Anti-Hypertensives and Hypertension Flashcards
What two factors determine blood pressure?
Cardiac output and periveral vascular resistance.
BP = COTPR
TPR = total peripheral resistance
What circulating factors affect the inotropic state of cardiac muscle, heart rate and filling pressure?
sympathetic and parasympathetic activity, circulating hormones, intrinsic cardiac muscle function, volume regulatory hormones, renal function, volume intake, posture
What are the factors affecting peripheral vascular resistance?
sympathetic and parasympathetic activity, vasoconstrictor and dilator hormones, blood viscosity, blood volume, cardiac function
What do ACEI do in terms of bradykinins?
ACEI inhibit the arm of bradykinins that leads to inactive peptides and thus forces the bradykinin pathway into nitric oxide and prostaglandin production
What are the common ACEI that are in use?
Lisinopril, benazepril, captopril, enalapril, ramipril
How do ACEI drugs work?
inhibit Angiotensin Converting Enzyme, blocking angiotensin-II-mediated vasoconstriction and stimulation of aldosterone release.
*blocks degradation of bradykinin so there is the side effect of bronchoconstriction and stimulation of irritant receptors (cough)
How fast do ACEIs work and how long do they last?
onset of action within an hour. duration of action is 24 hours
What are the Adverse Effects of ACEIs?
Cough Hyperkalemia contraindicated in pregnancy Mild increase in serum creatinine Angioedema (rare) Anemia (rare)
When do you use ACEIs?
HTN, Heart failure, CKD, diabetic nephropathy, polycythemia
What are the commonly used Angiotensin II Receptor Blockers?
ARBs
*losartan, irbesartan, candesartan, valsartan
How do ARBs work?
ARBs = Angiotensin II Receptor Blockers
- irreversibly block angiotensin II action at AT1 receptor (not AT2?)
- prevents vasoconstriction and aldosterone release
Are there any differences in when you would use an ARB or an ACEI?
You use ACEI first, then if there is a cough or hyperkalmia, switch to ARB as the cough isn’t associated with it and the hyperkalemia is less too.
*but you use it in the same hypervolemic states as you would the ACEI
What are the commonly used calcium channel blockers?
Dihydropyridines and Non-dihydropyridines (DHP and NDHP)
DHP = amlodipine, nislodipine, nifedipine, felodipine
NDHP = diltiazem, verapamil
How do calcium channel blockers treat Hypertension?
Cause arterial vasodilation and lower peripheral vascular resistance by blocking L-type calcium channels
- blocking L-type calcium channels will inhibit the influx of extracellular calcium ions through calcium channels in the cellular membranes of myocardial, vascular smooth muscle, or cardiac conduction cells
- loss of extracellular calcium influx leads to decreased phosphodiesterase and increased cGMP levels
- increased cGMP levels leads to less vascular smooth muscle contractility and less cardiac contractility
How does blocking of a calcium channel in vascular smooth muscle result in less constriction?
- blocking L-type calcium channels will inhibit the influx of extracellular calcium ions through calcium channels in the cellular membranes of myocardial, vascular smooth muscle, or cardiac conduction cells
- loss of extracellular calcium influx leads to decreased phosphodiesterase and increased cGMP levels
- increased cGMP levels leads to less vascular smooth muscle contractility and less cardiac contractility
What is the difference between DHP and NHP calcium channel blockers in terms of receptors?
DHPs are more selective for L-type Ca channels in blood vessels (don’t do anything in the heart)
*NDHPs are equally sensitive for peripheral vascular channels AND cardiac channels, thus decrease conduction through AV node and have more modest inotropic and chronotropic actions
Are there any drug interaction concerns associated with calcium channel blockers?
Yes, absolutely. Both are metabolized by P450 enzymes, in particular 3A4.
*However, NDHP are way more inhibitory to the P450 enzymes than the DHP drugs so NDHP are the worrysome ones
What are the adverse effects of NDHP use?
