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951: Hypertension
N/A
283
Pharmacology
Professional
08/25/2012

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Cards

Term
Definition of HTN and 2 stages
Definition
SBP > 140 and/or DBP > 90

Must be measured on multiple occasions

Stage 1: 140-159/90-99

Stage 2: 160+/100+
Term
In who does Isolated Systolic Hypertension most often occur?
Definition
Elderly (> 60 years)
Term
What is hypertensive crisis?
Definition
aka malignant hypertension

DBP > 110
accompanied by acute organ injury: stroke, HF, MI, aneurysm
Term
What are some symptoms of hypertension?
Definition
mood changes, dizziness, HA, decreased overall well-being
Term
Factors that can attribute to essential (primary) HTN
Definition
Genetic:
Dyslipidemia
Diabetes/elevated fasting glucose (>110)
Obesity
Age >55 (men) and 65 (women)
Family Hx of premature CV disease (<55 [M] and <65 [W])
Low GFR (<60 ml/min) or elevated urinary protein

Environmental:
Stress
Smoking
Inactivity
Obstructive sleep apnea
Diet: high Na
Excessive EtOH consumption
Term
What percentage of people with HTN are uncontrolled?
Definition
50%

30% of US population has HTN and 25% of those don't even know it
Term
What ethnicity has the highest proportion of HTN?
Definition
Blacks

they also progress faster once diagnosed
Term
Is HTN more prevalent in men or women?
Definition
Men, up until menopause
Term
What are 3 types of primary HTN?
Definition
Moderate/High renin: Most common; treat with RAS drugs and diuretics

Low renin: more common in blacks and elderly; treat with diuretics, CCB, beta-blockers

Resistant: requires 3+ drugs
Term
Effects of HTN (what it can lead to)
Definition
Stroke
CHF
CAD, angina, MI
Renal failure
PAD
Aneurysm
Retinopathy
Erectile dysfunction
Term
Classification of pre-hypertension
Definition
SBP: 120-139
or
DBP: 80-89
Term
Causes of secondary HTN
Definition
1. Renal/vascular:
renovascular stenosis
renal parenchymal disease (renal disease activates the RAS since translated as insufficient BP)
aortic coarction (narrowing of aorta)

2. Endocrine:
primary aldosteronism (Conn's disease) [MOST COMMON]
hyperadrenalism (Cushing's)/pheochromocytoma (glucocorticoid secreting tumor)
Hyperthyroidism
Pregnancy (self-limiting)

3. Medications:
OC - esp if overweight, smoker, black (HRT not a problem)
Corticosteroids
Amphetamines/appetite suppressants
MOAIs
Anti-depressants (venlafaxine)
Licorice (candy doesnt have true licorice in it)
Term
What physiological factors determine blood pressure?
Definition
1. CO
2. TPR

BP = CO x TPR

NOTE: CO = SV x HR
Term
What is the major physiological determinant of DBP?
Definition
TPR - sum of all vascular resistance of each organ
Term
In hypertension what physiological factor/contributor typically increases?
Definition
TPR is increased (while CO usually remains constant)

NOTE: in developing HTN, CO and HR are usually elevated, but over time CO becomes normal and TPR increases
Term
What are three BP control mechanisms?
Definition
1. Rapid: nervous system mediated (baroreceptor reflex)

2. Intermediate acting: circulating vasoactive agents (angiotensin)

3. Long acting: changes in blood volume (renal function)
Term
Which receptors in the kidney, when stimulated, trigger release of renin
Definition
beta (1) receptors

(why you can use a beta-blocker to control HTN)
Term
RAS order
Definition
beta receptor stimulation trigger the release of RENIN (from granular cells of JGA)

RENIN converts circulating ANGIOTENSINOGEN (from liver) to ANGIOTENSIN I

ANG I is converted to ANG II via ACE (in vasculature - thought to primarily occur in lungs)

ANG II controls BP and causes release of ALDOSTERONE

ALDOSTERONE is the ultimate regulator
Term
Actions of Ang II
Definition
1. potent vasoconstrictor
2. stimulates release of aldosterone (for adrenal gland)
Term
Renal mechanism of blood pressure control
Definition
controls ECF and blood volume

Decrease in BP or BV decrease GFR
-triggers kidney to retain Na and water to restore BV, GFR, renal perfusion pressure, and BP
-renin is released -->RAS mech -->ADH release, vasoconstriction, thirst, and ALDOSTERONE RELEASE (promotes Na retention)
Term
Release of ADH can be triggered by what?
Definition
1. Osmolarity of blood (osmoreceptors in hypothalamus)
2. Decreased blood volume (measured in kidney) [RAS system]
Term
Release of aldosterone is triggered by what?
Definition
1. Ang II
2. Hyponatremia
3. Hyperkalemia

From zona glomerulosa of adrenal contex (outermost)
Term
Actions of aldosterone
Definition
Retention of Na -->promotes water reabsorption (increase volume)
Term
What plays the most important role in controlling Na excretion and fluid volume
Definition
Aldosterone
Term
T or F: all essential HTN can be viewed as reno-vascular dysfunction
Definition
T: for HTN to persist, kidneys must fail to compensate for the elevated BP or volume expansion

NOTE: effective therapy requires renal function to be addressed
Term
What is first line treatment for HTN
Definition
diuretic (thiazide)
Term
T or F: Chronic Kidney Disease (CKD) is prevalent in pre-HTN
Definition
T: direct relationship between CKD and increasing HTN

GFR < 60 ml/min or urinary albumin:creatine >30 mg/g (macroalbuminuria)
Term
T or F: HTN is the result of neurological and renal mechanisms
Definition
T
Term
What is the genetic polymorphism associated with HTN
Definition
variants of STK39 (serine/threonine kinase)

Phosphorylates Na/K/2Cl (loop) and Na/Cl (thiazides) pumps

3.3 mmHg if heterozygous and 6.6 mmHg increase if homozygous
Term
Non-pharmacologic therapy for HTN
Definition
1. Weight reduction (upto 20 mmHg for 10 kg)
2. DASH diet (upto 14 mmHg)
3. K+ supplementation
4. Vit D supplementation: 800 IU + Ca
5. Magnesium supplementation: >270 mg/d (3-4 mmHg)
6. Aerobic exercise (up to 10 mmHg)
7. Na restriction: about 1/2 hypertensives are salt-sensitive (esp blacks) - recommended <4g/d, <3g/d if over 70 [Na increases vasoconstriction (SNS) NOT volume expansion]
8. EtOH restriction: moderation
Term
Common drugs for the treatment of HTN
Definition
Diuretics: first line (thiazides first)
CCB: more effective than beta-blockers and RAS drugs in LOW RENIN HTN (elderly/blacks)
RAS: becoming more popular (dont use with beta-blockers); preferred in diabetics
beta-blockers: vasodilating beta-blockers becoming preferred; preferred over diuretics in post-MI patients (but can increase chance of DM)
Term
Drugs not recommended for routine use
Definition
1. Vasodilators: hydralazine, minoxidil (use when diuretics, BB, ACEIs ineffective) 2. alpha-1-antagonists: doxazosin (ADRs big issue - orthostatic hypotension, fluid retention 3. Central sympatholytics/alpha-2-agonists: clonidine, guanfacine (CNS ADRs: sedation, depression, sexual dysfunction; best with a diuretic, can sub for beta-blockers) 4. Minor sympatholytics: guanadrel, reserpine (minor orthostatic hypotension, sexual dysfunction, volume expansion; Reserpine = sledgehammer ADRs)
Term
What makes up the ultra-fitration barrier of the glomerulus?
Definition
Basement membrane and vascular endothelial

