Antihypertensive Drugs Flashcards
Cutoff for hyeprtension
>130/80
Two pathways to reduce blood pressure
BP = CO x SVR
either decrease cardiac output or decrease systemic vascular resistance
4 main targets of antihypertensive drugs
1) decrease arteriole resistance
2) increase the blood volume held in reserve or capacitance vessels
3) decrease the force or volume with which the heart is pumping blood out into the vessels
4) decrease the intravascular volume by tricking the kidney into letting go of more salt..because where salt goes, water follows.
Major classifcations of hypertensives
- Diuretics: lower BP by depleting the body of sodium (Sodium=Satan when it comes to HTN), reducing blood volume
- Sympathoplegic agents: literally, “paralytics of the sympathetic system” turn down or block the signals of the sympathetic system, which means there is: decreased peripheral resistance, decrease inotropy or chronotropy of the heart, and increased venous pooling.
- Direct vasodilators: without using the SNS mechanism, these drugs cause vasodilation of resistance and/or capacitance vessels via relaxation of the smooth muscle in their walls
- Stuff that blocks any part of the angiotensin-renin-aldosterone pathway; this means less arterial resistance because the direct vasoconstrictor effect of ATII is blocked, as well as making it easier to excrete sodium by blocking the effect of aldosterone
How can diuretics reduce BV over time
6-8 weeks after initiation of diuretic therapy, cardiac output returns to normal and peripheral vascular resistance declines. The mechanism is thought to be that the overall decrease in sodium affects sodium-calcium exchange and reverses vessel stiffness and neural reactivity to sympathetic stimulation.
Loops diuretics and mechanism
Furosemide (Lasix) and Bumetanide (Bumex)
They poison a pump on the thick portion of the ascending limb of the loop of Henle, directly causing net excretion of sodium and potassium.
They also have an indirect effect that causes net excretion of magnesium and calcium.
Loop diuretics side effects
Lasix also causes a metabolic alkalosis, due mainly to its action causing volume contraction in the body which causes excretion of H+ ions down the nephron.
Patients who make calcium-containing renal stones will get more renal stones if you start these drugs!
Thiazide diuretics and mechanism
Chlorothiazide, chlorthalidone, hydrochlorothiazide
Thiazides poison a pump in the distal convoluted tubule that reabsorbs sodium chloride, which causes downstream increases in potassium loss and overall volume contraction.
Thus, both thiazides and loops cause a net loss of sodium and potassium and they both also cause a metabolic alkalosis.
However, thiazides cause a net reabsorption of calcium, the opposite of the loop diuretics.
Potassium-sparing diuretics and mechanism
Spironoloactone, eplerenone, triamterene
Spironolactone MOA: synthetic mineralocorticoids that fit the receptor but do not stimulate it to actually work, blocking its usual function on increasing ATP-dependent reclamation of NA and dumping of K+. Functionally, they are competitive antagonists.
Triamtere MOA: By blocking sodium influx into the cell and keeping it in the urine, this drug promotes net loss of sodium and blocks loss of potassium, promoting net gain of potassium.
Effects of aldosteorne on the tubule
- On the interstitial side, the ATP-dependent pumping of sodium back to body and potassium into the tubular cell.
- On the luminal side, the opening and closing of channels that promote diffusion of sodium back into cell and potassium out of cell and into urine for excretion.
Potassium-sparing diuretics side effects
Being a synthetic steroid, spironolactone also has activity on androgen and estrogen receptors and requires activation by the liver and takes a few days to a week to start working.
Thus, one of its major side effects include gynecomastia (increase in breast tissue.) Eplerenone does this less than spironolactone.
side effect of all diuretics
All diuretics increase serum uric acid levels and can precipitate gout.
How does the body respond to drop in bp from block to sympathetics
1) increased sodium resorption from kidneys via RAAT axis and 2) increasing heart rate
usually necessary to pair them with a diuretic and a beta blocker when they are used clinically for hypertension
Centrally acting alpha-2 agonists (brain) and mechanism
methyldopa, clonidine
These drugs act to decrease sympathetic outflow from the brainstem, while allowing these centers to retain their ability to respond to input from baroreceptors. This means that they have less postural hypotension than some other sympathoplegic drugs we will discuss later. They do this one of 3 ways, all of which involve norepinephrine:
intefere with the brain’s ability to make norepinephrine,
or the ability to release norepinephrine,
or the ability of N-epi to bind to a downstream receptor.
How is NE different in the CNS vs PNS
Methyldopa MOA
Removes effectiveness of negative feedback by acting as a substrate for the enzyme that makes NE
Clonidine MOA
Agonist for NE a-2 and autoreceptor post-synaptically
Methyldopa side effects and pregnancy?
This is also one of the agents that is able to be used in pregnancy for HTN.