NDHP, Calcium channel blockers
*nausea, headache, constipation, gingival hyperplasia, conduction deficits (can’t even use them in 2 or 3 degree heart blocks)
What are adverse effects in DHP drugs?
peripheral edema, reflex tachycardia, flushing, gingival hyperplasia, headache
what are the Beta blockers selective for Beta 1?
atenolol, metoprolol, bisoprolol
What are the Beta blockers that inhibit both beta-1 and beta-2 adrenergic receptors?
propanolol, timolol
What are the Beta AND alpha adrenergic blockers?
carvedilol, labetalol
How do Beta Blockers work?
compete with catecholamines at peripheral adrenergic neuron sites
- block cardiac receptors to decreased cardiac output
- blocks renin activity
What are the adverse effects of Beta Blocker use?
Fatigue, dyslipidemia, mask symptoms of hypoglycemia, sexual dysfunction, respiratory abnormalities
When might you use a Beta Blocker?
HTN, Angina, Prior MI/CAD (secondary prevention), Heart failure (metoprolol and carvedilol), migraine prophylaxis
Which two Beta blockers in particular were singled out for use in heart failure?
Heart failure Beta blockers = (metoprolol and carvedilol),
What two Direct Vasodilators did we talk about?
hydralazine and minoxidil.
*they act by directly vasodilating vascular smooth muscle
How does hydralazine do it’s work?
function = direct dilation of vascular smooth muscle. Alters calcium metabolism by release of NO from the drug and the endothelium. Calcium isn’t available to maintain contractile state.
How does Minoxidil work?
Potassium channel opener, which hyperpolarizes the cell and makes the membrane less susceptible to depolarization
Direct vasodilation will have what effect on the body?
Overall decreased peripheral vascular resistance (the desired effect in hypertension)
- preferential dilation of arterioles - protects against orthostatic hypotension
- increases HR and stroke volume
- increased renin secretion due to reflex sympathetic discharge
- aldosterone-mediated sodium reabsorption
What adverse effects do direct vasodilators have?
Headache, anorexia, nausea, vomiting, diarrhea, flushing, palpitations/tachycardia
what are the alpha-1 blockers we talked about?
prazosin, terazosin, doxazosin
What does blockade of the alpha-1 adrenergic receptors do?
causes a reduction in systemic vascular resistance (lowers blood pressure in a hurry)
*since the alpha-1 receptor is present to a large degree in the prostate and bladder neck it’s used in BPH to help relieve obstruction
What are the adverse effects of alpha-1 blockers?
orthostatic hypotension, headache, peripheral edema
What are the two centrally acting hypertension drugs we discussed?
Clonidine and Methyldopa
What does Clonidine do?
stimulates alpha-2-adrenergic receptors in CNS and periphery
- reduces sympathetic nerve impulses, decreasing peripheral vascular resistance
- increases parasymp outflow from vasopressor center to decrease heart rate
- causes presynaptic inhibition of peripheral norepinephrine release
What are the adverse effects of clonidine?
alpha-2-agonist
*orthostatic hypotension, dry mouth, sedation, rebound HTN if high dose discontinued abrubtly
What is considered HTN urgency vs. emergency?
urgency = severe hypertension but no signs of progressive end-organ damage emergency = BP over 180/120 with signs of end organ damage (neurologic, cardiac, renal)
What are examples of physical signs and symptoms that suggest HTN emergency?
encephalopathy, intracerebral hypertension, acute MI, acute left ventricular failure with pulmonary edema, unstable angina, dissecting aortic aneurysm, eclampsia
What drugs might you consider during a hypertension emergency?
- Sodium Nitroprusside - potent vasodilator by way of nitric oxide donor, dilates venous and arterial circulation
- Nicardipine and Clevidipine - DHP that has selectivity for vascular smooth muscle in cerebral, peripheral and renal vascular smooth muscle. Result is potent vasodilation and reduction of peripheral vascular resistance
- Fenoldopam - peripheral dopamine type agonist, vasodilation of peripheral arteries and the renal and splanchnic vasculature
What are the three mechanisms of damage the kidney can sustain that messes with sodium handling and might lead to hypertension?
loss of nephron mass
activation of the sympathetic nervous system and the neurohormonal axis
abnormal blood vessel response to vasoconstrictors
In essential hypertensin, what is going on with pressure naturesis?
It isn’t working quite right. It takes a higher perfusion pressure to achieve pressure naturesis in HTN kidneys than in normal kidneys.