prevents passage of blood cells and proteins
Term
Blood flow of kidney
Definition
Afferent arterioles (from renal cortex)
Glomerulus (Bowman's capsule)
Efferent arteriole
Peritubular capillaries (surround loop of Henle and allow for reabsorption)
Renal venule
Term
What gets reabsorbed at the proximal tubule
Definition
Active:
1. Glucose (100%)
2. AA (100%)
3. K, Ca, phosphate, bicarbonate, uric acid (>90%)
4. Na (>66%)

Passive reabsorption: Cl, water, urea
Term
What gets actively secreted at the proximal tubule and why is it significant to HTN?
Definition
organic acids and bases (exchange H+ or Na+)

Diuretics get secreted here; this is crucial because they must be in the the tubule to illicit their action.
Term
What diuretics are active at the proximal tubule?
Definition
1. carbonic anhydrase inhibitors
2. osmotic diuretics (active throughout the tubule)
Term
What are the osmotic diuretics?
Definition
Mannitol
Glycerin
Isosorbide
Term
What are some carbonic anhydrase inhibitors
Definition
acetazolamide (Diamox)
dichlorphenamide (Daranide)
methazolamide (Neptazane)
Term
How is sodium and water treated in the Loop of Henle?
Definition
Descending: both flow readily in/out via passive diffusion (water flows out and Na flows in in accordance with concentration gradients)

(Thick) Ascending Loop:
-impermeable to water
Na/K/2Cl transporter = all pumped out of tubule (25% Na recovery)
Term
Examples of loop diuretics
Definition
Furosemide
Ethacrynic acid (Edecrin)
Bumetanide (Bumex)
Toresemide (Demadex)
Term
What sodium transporter is unique to distal tubules/CD
Definition
Na/Cl transporter
Term
What can alter water movement in the distal tubules/CD
Definition
ADH - causes formation of aquaporins (facilitate water reabsorption)
Term
Diuretics that act on distal tubule
Definition
Thiazides (Na/Cl transporter)

K+-Sparing Diuretics (work on CD too)
Term
Potassium sparing diuretics should always be used with another diuretic
Definition
True - very weak, but prevent potassium loss (dont need to be on potassium supp too)
Term
Examples of thiazide diuretics
Definition
HCTZ (Hydrodiuril)
Chlortalidone (Hygroton)
Indapamide (Lozol)
Term
Examples of potassium-sparing diuretics
Definition
Triamterene (Dyrenium)
Amiloride (Midamor)
Eplerenone (Inspra)
Term
What two diuretics directly antagonize aldosterone?
Definition
Spironolactone (Aldactone)
Eplerenone (Inspra)
Term
Action of aldosterone
Definition
Promotes Na reabsorption in late distal tubule and collecting duct

HOW...
K is exchanged Na
Na retention promotes water reabsorption (causes increased BP/blood volume)
Promotes K+ Loss
Term
What is the primary regulator of aldosterone?
Definition
Ang II
Term
What regulates aldosterone release
Definition
ANG II
decreased blood pressure (which will also stim ANG II release)
Decreased Na
Increased K
Term
Diuretic response of osmotic diuretics
Definition
BIG increase in urine flow with little increase in salt excretion = water diuresis

response proportional to dosage

Reduces ECF voluem (edema) and aqueous humor volume/pressure (glaucoma)
Term
When would you use an osmotic diuretic?
Definition
NOT for HTN, emergency use

1. Shock: hypotension causes peripheral pooling of fluids and oliguria (will restore urine flow/decrease edema)

2. Brain edema/trauma

3. Rhabdomyolysis (crush injuries release myoglobin - clog glomerulus)

**Critical to maintain urine flow or kidneys will die**
Term
ADR of osmotic diuretics
Definition
Immediate EXPANSION of ECF and vascular volume - can further stress cardiac decompensation (risk for pulmonary edema especially if HF)

Mild hyperkalemia and/or hypernatremia (big loss in fluid without proportional loss of ions)

Common: HA, N/V
Term
MOA of osmotic diuretics
Definition
Distribute through ECF: water moves out of cells (diffusion) -->causes an immediate expansion of ECF -->increases renal blood flow

Na excretion is slightly increased due to increased fluid volume in tubule (pulls Na out of medullary interstitium)
-because decreased tonicity in peritubular capillaries, less water is pulled out of tubule (reabsorbed)
-increased excretion of all electrolytes b/c water cant be reabsorbed

Initially extracellular electrolyte content is NOT decreased (hypernatremia/hyperkalemia)
Term
Which osmotic diuretic is only given IV?
Definition
Mannitol - used in hospitals primarily
Term
Which osmotic diuretics are orally administered?
Definition
Glycerin and isosorbide
Term
Which osmotic diuretic can cause hyperglycemia?
Definition
Glycerin
Term
What are some uses for osmotic diuretics?
Definition
NOT HYPERTENSION

1. Shock (hypotensive): fixes the peripheral pooling of fluids and oligouria (restores urine flow)
2. Brain edema from trauma
3. Rhabdomyolysis (from crush injuries) - helps maintain urine flow
Term
Which diuretic is self-limiting?
Definition
Carbonic anhydrase inhibitors

Stimulate HCO3- secretion (pair with Na) by preventing CA from making water and CO2 from H2CO3

Once no more base, action is very limited.
Term
What are the carbonic anhydrase inhibitors (PO)
Definition
acetazolamide (Diamox)
dichlorphenamide (Daranide)
methazolamide (Neptazane)
Term
Clinical uses of carbonic anhydrase inhibitors?
Definition
1. Open-angle glaucoma
2. Altitude sickness (counteracts resportory alkalosis) - best if prophylaxis
3. Alkalinization of urine in OD (barbiturate, ASA, myoglobinuria)
4. Refractory CHF: when hospitalized patients develop "contraction alkalosis" from over diuresis (thiazides + loop)
Term
Actions and Adverse Effects of CA Inhibitors
Definition
Excessive bicarbonate excretion: self limiting, acidosis
Increased excretion of Na, K, HCO3 (K+ loss can be significant)

CNS: paresthesias, drowsiness/fatigue, depression

Acetazolamide is shorter acting than methazolamide
Term
3 people who CA inhibitors are CI?
Definition
Pregnancy - teratogenic
Hepatic cirrosis - ammonia excretion is decreased
Severe COPD - will worsen respiratory acidosis
Term
T or F: all thiazides are therapeutically equivalent?
Definition
F - different potencies
Term
MOA of thiazides
Definition
blocks Na/Cl transporter in early distal tubule