Side effects and toxicity: sedation, nightmares, depression, vertigo, and lactation due to inhibition of dopamine and its effect on prolactin secretion. 10%-20% of patients taking for a year or more develop a positive direct Coombs test.
Hepatitis and drug fever are also relatively common, and these abnormalities reverse with stopping the drug.
Clonidine side effects
The decrease in HR is REALLY IMPORTANT as you can throw folks into cardiogenic shock if you forget that central alpha-agonists have this effect and start them on a second drug that lowers HR.
Side effects and toxicity: dry mouth, sedation due to its primary autonomic effect. Depression can occur and can be serious; the drug should not be used in patients with depression and if depression occurs the drug should be stopped.
This drug should not be used with tricyclic antidepressants as it blocks their major mechanism of action.
Clonidine is also used to treat abuse drug withdrawal syndromes from opioids and benzodiazepines and through its effect in decreasing sympathetic tone and if given with these CNS depressant drugs can potentiate the effect (and CNS toxicity or death.)
Sudden discontinuation of clonidine in a patient who is used to it can cause dangerous reflexive increases in sympathetic output, and all patients must be warned not to stop the drug suddenly.
Adrenergic neuron storage and release blockers
guanethidine and reserpine
Guanethidine MOA
Blocks the release of N-epi from the sympathetic nerve ending by replacing it in the synaptic vesicle.
Because uptake of the drug by the neuron is required for it to work, anything that blocks the uptake of catecholamines into the neuron or the amine pathway blocks the activity of the drug. Thus, cocaine, amphetamine, tricyclic antidepressants, and other drugs block its effects.
Guanethidine side effects
Its side effect profile is remarkable for postural hypotension and retrograde ejaculation (yowza!) and the precipitation of hypertensive crisis in patients on the drug who take sympathomimetic cold medicines.
Reserpine MOA
Blocks the vesicle-membrane-associated transporter (VMAT) that takes up biogenic amines for storage in the synaptic vesicle.
Works centrally and peripherally and thus affects the production of N-epi, dopa, and serotonin, decreasing their production.
Irreversible until new VMAT made
Side effects of reserpine
causes a Parkinson’s like syndrome due to dopa depletion in corpus striatum as well as, predictably, horrible depression, and both conditions are a contraindication to as well as a reason to immediately discontinue the drug.
Do not give in peptic ulcer disease as it increases gastric acid secretion.
Non-selective alpha blockers and MOA
phentolamine and phenoxybenzamine
Equally block a1 and a2 receptors so produce vasodilation (block a1) and reflex tachycardia (bloack a2)
Both are predominantly used in pheochromocytoma, a tumor of the adrenal medulla that produces catecholamines and causes hypertensive crisis.
Phentolamine is a very short acting, reversible blocker of these receptors.
Phenoxybenzamine is an irreversible antagonist, a prodrug that is activated in the body.
Selective alpha 1 blockers and MOA, side effects
Doxazosin, prazosin, tamsulosin, terazosin
Block the hypertensive effects of alpha-1 peripherally but leave the presynaptic alpha-2 receptor UNBLOCKED, preventing reflex tachycardia that occurs with the nonselective alpha-1 blockers.
because the reflex tachycardia is blocked, folks tend to pass out when they stand up suddenly, particularly right after they start this med. This is called “first dose effect’
Tamsulosin has the most selectivity for alpha-1-blockade in the prostate with least impact on blood pressure
What is an urgent indication for the use of beta blockers?
Post MI and heart failure
Action of Beta receptors
Beta-1 agonist effects
Heart: + chronotropic, + inotropic, + dromotropic (conduct thru AV node faster). So, beta blockade would do the opposite.
Kidney: stimulate renin release, increasing conversion of ATI to ATII in the lungs. So, beta-blockers do the opposite.
Other tissue: stimulate cAMP, So beta-blockers do the opposite.
Beta-2 agonist effects
Generally, these cause relaxation of smooth muscle.
They also have the same effect of turning on adenylate cyclase and increasing cAMP as B1 receptors. So, beta-blockers with beta-2 activity do the opposite.
Rules for naming of beta blockers
Drugs that end in “lolol” have functionally nothing but beta-blocking action anywhere.
If the name starts with A-N, it’s beta-1 selective
If the name starts with O-Z, it’s non-selective.
-Drugs that end in “alol” or “ilol” have another partial action outside of their beta-blocking function. They act like a combination of alpha-blockers and beta-blockers.