*THIS WILL LEAD TO AN INCREASE IN TPR
Increased blood pressure is thought to result in TPR increase how?
Through autoregulation. The arterioles in the kidney are designed to constrict or dilate to keep GFR pretty well constant. all the contraction they have to do to keep up with HTN will end up thickening them
*thick tubes, increased TPR that doesn’t really come back down well
what is the first line anti-hypertensive for the vast majority of patients?
Thiazide diuretic, which is due to the alteration of sodium handling to try and fight the root cause of the increasing BP
What is renovascular HTN?
HTN that occurs because of inappropriate renin release by the kidney
- can be from activation of renal beta-sympathetic nerves,
- stimulation of renal baroreceptors by decreased arteriolar pressure, or by
- activation of the macula densa chemoreceptor by reduced delivery of NaCl to the distal tubule
- end result is renin release and RAAS activation
Where is ACE located?
Mostly in the lungs, but also in the kidney and endothelium, so there is some activation right when there is release
What do AT1 receptors do?
tranduce most of the effects of A2 (angiotensin II) including vasoconstriction, sodium reabsorption in the proximal tubule, aldosterone release from teh adrenals and mitogenesis.
*Thus Angiotensin two leads to sodium and water resorption (increase pressure mechanism one) and to arteriolar constriction (increase pressure mechanism two)
Is there a situation where fixing the renal arterial stenosis would not correct HTN?
Yes. The whole principle of the super stuck and stiff pipes (increased TPR due to autoregulation to a higher salt/water retention scheme) takes over here.
*if you wait too long, even removing that stenosis won’t fix the broken kidneys
What are the two patterns of HTN seen in patients with ESRD?
10% - renin levels are markedly increased and maneuvers aimed at decreasing A2 result in a substantial lowering of MAP
90% - volume overload is the primary problem
What’s up with secondary hyperaldosteronism?
aldosterone secretion is driven by increases in plasma renin activity which may occur in a variety of hypertensive and non-hypertensive states
What’s the driving force behind primary hyperaldosteronism?
pathological defect in the adrenal corte usualyl caused by an adenoma or hyperplasia of the adrenal glands
- aldosterone is secreted in large quantities, independent of extra-renal signals
- results in mild expansion of ECF and suppression of plasma renin activity
What clinical features suggest primary hyperaldosteronism?
hypokalemic metabolic alkalosis and resistant HTN
*the aldosterone escape mechanism results in these patients not being edematous though
When you are diagnosing HTN and essential HTN at that, you need to look at what?
First, document increased BP over time.
Second, look for end-organ damage on retinal blood vessels, cerebral vessels, the heart and the kidneys
What elements of overt cerebrovascular or cardiovascular damage can be determined on H and P?
Focal hemorrhagic infarction, transient ischemic episodes, angina, myocardial infarction
What is a hypertensive crisis?
turning point in the course of an illness which acute management of the elevated BP plays a decisive role in the outcome
*examples =
On average, how many different medications a day are patients taking when they reach stage 5 kidney disease?
11 medications. Crazy complicated mess of symptoms
What factors likely diminish F (bioavailability) of drugs in CKD?
the associated symptoms: altered gastric movement, changes in pH, nausea/vomiting, diarrhea
*in particular, cation-containing phosphate binders (used for hyperphosphatemia) and bile acid sequenstrants (hyperlipidemia)
What are the 8 categories of severe hypertensive crisis?
1) Malilgnant hypertension (neuroretinopathy present)
2) hypertensive encephalopathy
3) Non-malignant HTN with acute complications (evidence of end-organ damage but no neuroretinopathy)
4) Catecholamine excess states
5) Preeclampsia and eclampsia
6) Poorly controlled blood pressure in a patient needing an emergent surgery
7) Severe postoperative hypertension
8) scleroderma renal crisis
What are some examples of Non-malignant hypertension (neuroretinopathy is not present) that is still worrisome because of end-organ damage evidence?
- Acute pulmonary edema (hypertensive heart failure)
- acute MI, unstable angina
- acute aortic dissection
- Active bleeding including postoperative bleeding
- ischemic stroke or intracerebral hemorrhage
What are some examples of “catecholamine excess” states?