Modest diuretic effect - because 90% of Na is reabsorbed before reaching distal tubule

Increased Na in CD results in K exchange and concommitant loss of K
Term
Therapeutic uses of Thiazides
Definition
1. First line for HTN

2. Edema: CHF, hepatic cirrhosis, renal (glomerulonephritis, chronic RF, nephrotic syndrome)
-most diuretics are ineffective with low GFR (<40 ml/min) because must get into urine to be effective

3. Diabetes insipidus

4. Kidney stones: because decrease Ca excretion by unknown MOA
Term
How many mmHg does a thiazide usually lower BP?
Definition
~15-20 mmHg
Term
thiazides in diabetes insipidus
Definition
(ADH insensitivity)

causes hyponatremia -->increases Na and water reabsorption in proximal tubule and loop of Henle--> less water reaches distal tubule-->decreased urine volume (up to 50% decrease)
Term
What are kidney stones usually composed of?

What minerals/vitamins can decrease the incidence of kidney stones?
Definition
oxalate (big issue) and calcium

intake of K, citrate, and Mg can reduce incidence
Term
Thiazides effects on aldosterone production
Definition
The decreased ECF volume caused by thiazide stimulates aldosterone secretion. Aldosterone promotes synthesis of Na/K exchange transporter

This decrease in K is usually small and can be controlled by diet/supplementation
Term
What are the overall changes in ions normally excreted renally?
Definition
Increased excretion of Na, K, Mg (unknown MOA)

Decreased excretion of Ca (indirectly due to decreased ECF volume), uric acid (competition for organic transporter in proximal tubule with actual drug)
Term
Examples of thiazides diuretics?
Definition
Chlorthiazide (Diuril)
HCTZ (Hydrodiuril)
Hydroflumethiazide (Saluron)
Methychlorthiazide (Enduron)
Polythiazide (Renese)
Chlorthalidone (Hygroton)
Indapamide (Lozol)
Metolazone (Mykrox)
Term
When does hypokalemia with thiazide diuretics become an issue?
Definition
patients with ventricular arrhythmias

-Quinidine (anti-arrhythmic) can cause torsades de points which is aggrevated by K depletion
-Mg deficiency increases risk

Liver cirrhosis, HF (patient on cardiac glycosides)

SHOULD GIVE WTIH K+ SUPP OR K+ SPARING DIURETICS
Term
Adverse effects of thiazides
Definition
Hypokalemia
Hyperglycemia (possibly causes new onset DM)
Hyperlipidemia (modest increase)
Hyperuricemia (issue only if have gout) - gout attacks may occur more frequently
Hypomagnesia: more common in elderly

Contraindicated if have sulfonamide allergy
Term
Thiazides and New Onset Diabetes
Definition
Controversial

-can cause hyperglycemia
-K+ depletion thought to play a role by decreasing insulin secretion and sensitivity (dr. should establish baseline K levels for patient) --- other studies oppose this
-Overall, no increase in incidence of CV disease (ultimate issue with DM)
Term
Comparison of thiazides (ADME)
Definition
Different potencies - baseline is HCTZ (=1)
-Chlorothiazide is least potent (0.1)
-Others are 20-25x's the potency of HCTZ

HCTZ - short half-life [2.5 hr] (chlorthalidone has same potency, but much longer half-life)

More longer acting = more lipid soluble = bigger volumes of distribution

All renal clearance except newer agents (Indapamide, Methychlothiazide)
Term
Chlorthalidone versus HCTZ
Definition
Chlortalidone has:
-Longer half-life: QD versus HCTZ which can be BID
-Better inhibitor of carbonic anhydrase: possible benefit in platelet aggregation, angiogenesis
Term
What other drugs can HCTZ be found in combo with?
Definition
ACE inhibitors (ex: lisiinpril, benazepril) - good in very elderly

Potassium-sparing diuretics (ex: triamterene)

ARBs (losartan)

Tribenzor: HCTZ, ARB, CCB
Term
Examples of loop diuretics
Definition
aka high ceiling diuretics

Furosemide (Lasix)
Ethacrynic Acid (Edecrin)
Bumetanide (Bumex)
Torsemide (Demadex)
Term
Uses of Loop diuretics
Definition
1. Edema (cardiac, hepatic, renal)
2. Pulmonary edema: venodilation decreases left ventricular filling pressure
3. Hypercalcemia
4. HTN (if unresponsive to thiazides)
5. Renal failure: acute or chronic) - potent diuresis to maintain urine flow
Term
MOA of loop diuretics
Definition
block Na/K/2Cl uptake in thick ascending loop of Henle

overall increased excretion of Na (K, and Cl) and therefore water

~25% of Na is usually reabsorbed in Loop of Henle

Less Na in late distal tubule and CD means less K and Na exchange (where Na would normally be secreted into tubule and K would be saved from excretion) BUT less Na = decreased ECF volume -->aldosterone synthesis
Aldosterone causes increases in the K/Na exchanger is late tubule = more K is lost

Increased excretion of: Ca, Mg, H
Term
What is the overall ion loss with loop diuretics
Definition
Loss of:
Na
K
Ca
Mg
H
Term
Why is H+ excretion increased with loop diuretics?
Definition
Distal tubule has an H/Na exchanger tries to save some of the Na from being excreted by exchanging with H --> can cause mild alkalosis -less likely with furosemide - has weak ability to inhibit carbonic anhydrase and promote HCO3- elimination
Term
Affect of loop diuretics on macula densa signaling
Definition
Loop diuretics block Na uptake into macula densa

Effects: GFR is not reduced (even though sig loss of Na), Renin secretion is NOT suppressed (so aldosterone cant be suppressed this way)

-Appears to involve increased PGI/E2 synthesis
Term
T or F: uric acid excretion is increased with Loop Diuretics
Definition
T, at first

increased acutely (because of contraction of ECF), but then decreased chronically because of competition at organic acid transporters

Rare instances can cause gout
Term
T or F: loop diuretics can cause venodilation and increased renal blood flow.
Definition
T: via prostaglandin synthesis

(inhibited by NSAIDs)

can help with acute pulmonary edema (venodilation)