B-1 selective beta blockers and effects
Metoprolol, Esmolol:
Esmolol is a very short acting IV beta-blocker that is used for arrythmia management. Metoprolol and atenolol are oral BBs that are 100x more beta-1 selective blocking than beta-2, thus having a major effect on:
lowering HR,
lowering force of heart muscle contractility and calcium influx inside cardiac myocytes, and
slowing conduction through the AV node.
nonselective beta blocker and use
Propranolol: nonselective, beta-1 activity is = to its beta-2 activity. It does have a role in migraine headache prevention, treatment of essential tremor, and (due to its good lipid solubility) treatment of performance, social, and test-taking anxiety. Lots of med students take it!
Labetalol effects and use
Labetalol is a mixed BB and alpha-blocker. Its activity is about 3:1 for beta blockade vs alpha blockade.
Its vasodilator effects are due predominantly to the blockade of peripheral alpha-1 receptors while still blocking B1 and B2 receptors,
This means it is a vasodilator that is less likely to cause tachycardia.
This is first-line for hypertension in pregnancy.
Carvedilol effects and use
Carvedilol has nonselective peripheral alpha and beta blocking properties!
This makes it a more effective antihypertensive than beta-1 selective agents.
Its beta-blocking properties help it retain all of the other benefits of beta-blockers.
This combination makes it a great choice of beta-blocker for patients with congestive heart failure, in whom it has been shown to decrease mortality.
Which hypertensives can have rebound effect if stopped suddenly
Clonidine, beta-blockers
Hydralazine MOA
Hydralazine works directly on arteriolar smooth muscle to cause it to relax.
Hydralazine side effects
First-dose effect can make patients have symptomatic orthostatic hypotension, causing falls and injuries; patients should be warned to get up slowly for the first few doses as their body adjusts to the medication
Tachyphylaxis can develop, (decreased effectiveness with continued use) and so it is best used in combination therapy with other drugs.
The combination of hydralazine with long-acting nitrates (isosorbide dinitrate or isosorbide mononitrate, which will be covered later) is particularly effective in patients with heart failure and hypetension
The drug is metabolized via acetylation, and slow acetylators have an increased risk of a lupus-like syndrome with positive anti-histone antibodies when on the drug.
Other side effects are related to vasodilation, including headache, tachycardia, nausea, sweating, and flushing.
It can provoke angina in patients with ischemic heart disease if reflex tachycardia occurs due to not using it with a beta-blocker.
Minoxodil MOA
opening of potassium channels, causing hyperpolarization of smooth muscle and thus making depolarization and contraction less likely.
Very potent vasodilator, dilates arterioles, not veins.
Minoxodil side effects
Must be given with very large doses of loop diuretics to prevent sympathetic reflexive fluid retention, edema, and CHF.
Also give with B-blockers to prevent reflexive tachycardia.
A unique side effect, hair growth (hypertrichosis), caused the drug to also be licensed as a topic agent for baldness!
Sodium nitroprusside MOA and use
MOA is activation of guanylyl cyclase via release of NO or by direct stimulation of the enzyme. This increases intracellular cGMP, relaxing vascular smooth muscle.
Administered IV in the ICU or ER or OR environments for hypertensive emergencies as well as severe CHF exacerbations.
Dilates arteries AND veins, resulting in decreased PVR and venous return to the heart, decreasing preload.
Sodium nitroprusside side effects
It is literally made from cyanide, which is also the source of its most serious toxicity: cyanide poisoning in patients that can’t metabolize the drug fast enough when it is given at a high rate, especially patients with renal failure.
This looks like metabolic acidosis (due to lactic acidosis from poisoning of mitochondria), arrythmias, hypotension, death.
Hypothyroidism or methemoglobinemia can also occur.
Diazoxide MOA and use
MOA is theorized to be similar to minoxidil, blockade of potassium channels.
It is now being abandoned as an antihypertensive but because of its mechanism of action is used for the treatment of insulin-secreting tumors in the pancreas (insulinoma) to prevent hypoglycemia by blocking release of insulin from the tumor.
Fenoldopam MOA and use
D1 dopamine receptor agonist, dilating arteries and veins.
One of the few antihypertensives that is theorized to increased renal perfusion
Fenoldopam side effects
Major toxicities related to vasodilation: headache, flushing, etc common to all vasodilators.
Another toxicity is increased intraocular pressure, this should thus be avoided in patients with glaucoma.
Dihydropyridines bind preferentially to:
vascular smooth muscle only and are thus used extensively for hypertension
Non-dihydropyridines bind to:
cardiac myocytes and electrical tissue, resulting in reduction of contractility, decreases in sinus node rate of firing, and AV nodal conduction. (Inotropy, chronotropy, and dromotropy, like the effect seen with a beta-blocker!) These drugs depress cardiac function at doses that have little to no effect on HTN, and are thus used for arrhythmias primarily.
Common mechanism for calcium channel blockers
They all bind intracellularly on the the alpha-1 subunit of the transmembrane voltage-gated L-type calcium channel, but the two groups bind at different sites.