- phechromocytoma crisis
- monoamine oxidase inhibitor (tyramine interactions)
- Antihypertensive drug withdrawal syndromes (clonidine)
- cocaine and phenylpropanolamine overdose
What is the difference between benign and malignant hypertension?
Based on fundoscopic evaluation
- hypertensive neuroretinopathy (HNR) is the clinical pathognomonic sign for malignant hypertension. If HNR isn’t there, it can’t be malignant hypertension no matter the severity
- HNR is defined by teh presence of striate hemorrhages and cotton-wool spots with or without papilledema. the clinical importance of the finding of HNR is that it signifies the presence of a systemic hypertensive vasculopathy with fibrinoid necrosis and obliterative arteriopathy.
- untreated, malignant hypertension leads to ESRD or death within 1 year
What is HNR?
- HNR = Hypertensive neuroretinopathy is defined by teh presence of striate hemorrhages and cotton-wool spots with or without papilledema. the clinical importance of the finding of HNR is that it signifies the presence of a systemic hypertensive vasculopathy with fibrinoid necrosis and obliterative arteriopathy.
- untreated, malignant hypertension leads to ESRD or death within 1 year
What are the fundascopic signs that scream “malignant hypertension?
*HNR signs = generalized artiolar narrowing, striate (flame-shaped) hemorrhages, cotton-wool spots (soft exudates), bilateral papilledema, star figure at the macula
What does fundascopic evidence of HNR really mean?
(flame-shaped hemorrhages, cotton-wool spots, papilledema, etc). - all evidence of hypertensive neuroretinopathy and pathognomonic for malignant hypertension
- the underlying problem here though is a hypertension induced arteriolitis that may involve the kidneys, heart, and CNS.
- flame-shaped hemorrhages show that autoregulation has failed and the pressure is bursting arterioles
- cotton-wool spots are signs of ischemic infarction of retinal nerve fiber bundles due to such crazy endothelial cell proliferation that arterioles are occluded.
If you see papilledema alone on fundoscopy, does that point to malignant hypertension?
Nope. It more points to something else primarily causing increased ICP.
*when accompanied by flame-shaped hemorrhages and cotton-wool spots, that’s when you think malignant hypertension
What is the pathological evidence of malignant hypertension?
necrotizing arteriolitis in the kidneys and other vital organs
- fibrinoid necrosis of the afferent arterioles is the hallmark of malignant nephrosclerosis
- severe narrowing of interlobular arteries is a common finding due to intimal thickening and fibrin thrombi = proliferative endarteritis or the “onionskin lesion”
what is unfortunately true about black men vs. white men in terms of hypertension?
Black dudes have a much higher risk of developing chronic renal failure due to hypertension then white dudes
what are the goals of hypertension treatment?
Reduce CVD and renal morbididity and mortality
- treat to less than 140/90mmHg non-diabetes
- treat to less then 130/90mmHg in chronic kidney disease and diabetes
- if pt is over 50, work hard to achieve SBP goal
what are the initial drug choices for hypertension without compelling indications?
Stage 1 = SBP 140-159 or DBP 90-99 (give thiazide diuretics as first line. consider ACEI, ARB, BB, CCB or combo)
Stage 2 = SBP over 160 or DBP over 100 (give 2 drug combo for most pts, usually thiazide + ACEI, ARB, BB, CCB)
What’s the main difference between your initial pharm treatment of hypertension in compelling situations vs. non-compelling situations?
non-compelling starts with thiazide and considering the use of thers.
*compelling skips that and goes to the big guns and likely a combo
What are the biggest life-style modifications that can be made in terms of expected blood-pressure changes?
Weight reduction = 5-20mmHg for 10kg loss
- Physical activity = 4-9mmHg drop
- DASH diet (partly salt, partly fats) = 8-14mmHg drop
What is meant by the ABCDs of anti-hypertensives?
A = ACEI/ARB B= Beta blockers C= CCB (dhp or non-dhp) D= diuretics (distal tubule, loop, potassium sparing)
What class is Clonidine and what does it do?
Class= central adrenergic inhibitor Mechanism = decreases CO and TPR
What class is minoxidil and what does it do?
Class = direct vasodilator Mechanism = decreases TPR
What class is doxazosin and what does it do?
Class = peripheral alpha-1 receptor blocker Mechanism = decreases TPR