Increased renal blood flow also partially contributed to macula densa sensing being blocked
Term
Pregnancy and Loop diuretics
Definition
Teratogenic in first trimester
Term
Adverse effects of loop diuretics
Definition
1. Electrolyte imbalances: decreased K, Na, Ca, H (alkalosis)
2. Ototoxicity: rare (esp with ethacrynic acid) deafness can be temporary or permanent; more likely to occur with concurrent use of other ototoxic drugs and renal insufficiency
3. GI: bleeding, diarrhea (esp with ethacrynic acid)
4. Sulfonamide sensitivity (low risk) - rashes, paresthesias, anemias, photosensitivity (common with furosemide)
5. CHO intolerance (because K depletion) can aggravate diabetes
6 Elevate uric acid (increase gout attacks)
7. HIGH fracture risk in post-menopausal women
5.
Term
T or F: there are loop and thiazide diuretic combinations
Definition
F - synergistic effect/too similar
Term
Which is the longest acting loop diuretic?
Definition
torsemide
Term
T or F: loop diuretics are highly protein bound
Definition
T - be aware of potential competition with other meds for binding sites (ex: warfarin)
Term
What is the only loop diuretic to undergo significant metabolism (all others excreted renally unchanged)?
Definition
Torsemide
Term
What are the potassium sparing diuretics?
Definition
Sprionolactone (Aldactone)
Eplerenone (Inspra)
Triamterene (Dyrenium)
Amiloride (Midamor)
Term
Uses of K+ Sparing Diuretics
Definition
1. HTN
2. CHF
3. Ascities (cirrhosis) **Preferred diuretic in hepatic cirrhosis
4. Primary and secondary aldosteronism
5. Hypokalemia
Term
Which type of diuretic is preferred in patients with hepatic cirrhosis
Definition
K+ sparing diuretic
Term
MOA of triamterene?

Which other drug has the same MOA
Definition
Block Na+ channel in late distal tubule/CD (on luminal membrane)

Prevents the exchange of K and Na on blood side

Overall, the sodium in the tubule will stay in the tubule

Amiloride = same MOA
Term
MOA of spironolactone.

What other drug has the same MOA
Definition
Competitive aldosterone antagonist at the MR (mineralocorticoid) receptor

Prevents aldosterone from binding and thus increasing synthesis and activity of the luminal Na+ channel (which is directly blocked by the other K+ sparing diuretics)

Eplerenone (same MOA)
Term
T or F: All potassium sparing diuretics are ineffective in the absence of aldosterone
Definition
F - the aldosterone antagonists are (spironolactone, eplerenone) but the Na-channel blockers (triamterene, amiloride) have limited effectiveness
Term
K+ sparing diuretics are the drugs of choice with HTN due to what?
Definition
Primary or secondary aldosteronism (this way they are fixing the cause more than just adjusting the BP by another mechanism)
Term
Role of K+ sparing diuretics in the treatment of HTN
Definition
Use as dual therapy always!
(much more effective with a drug (thiazide or loop) that will increase the Na in the late distal tubule/CD.

Use to prevent hypokalemia due to other drugs
Term
Which is more specific, eplerenone or spironolactone?

What is the result of this?
Definition
Eplerenone is more specific for the MR

Fewer sex hormone related ADRs (impotence, gynecomastia)
Term
Can eplerenone be used with RAS drugs?
Definition
Yes, even though aldosterone will decrease with RAS drugs, there are other sources of aldosterone and
Term
Which would be more effective in blacks, eplerenone or lostartan?
Definition
Eplerenone
Term
Which is the most effective K+ sparing diuretic at lowering BP (alone)
Definition
Eplerenone (~10 mmHg)

possibly because higher specificity for MR
Term
What is a common drug interaction to be aware of with eplerenone and how does it manifest?
Definition
CYP3A4 inhibitors will block its metabolism

causes hyperkalemia
Term
T or F: Hyperkalemia cant occur with potassium sparing diuretics if a K wasting diuretic is coadministered
Definition
F
Term
When are K supplements contraindicated in HTN therapy?
Definition

K+ Sparing Diuretics risk of hyperkalemia

 

RAS drugs can also cause hyperkalemia, use with caution in these patients

Term
T or F: it is okay to give triamterene and spironolactone concomitantly?
Definition
F - both are K+ sparing and work by different mechansisms - elevated risk of hyperkalemia
Term
ADRs of spironolactone
Definition
1. Sex hormone issues:
-Men: gynecomastia, decreased libido, impotence
-Women: hirsutism, menstrual irregularities, breast tenderness
2. GI: ulcers/bleeding, gastritis, diarrhea
3. hyperkalemia
Term
ADRs of triamterene
Definition
N/V
Leg cramps
Dizziness
Photosensitivity
Patients with cirrhosis - risk for megaloblastic anemia
Kidney stones (containing drug and metabolites)
Hyperkalemia
Term
ADRs of amiloride
Definition
N/V, diarrhea, HA
Hyperkalemia
Term
When starting spironolactone when should you expect to see an effect?
Definition
Can take up to 2-3 days to see maximal effect because principal metabolite is active and has a very long half-life
Term
What are signs of hyperkalemia and how should people on K+ sparing diuretics be monitored?
Definition
Numbness, paresthesias
Confusion, SOB, fatigue

Biggest concern = heart issues

Monitor blood levels
Term
What is the number one sign for hypernatremia?
Definition
Thirst

Otherwise, it can have a similar presentation to hyperkalemia)
Term
What 3 things does the JGA regulate?
Definition
1. GFR
2. glomerular blood flow
3. Renin release
Term
The JGA is reacts to changes in ____ and ____ and reacts by ____ and _____.
Definition
The JGA is reacts to changes in NaCl IN DISTAL TUBULE (via macula densa PGI2/PGE2) and DECREASED BP and reacts by VASODILATING AFFERENT ARTERIOLE and RELEASING RENIN
Term
To increase GFR should the afferent and efferent arterioles be constricted or dilated?
Definition
Afferent should be dilated
Efferent should be constricted
Term
Where is ACE found?
Definition
in all vasculature, but thought to activate Angiotensin in lungs (all blood must flow through here)
Term
Angiotensinogen
Where is it made?
What stimulates its release?
Definition
Constantly being secreted from the liver

Plasma levels are increased by: glucocorticoids, estrogen, thyroid hormone, Ang II, inflammation, insulin, pregnancy
Term
Actions of Ang II, which is the most important?
Definition
1. Increases aldosterone synthesis (MOST IMP)
2. Vasoconstrictor
3. ADH release
4. Na+ reabsorption in proximal tubule
5. Stimulates thirst center in hypothalamus
Term
How do NSAIDs affect the RAS system?
Definition

Questioned about their role in the signaling of the macula densa to the JGA (mediated by PGI2/PGE2)

Block PG in the afferent arteriole, which normally cause it to be vasodilated - so NSAIDs cause vasoconstriction of afferent arteriole.

