is a ________ that exerts its antihypertensive action via active metabolite
prodrug
Methyldopa is an __________ at presynaptic alpha2 adrenergic receptors
agonist
Can methyldopa be used in hypertension for pregnacy
yes
Main CNS adverse effect of methyldopa
diminution in psychic energy
NE and EPI are endogenous substrates known as what active substances
catecholamines
What three drugs are antihypertensive quinazoline selective alpha 1 blockers
prazosin
terazosin
doxasosin
Alpha 1 blockers possess a ___________ effect which means that orthtostatic hypotension frequently occurs within the first couple doses of the drug
first-dose
(decreased by increasing dose slowly)
What parts of alpha 1 selective adrenergic blockers are part of the drug class pharmacophore
quinazoline ring (2 rings, one has two nitrogens)
Piperazing ring (ring with 2 nitrogens)
Acyl Moiety
What part of alpha 1 selective adrenergic blockers changes with each drug
acyl moiety (attached to second nitrogen on piperazine)
alpha 1 selective adrenergic blockers block the effect of sympathetic nerves on blood vessels by selectively binding to alpha 1 adrenoceptors located where
vascular smooth muscle
Do alpha blockers dilate both arteries and veins
yes because they are both innervated by the sympathetic adrenergic nerves (used for stress)
Vasodilation via alpha 1 blockers lower peripheral vascular resistance to maintain cardiac output preventing __________ more effectively when compared to BB
bradycardia
How many chiral centers and stereoisomers does carvedilol have
one chiral
2 stereoisomer
How many chiral centers and stereoisomers does labetalol have
2 chiral
4 stereoisomers
Carvedilol has a 10 to 100 fold alpha 1 blocking activity due to the presence of the _________________ amine pharmacophore
aryloxypropanol
What group in labetalol is responsible for its alpha-adrenergic blocking effect
methyl attached to N-arylalkyl
Dilevalol is a ________ isomer which is a mixed non-selective beta-adrenergic receptor blocker and selective alpha 1 blocker
RR
Hypertension is sometimes caused by emotional stress which causes ______ blockers to be effective
beta
When using BB in treating hypertension caused by pheochromocytoma this results in elevated circulating _______________
catecholamines
The first-generation nonselective beta adrenergic blockers all have what two things and have no _______ substituents
aryloxypropanolamine pharmacophore and 2 rings
ortho
The first-generation beta 1 selective adrenergic blockers all have what and what kind of substituents
one ring
para
beta 1 selective adrenergic blockers are characterized by the presence of a substituent at _______ position of the aryloxy ring
para
aryloxypropanolamine BBs are active in the ___ absolute configuration
S
What is the stereochemical nomenclature difference between arylethanolamines and aryloxypropanolamines
aryloxypropanolamines have an extra oxygen atom which changes the absolute configuration to the S stereoisomer
Nebivolol is a cardioselective beta 1 receptor blocker that differs chemically and pharmacologically from other BBs because it has a bis-p-substituted ________________ where the oxymethylene bridge is part of the ring
aryloxypropanolamines
Nebivolol is highly cardioselective at low doses, but at higher doses, it loses its cardioselectivity and block both ______ and ______ receptors
beta 1
beta 2
Nebivolol also acts on the vascular endothelium by stimulating ______________ synthase which induces ____-mediated vasodilation
nitric oxide
NO
Patients with DM, erectile dysfunction, and vascular disease may have abnormal endothelial function, and nebivolol is more effective in these population due to its ____-induced vasodilatory effect
NO
What short-acting cardioselective beta 1 blocker is administered by infusion because it rapidly excretes as a zwitterionic metabolite
esmolol
What makes esmolol susceptible to hydrolysis by serum esterases to inactive metabolite and readily excreted as a zwitterion
methyl ester of a carboxylic acid
The more lipophilic drugs are primarily cleared by the _______ whereas hydrophilic agents are cleared by the _______
liver
kidney
____________ is not cardioselective when taken by patients who are poor CYP2D6 metabolizers
Nebivolol
What amino acid does methyldopa most closely mimic causing the methyldopa to use its carrier to transport it across the BBB
tyrosine
Which two drugs are used alone or in combination with other antihypertensive drugs to manage severe hypertension in patients that fail to respond to therapy with a stage 1 drug
methyldopa
clonidine
____________ is structurally and chemically related to L-DOPA and the catecholamines. Also at physiological pH, it is found under zwitterion form
methyldopa
Methyldopa is unstable in the presence of ___________ agents, and since they are closely related to catecholamines, patients with asthma can experience _________ hypersensitivity reactions
oxidative (pH and light)
sulfite
Steric crowding by the bulky ortho-chlorine groups in clonidine does not permit a __________ conformation of the two rings
coplanar
Methyldopa is transported across the BBB and then is changed in order to produce its effect, what kind of drug is this and why does it do this
prodrug
needs to mimic tyrosine before crossing barrier, also needs to be more lipophilic