Binding of the drug reduces the frequency of opening of the calcium channel in response to depolarization of the membrane.
This decreases calcium influx, resulting in relaxation of muscle or decreased rate/preference for depolarization.
Dihydropyridines and MOA
“dipine” amlodipine, nifedipine
All have selectivity for peripheral tissue smooth muscle and act on vascular smooth muscle much more than on cardiac myocytes or the electrical conduction of the heart. They are thus used for HTN and not for arrythmias!
Difference between amlodipine and nifedipine
The main difference between these agents is their half life; when starting amlodipine (Norvasc), it will work sometime next week vs. that day. It’s great for compliance, though, because it can be taken once a day. So, other agents need to be used while waiting for the amlodipine to take effect.
Short-acting CCBs from this class are also used to treat Raynaud’s phenomenon or coronary vasospasm and angina. Nifedipine is another preferred drug for HTN in pregnancy.
Non-dihydropyridines and MOA
verapamil and diltiazem
The non-dihydropyridines verapamil and diltiazem have more effect on the heart than on the peripheral BP at usual doses. Its major use is as an antiarrythmic.
Non-dihydropyridine CCB’s are contraindicated in heart failure patients with a decreased ejection fraction, as they will decrease contractility.
CCBs side effects
All CCBs have similar other toxicities to other vasodilators; flushing, dizziness, nausea, peripheral edema. They are some of the easiest drugs to use in paients with renal failure as their effect on renal perfusion is negligible (as long as the pt remains normotensive.)
What are the 4 options when blocking the renin-angiotensin-aldosterone response
1) Block the enzyme renin, which blocks Angiotensinogen–>ATI conversion (aliskiren) Note that this will have downstream effects in two ways.
2) Block the enzyme ACE, which blocks ATI–>ATII conversion (many ACE inhibitors, know lisinopril, enalapril, captopril in this class. They all end in -pril to help you.) Note that this will have downstream effects in three ways. Note also that this will also block the breakdown of bradykinin and cause buildup of bradykinin, with downstream positive effects.This is the only step that interferes with bradykinin.
3) Block ATII from binding to its target receptor (several angiotensin receptor blockers, or ARBs) Note that this will have downstream effects in two ways. They all end in -sartan: losartan, valsartan, and there are many more.
4) Block the endocrine response from the adrenal medulla, aldosterone, from binding to and activating its 2 major effects on the renal collecting duct cell. (we covered those on the diuretics page when we talked about the 2 groups of potassium-sparing diretics.)
What are the ACE inhibitors and MOA
lisinopril, enalapril, captopril
The normal effect of ATII on the renal arteriole is to preferentially constrict the efferent arteriole more than the afferent, preserving GFR. The kidney thinks you are bleeding to death and adjusts accordingly.
Unfortunately, in chronic HTN, AT II is chronically elevated, and that action of AT II on the GFR causes hyperfiltration injury to the glomerulus long term.
Giving an ACE-I causes relaxation of the efferent arteriole (due to decreased ATII effect at that site) and decreased filtration pressure.
Inhibiting this efferent arteriolar constriction decreases filtration pressure, preserving renal function in chronic diseases like HTN and diabetes
This will also cause the creatinine to rise, since less of the blood is being filtered. A rise to total of 130% of former baseline is acceptable as long as potassium and phosphate stay within normal range.
ACE inhibitors toxicity
Renal function MUST be checked a week or so after starting an ACE-I; an increase of up to 130% of the former baseline creatinine is expected and is OK; more than that, or hyperkalemia or hyperphosphatemia may indicate renal artery stenosis should be evaluated and is a reason to stop the drug.
Hyperkalemia can also occur and can be dangerous
Dry cough due to bradykinin buildup is common and can be annoying anough that people stop the drug. Patients susceptible to angioedema can be triggered by starting this drug, due again to bradykinin. These drugs are absolutely contraindicated in pregnancy because they are direct teratogens and affect fetal renal development. NSAIDs may interfere with the bradykinin effect and block usefulness of these drugs.
Angiotensin-receptor Blockers (ARBs) and uses
Losartan, candesartan, valsartan
Have no effect in bradykinin
They have similar benefits to patients with heart failure and chronic kidney disease as ACE-I’s. These are commonly used in patients that can’t tolerate an ACE-I due to cough. Their clinical use, side effect and toxicity profile is otherwise very similar to the ACE-I’s. We prescribe one or the other to patients, not both!
DIrect renin inhibitor and use
Aliskiren
Aliskiren suppresses plasma renin activity and produces similar BP effects as ACE-I and ARBs. It is also contraindicated in pregnancy, and was initially used in combination with an ACE-I or ARB to combat the rise in renin seen when those drugs are used, but combination use of aliskiren with these agents has stopped due to increased toxicity seen in recent trials.