Term
What is the only renin inhibitor
Definition
(Tekturna) Aliskiren

Decreases plasma renin ACTIVITY

lowers BP ~10-15 mmHg

NOTE: bonus - decreases B-type natriuretic peptide (BNP) [high levels associated with worsening HF]
Term
T or F: when discontinuing Aliskiren you can abruptly stop it without any concerns
Definition
F - aliskiren increases plasma renin (body trying to compensate for decrease in renin activity) so if d/c abruptly the will cause a spike in renin = spike in BP
Term
What is the only contraindication of aliskiren?
Definition
Do NOT use with ACEI or ARB in diabetic patients (probably shouldn't with anyone) -increased risk of renal impairment, hyperkalemia, hypotension
Term
Administration of aliskiren
Definition
Avoid taking with high fat meals (already low bioavailability that decreases with fat)

QD

Max of 300 mg/day
Term
Pregnancy and RAS drugs
Definition
fetal/neonatal morbidity
oligohydramnios (kidney injury)
Greatest risk in 2nd/3rd trimesters
Term
Common ADRs for all RAS drugs
Definition
1. Dont use in preg
2. Head/neck angioedema
3. Hypotension
4. Slight suppression of hematopoiesis
Term
ADRs of Aliskiren
Definition
Diarrhea
hyperkalemia (esp with combined with other RAS drugs or K-sparing diuretics)
slight suppression of hematopoiesis

fetal/neonatal morbidity assoc with use in pregnancy
head/neck angioedema
hypotension
Term
Actions of ACE
Definition
1. Converts Ang I to Ang II
2. Degrades Bradykinin (vasodilator)
Term
What causes the cough associated with ACE inhibitors?
Definition
Bradykinin (cant be degraded)
Term
Degradation of Angiotensin II
Definition
Plasma half-life only ~30 seconds
Degraded by angiotensinases (in blood cells and endothelium)

Breaksdown to Ang III (agonist) and Ang(1-7) (antagonist)

Ang III gets further broken down to Ang IV (antagoinst)

Agonist = AT1
Antagonist = AT2
Term
T or F: All ACEI are therapeutically equivalent?
Definition
T - but differ in potency

Even though there are three classes (most are dicarboxylates)
Term
What are three biological chemical levels that ACEI alter?
Definition
1. Renin: increase levels (attempt to compensate)
2. Ang I: increase levels (attempt to compensate)
3. Bradykinin: increase levels (because cant breakdown)
Term
What type of enzyme is required for ACEI activation in the body?
Definition
Esterases - should use an ACEI that inst a prodrug if patient has hepatic disease
Term
Which ACEI are not prodrugs?
Definition
Lisinopril
Captopril
Enalaprilat (IV only)
Term
How effective are ACEI at lowering BP?
Definition
work in about 50% of patients with mild/moderate HTN

Lower SBP 6-9 mmHg (average)

Addition of a diuretic = effective therapy in 90% of patients
Term
Which maintains a fall in BP for a longer time, thiazides or ACEI?
Definition
ACEI, fall in BP maintained over long-course treatment without compensation
Term
T or F: ACEI prevent incidence of diabetes in people with HTN?
Definition
F - does not prevent diabetes, but are cardioprotective and renoprotective in people with diabetes
Term
What is the best agent to use for HTN in people with diabetes?
Definition
ACE inhibitors (Cardio and reno-protective)
Term
Major ADRs with ACEI?
Definition
1. Hypotension - titrate up and down
2. Cough - (20%) not dose related, more common in women, develops between 2 weeks and 6 months, ASA may reduce cough
3. Angioedema - usually with first dose (during first week), 2x greater in blacks and more common in women, resolves when d/c drug
4. Skin rash (esp captopril)
5. Dysgeusia (esp captopril)
6. Neutropenia (rare)
7. Hyperkalemia (rare, unless taking K supp or K sparing diuretics)
Term
Why does ACEI cause hyperkalemia?
Definition
Because aldosterone is being blocked which usually depletes K
Term
What can ACEI cause in patients with bilateral renal artery stenosis and severe CHF?
Definition
Acute renal failure because it decreases GFR in renally compromised patients
Term
T or F: Dose determines the duration of effect for ACE inhibitors
Definition
T - too low of a dose will not maintain lowered BP throughout dosing interval

Exhibits a flat dosing curve (not true with ARBs)
Term
Which ACE inhibitors have a long duration of action?
Definition
Lisinopril
Benzaepril
Enalapril
Ramipril
Citazapril
Fosinopril
Perindopril
Trandolapril
Zofenopril

QD
Term
T or F: all ACEI are cleared the same way
Definition
NO!

Lisinopril, Captopril, and Enalapril are only cleared renally, the others are mix of hepatic and renal (varying degrees)

pay attention in renal/hepatic disease
Term
Which receptor dose ARBs block
Definition
AT1 - block all the major effects of Angiotensin II (aldosterone, ADH release, thirst, vasoconstriction)

10,000x more selective for AT1 than AT2
Term
What type of receptor is AT1?
Definition
Gq (in most cells) but can be Gi too
Term
Which ARB is the most selective for AT1?
Definition
Candesartan = Omesartan > Irbesartan = Eprosartan > Telmisartan = Valsartan > Losartan
Term
Are ARBs irreversible or reversible inhibitors?
Definition
competitive and reversible, but have such affinity, they are essentially insurmountable

(receptor internalization may contribute)
Term
T or F: ARBs are not effective in low-renin HTN?
Definition
T
Term
T or F: ACEI and ARBs are therapeutically equivalent
Definition
T
Term
What is a big advantage (in terms of ADRs) that ARBs have over ACEIs?
Definition
NO cough

They also block non-ACE pathways of Ang II, permit activation of AT2 (possibly more popular as they become generic)
Term
Irbesartan and losartan have a second unique indication, what is it?
Definition
diabetic neuropathy in patients with HTN

DOC for renoprotection in diabetic patients
Term
Neprilysin inhibitor
Definition
New drug (LCZ696)

MOA: inhibits neprilysin (neutral endopeptidase) to black atrial natriuretic peptide (ANP) degradation
-ANP is a potent vasodilator made by heart in response to high BP, hypernatremia, and ANGII
-ALSO an AT1 antagonist (AKA ARB)
Term
Which two types of patients are CCBs often used in?
Definition
Elderly and Blacks

Low renin producers
Term
How do each class of CCB differ in mechanism?
Definition
They each bind to different sites in the alpha1-subunit of the L-type voltage gated Calcium Channel
Term
Which type of Calcium channel to CCBs act on?
Definition
L-type calcium channels
Term
MOA of CCBs
Definition
Bind to L-type voltage-gated Ca channels on cell membrane

Inhibit Ca entry into cells needed for contraction
-Vasodilation (periphery and coronary)
-Decreased heart contractility/conduction (bind to cardiac myocytes and SA/AV nodes)
Term
T or F: CCBs are therapeutically equivalent to ACEIs
Definition
T, they are also therapeutically equivalent to beta-blockers
Term
Which type of CCB are used most often
Definition
Dihydropyridines
Term
Which CCB(s) is/are most vasodilating?
Definition
dihydropyridines (nifedipine, nicardipine, nimodipine) >> verapamil > diltiazem

Associated with baroreceptor reflex causing tachycardia and increased CO
Term
Which CCB(s) cause the most cardiac contractility and conduction
Definition
Verapamil > diltiazem >> dihydropyridines
Term
What types of patients should CCBs be avoided?
Definition
HF (including left ventricular hypertrophy)
post-MI
SA or AV node conduction defects
Term
What other drugs are CCBs usually combined with?
Definition
ACEIs, beta-blockers, methyldopa
Term
does diltiazem act more similarly to verapamil or nifedipine?
Definition
Verapamil
Term
Can you combine two CCBs with different mechanisms?
Definition
No, even though they might have different predominant mechanisms, they still have same mech

Only dihyropyridine + diltiazem is okay in hard-to-control cases
Term
What are some longer acting CCBs
Definition
amlodipine, isradipine, felodipine

QD
Term
What enzyme does verapamil inhibit? What might this effect?
Definition
PGP transporter

decreased clearance of digoxin

also a CYP3A4 substrate
Term
When might doses of CCB might need to be adjusted?
Definition
Impaired hepatic function (metabolism)

Elderly
Term
What is the biggest ADR concern with CCBs
Definition
Hypotension (probably with just about any HTN med)

+EDEMA big complaint - why many stop these
Term
ADRs of CCBs
Definition
1. Hypotension: dizzy, HA, flushing, nausea, PERIPHERAL EDEMA
-Myocardial ischemia related to hypotension/decreased coronary perfusion (most common with IR formulations)
2. GERD: relaxation of esophageal sphincter
3. Gingival hyperplasia
4. Occasional: Constipation, coughing, wheezing, pulmonary edema, rash
5. Rare elevations in liver function tests (verapamil/diltiazem)
6. Bradycardia (verapamil, esp IV) - potentiated with beta-blockers - bad if SA/AV defects
Term
CCB vs Diuretic as second line agent with ACEIs
Definition
equivalent effectiveness for BP, but with CCB reported CV events was lower
Term
What alpha-1 blockers are used in HTN
Definition
prazosin (Minipress) BID-TID
terazosin (Hytrin) QD
doxazosin (Cardura) QD
Term
MOA of alpha-1 blockers
Definition
antagonize post-synaptic alpha-1 receptor found in the periphery on vascular smooth muscle

prevent vasoconstriction: this will persist but initially there is also in increase in HR, CO, and renin (baroreceptor reflex) that goes away
(and may suppress sympathetic outflow from CNS)
Term
What is an additional benefit of alpha-1 blockers?
Definition
improve serum lipids (good if have atherosclerosis too)
Term
Administration of alpha-1 blockers
Definition
QHS (prazosin = BID/TID)
taper up (if dont take for a few days then need to re-taper again)

Start at 1 mg, Do not exceed 20 mg (usually need 1-5 mg dose)

undergo hepatic metabolism (possibly require dose adjustment)

If BP doesnt stay down for the entire dosing interval then need to increase dose.
Term
ADRs of alpha-1 blockers
Definition
Postural Hypotension (take at night): dizziness, edema, fatigue
Nausea
Nasal Congestion
Palpitations
Rarely: anaphylaxis, priapism

Generally ADRs decrease with continued use

Preg Cat C (teratogenic in animals)
Term
How should alpha-1 blockers be used in the treatment of HTN?
Definition
Not usually recommended as monotherapy with HF

Use in conjunction with diuretics, beta-blockers, RAS drugs

Appropriate for diabetics, gout, BPH
Beneficial in atherosclerosis (improves lipids)
Term
MOA of beta-blockers in HTN
Definition
1. Blockade of RAS via beta-1 (MOST IMP)
-But antiHTN effect does not always correlate with plasma renin levels
2. Decrease cardiac contractility and HR to decrease CO
Term
T or F: all beta-blockers are equally effective in HTN?
Definition
T - doesnt matter if selective or non-selective
Term
T or F: Beta-blockers do NOT lower BP in normotensive patients?
Definition
T - because no sympathetic nervous system overactivation
Term
MOA of labetalol and carvedilol
Definition
alpha-1 blocker: lowers TPR
beta-1 and -2 blocker with intrinsic activity (aka partial agonist): vasodilation and blocks RAS
Term
Which provides better glycemic control in diabetes, carvedilol or metoprolol?
Definition
Carvedilol because of addition of alpha blocker, can lower the required dose of beta-blocker
Term
Name brand of nebivolol
Definition
Bystolic
Term
MOA of Nebivolol
Definition
high specificity of blocking beta-1
vasodilation by stimulating NO production
Term
How long will it take to see a full effect of a beta-blocker
Definition
may take several weeks
Term
When are beta-blockers first line for the treatment of HTN
Definition
after MI
HF
arrhythmias
angina

(because will be used anyways)
Term
Why are beta-blockers not generally recommended to be used with ACEIs and ARBs?
Definition
mechanism is too redundant - renin system
Term
Would beta blockers be a good choice of blacks and elderly?
Definition
Not generally, because they are low renin producers, which is the primary way beta-blockers elicit their anti-HTN effect
Term
T or F: a diuretic should always be added to beta-blocker anti-HTN therapy
Definition
F - because beta-blockers do not cause water/Na retention, it is not needed HOWEVER, addition of a diuretic is common

Diuretic + minoxidil (vasodilator) + BB = effective in almost all patients
Term
What anti-hypertensive drug class should be avoided in patients with COPD?
Definition
beta-blockers (block b2 - studies are showing specific beta-blockers are generally safe)
Term
Who should avoid beta-blockers?
Definition
1. Insulin dependent diabetics - mask symptoms of hypoglycemia
2. COPD - bronchoconstriction risk (starting to decrease)
3. Cardiac Conduction Issues - cause bradycardia, may not be able to tolerate initial drop in CO
Term
What HTN drugs should be used for people with cardiac conduction issues?
Definition
Diuretics or vasodilators
Term
What would you expect to see if someone abruptly discontinued a beta-blocker they were taking for HTN?
Definition
rebound HTN

taper over 2 weeks
Term
ADRs associated with beta-blockers
Definition
fatigue, dizziness, depression
bronchoconstriction
bradycardia
Term
T or F: even though beta-blockers decrease BP, morbidity/mortality has not shown to decrease with beta-blocker monotherapy
Definition
T - still at higher risk for complications than other anti-HTN drugs (ex: stroke, cause insulin resistance, increased risk of DM)
Term
Which beta-blocker has not been found to cause new onset diabetes?
Definition
Carvedilol (probably because alpha action)
Term
What are the centrally acting drugs used in HTN and what is their class
Definition
alpha-2-agonists

Guanfacine
Clonidine
Guanbenz
Methyldopa
Term
MOA of alpha-2-agonists
Definition
Reduce sympathetic outflow by decreasing CNS NT release
Term
Role of alpha-2 agonists in the treatment of HTN
Definition
Not usually first line (b/c ADR)

Appropriate in drug resistance and pregnancy

Used in combination (with diuretics or vasodilators[can replace beta-blocker])
Term
Methyldopa is an analog of what? How does it work
Definition
DOPA

gets converted to methylNE (replaces NE) in neurons of brainstem (central site of action)

Because MNE is not broken down by MAO (like NE is) it will accumulate and overcome NE ->why it works

Also: acts as dopa decarboxylase inhibitor -decreases peripheral NT synthesis ->more hypotension (probably contributes to ADRs in brain)
Term
Effect of methyldopa on TPR, CO, and HR
Definition
Decreases TRP

Little effect on CO or HR except in elderly
Term
Is orthostatic hypotension an issue with methyldopa?
Definition
No, only a modest problem (because turning the SNS down, not off)
Term
Effect of methyldopa on renal blood flow and function
Definition
Not affected

but plasma renin levels do decrease (b/c decrease SNS)
Term
When would you expect to see an effect from methyldopa?
Definition
Peak effect is 6-8 hours and lasts 24 hours (b/c must be metabolized then packaged into vesicles)

QD dosing
Term
ADRs of methyldopa
Definition
CNS: sedation, inattentiveness, depression, dry mouth, parkinsonian signs, loss of libido, hyperprolactinemia, severe bradycardia

Hepatotoxicty (uncommon, usually reversible)

Na retention (with longterm therapy)

Hemolytic anemia/blood disorders - 20% develop autoantibodies to Rh on RBC - leads to anemia (d/c drug fixes anemia)
Term
With which drug class is the CV response to exercise impaired?
Definition
beta-blockers
Term
Normally, clonidine activates the alpha-2a receptor but if dosed to high it can activate the alpha-2b receptor in the vasculature, what is the effect of this?
Definition
Causes vasoconstriction (counterintuitive)
Term
What is the effect on the alpha-2a agonists on CO and TPR
Definition
decreases both

CO dominates in supine position
Vasodilation dominates in upright position
Term
T or F: Na retention can occur with all alpha-2 agonists?
Definition
T - advise giving a diuretic too less with guanabenz
Term
Renin levels decrease with all sympatholytics used in HTN except which class?
Definition
Alpha-blockers (ex: doxazosin)
Term
Which is the most selective alpha-2 agonist?
Definition
guanfacine

no better activity, but fewer ADRs
Term
What is Intuniv?
Definition
Guanfacine Extended Release

Used in ADHD
Term
Which alpha 2 agonist is available as a patch
Definition
Clonidine - lasts for 1 week
Term
What is the preferred antihypertensive in pregnancy?
Definition
Methyldopa
Term
ADRs of alpha-2-agonists
Definition
CNS: sedation, dry mouth, vivid dreams/nightmares, depression, severe bradycardia, sexual dysfunction
Term
Overdosage of an alpha-2 agonist resembles what other common OD?
Definition
opioid

disorientation, HTN followed by hypotension, bradycardia, respiratory depression, miosis
Term
T or F: you can get withdrawal from clonidine?
Definition
T with any alpha-2 agonist

Sx: HA, apprehension, tremors, sweating, tachycardia, rebound HTN (greater than was before starting drug)

more likely with higher doses
Term
What are the two minor sympatholytics?
Definition
Reserpine
Guanadrel (Hylorel)
Term
MOA of guanadrel
Definition
targets postganglionic adrenergic neurons

taken up by PREsynaptic terminal by NE transporter- replaces NE - released as inactive NT
HAS NO AGONIST activity, just depletes NE (different than methyldopa)

Causes vasodilation
Term
What types of drugs would inhibit/blunt the effects of guanadrel?
Definition
TCAs, cocaine, chlorpromazine, strattera

Anything that will block the uptake of NE
Term
ADRs of guanadrel
Definition
orthostatic hypotension
volume expansion (Na retention)
weakness, sexual dysfunction, diarrhea

Contraindicated in CHF b/c block sympathetic stimulation
Term
Administration of Guanadrel, what should be monitored
Definition
PO BID
delayed effect because MOA requires uptake

use if other drugs fail/are insufficient
don't use as monotherapy (b/c postural hypotension)

Monitor renal and hepatic clearance
Term
MOA of Reserpine
Definition
binds to NT storage vesicles and impairs transport of storage vesicles (in CNS and PNS)

Decrease TPR, renin, CO/HR (Na retention counteracts hypotensive effect, so orthostatic hypotension not a concern)
Term
Is the pharmacologic half-life of reserpine long or short
Definition
Very long - half-life is on the order of weeks and has a slow onset
Term
What NTs does reserpine inhibit?
Definition
adrenergic, dopamine, and serotonin
Term
ADRs of reserpine
Definition
Sedation
Inattention
Nasal congestion
Sexual dysfunction
Depression with suicidal thoughts/psychosis - screen patients
Term
What are some vasodilators used for HTN?
Definition
Hydralazine (Apresoline)
Minoxidil (Loniten/Rogaine)
Sodium nitroprusside (Nipride)
Diazoxide (Hyperstat)
Term
Is orthostatic hypotension a concern for patients on vasodilators?
Definition
NO!
Because they directly relax arteriolar smooth muscle, they:
1. dont require innervation
2. dont rely on receptor activation
3. Dont affect SNS (SO NOT ortho hypotn)
AND dont cause VENOdilation
Term
When you give a vasodilator the body tries to compensate for the changes, how?
Definition
Increase SNS activity (vasoconstriction, CO/HR, renin release)
Decreased blood flow to kidney also stimulates increased renin release

Because of this attempt to compensate must be used with other anti-HTN drugs
Term
What other anti-HTN drugs must vasodilators be used in combination with?
Definition
1. beta-blocker (alpha-2 agonists can be substituted): prevents increased SNS activity (wont cause increased CO/HR/TPR/renin)

2. Diuretic: prevents Na loss so kidney wont trigger release of renin -->RAS
Term
MOA of sodium nitroprusside
Definition
requires activation by blood vessels to NO (which relaxes vascular smooth muscle)
Term
Which vasodilator also relaxes veins?
Definition
nitroprusside

its also the only one that doesnt cause a compensatory increase in CO (but may increase HR)
Term
What is the mechanism of Minoxidil and Diazoxide?
Definition
activate the ATP-dependent K+ channel which hyperpolarizes and relaxes arteriolar smooth muscle cells
Term
Which vasodilator can elicit the greatest drop in BP
Definition
Minoxidil (~35 mmHg)
Term
T or F: Vasodilators elicit their effect on all smooth muscle.
Definition
F - other smooth muscle is not affected (ex: GI)
Term
Which vasodilators are administered orally?
Definition
Hydralazine and minoxidil
Term
Which vasodilators are administered IV?
Definition
nitroprusside and diazoxide
Term
For PO vasodilators, why is their therapeutic half-life longer than their plasma half-life?
Definition
may accumulate in artery walls
minoxidil active metabolite may have longer half-life than parent drug
Term
Which PO vasodilator has a longer half-life and is used in more severe HTN
Definition
minoxidil
Term
When are diazoxide and nitroprusside used?
Definition
Hypertensive emergencies/crisis
Term
How long does it take to see an effect from nitroprusside (diazoxide)? How does this play into their therapy?
Definition
30 seconds (3-5 minutes) when given IV

Good, because used for HTN-ive crisis

Nitroprusside: within 2-3 minutes of d/c infusion, vasodilation will end
(D: action lasts 4-12 hr)
Term
Why does diazoxide need to be administered as a rapid injection?
Definition
to prevent binding to plasma proteins
Term
Which vasodilator requires activation by the liver?
Definition
Minoxidil
Term
In order to prevent cyanide toxicity with nitroprusside, how long is an infusion of it limited to?
Definition
24 hours
Term
If a patient has renal failure, which vasodilator is ideal to use?
Definition
Minoxidil: only hepatic activation and biliary excretion

Hydralazine: renally eliminated
Diazoxide: renal + hepatic elimination
Nitroprusside: CN can be toxic in renal failure
Term
When is nitroprusside used?
Definition
hypertensive crisis associated with MI and ventricular failure
Term
What are some ADRs (in general) associated with vasodilators used in HTN?
Definition
1. Vasodilation: HA, flushing, congestion, vertigo, N/V
2. Cardiac stimulation: tachycardia, palpitations (prevent with beta-blocker)
3. Fluid retention: lead to CHF, pulmonary HTN (give diuretic)
Term
What specific issue might hydralazine cause that is unique
Definition
Autoimmune reactions

Lupus syndrome (arthritis, arthralgia, fever) - long-term, dose-dependent, more common in WOMEN and WHITES, resolves when d/c
Term
What specific ADR is associated with minoxidil?
Definition
Hypertrichosis

remember, topical minoxidil (Rogaine) used for male pattern baldness
Term
What two unique ADRs does diazoxide cause
Definition
1. Hyperglycemia: esp in non-insulin-dependent diabetics (but not used for long so not usually a problem) b/c inhibits insulin secretion (via K channel stimulation)
2. Can stop labor by relaxing uterine smooth muscle
Term
What patient population should nitroprusside be used with caution in because it can worsen hypoxemia?
Definition
COPD patients
Term
Is pulmonary arterial hypertension more common in men or women?
Definition
Women
Term
What are the three forms of pulmonary arterial hypertension?
Definition
1. Idiopathic (~40%)
2. Familial (few)
3. Associated (with certain diseases)
Term
What diseases can pulmonary arterial hypertension be associated with?
Definition
Connective tissue diseases
Congenital heart disease
Portal hypertension (hepatic disease)
HIV
COPD
Schistosomiasis
Sickle Cell

Anorexic Drugs: FenFen, amphetamines, some chemo
Term
Presentation of pulmonary arterial hypertension
Definition
Exertional dyspnea, fatigue
Edema
heart murmurs
Term
Who is pulmonary arterial hypertension confirmed
Definition
Right heart catheterization: mean pulmonary arterial pressure >25 mmHg; pulmonary wedge pressure <15 mmHg

6 minute walking test for disease severity
Term
T or F: people with pulmonary arterial hypertension will have very high blood pressures
Definition
F - wont know - it is not evident with a cuff
Term
What changes in endothelial function/factors occur with pulmonary arterial hypertension

PATHOPHYSIOLOGY
Definition
Decreased: prostacyclin (PGI2), Nitric oxide synthase

Increased: thromboxane, endothelin-1 (vasoconstrictor)

Pro-coagulant state (incresaed von Willebrand factor)
Vascular inflammation: autoantibodies, proinflam. cytokines

FIBROSIS- leads to right ventricular hypertrophy and eventual failure
Term
What is the general pharmacologic treatment of pulmonary arterial hypertension?
Definition
1. Oral anticoagulants: TE common
2. Diuretics: in right side failure/edema
3. Oxygen: apnea, dyspnea
4. Digoxin: use in heart failure
+Other agents to help with the HTN specifically (CCBs, PDE inhibitors, prostacyclin analogs, endothelin antagonists)
Term
T or F: everyone with pulmonary arterial hypertension should be on an CCB
Definition
F - only effective in under 15% of patients with pulmonary arterial hypertension

-to know who should take a CCB test at same time catheterized for confirm diagonsis
Term
If chose to use a CCB in pulmonary arterial hypertension, which class is usually preferred?
Definition
dihydropyridines = peripheral vasodilators (less effect on heart)
Term
Name some phosphodiesterase inhibitors
Definition
sildenafil
tadalafil
vardenafil
Term
Why are PDE inhibitors used in pulmonary arterial hypertension
Definition
Increase nitric oxide = vasodilation

decrease pulmonary arterial pressure
decrease plasma endothelin-1 levels
improved exercise tolerance
Term
What should be avoided if on a PDE inhibitor
Definition
nitrates
Term
ADRs of PDE inhibitors
Definition
blue vision, HA, diarrhea
Term
administration of PDE inhibitors in pulmonary arterial hypertension
Definition
PO or injection TID
Term
Actions of prostacyclin
Definition
vasodilator (G-protein coupled to cause K+ hyperpolarization--> smooth muscle relaxation)
platelet inhibitor
antiproliferative
Term
What are some major limitations to using prostacyclin to treat pulmonary arterial hypertension?
Definition
VERY SHORT HALF-LIFE (3-5 min)
Must be kept on ice

Dose is limited by ADRs (cough, flushing, HA, jaw pain, diarrhea)

Sepsis is greatest risk
Term
Iloprost
Definition
first inhaled prostacyclin analog used to treat pulmonary arterial hypertension.

given 6-9 times daily or Q2H
Term
Treprostinil (Remodulin)
Definition
stable prostacyclin analog give SQ or IV and now inhaled (PREFERRED)

can be used in combination with Bosentan and sildenafil
Term
What are two prostacyclin analogs?
Definition
Iloprost

Treprostinil
Term
Actions of ET-1 (endothelin-1)
Definition
VASOCONSTRICTION
stimulates vascular smooth muscle proliferation
promotes aldosterone synthesis
Term
Two receptors that ET-1 can bind to? What are their effects?
Definition
ETa: contraction vascular smooth muscle
ETb: contraction of vascular smooth muscle AND nitric oxide release (mix of vasodilation and contraction)

Want to block ETa
Term
What are the primary benefits seen with endothelin antagonists?
Definition
improve exercise capacity
hemodynamics
slow disease progression
Term
Name two approved endothelin antagonists (and one still being studied)
Definition
1. Bosentan (Tracleer)
2. Ambrisentan (letaris)

(3. Darusentan (Dorado))
Term
Challenges of Bosentan
Definition
Blocks both ETa and ETb receptors

-dosed based on body weight
-elevates hepatic enzymes - monitor monthly
-metabolized by CYP2C9, 3A4, and 2C19 and induces them
-Cat X for pregnancy - monthly pregnancy tests required and 2 forms of birth control
-REMS because of hepatotoxicity (and preg)
Term
Administration of Bosentan
Definition
orally active BID

dosed based on body weight
Term
Which endothelin antagonist is selective for ETa?
Definition
Ambrisentan
Term
Dosing of anbrisentan
Definition
QD (orphan drug)
Term
ADRs/Issues with ambrisentan
Definition
Cat X for pregnancy (REMS)

NO hepatotoxicity -no testing

metabolized by CYP 3A4, 2C19

ADRs: edema, congestion, flushing, palpitations (prob will be on beta-blocker and diuretic anyway to help)
Term
Can endothelin antagonists be used in normal HTN?
Definition
No evidence yet. Darusentan trials tried, at first just peripheral edema, but second trial failed
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