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Flashcards in Antihypertensives Deck (59):




Four major TARGETS of HTN meds

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, thereby decreasing the amount of water in circulation


Four major CLASSIFICATION of HTN meds

1. Diuretics: lower BP by depleting the body of sodium, and thereby reducing blood volume.
2. Sympathoplegic agents: block signals from the SNS, leading to decreased peripheral resistance, decreased inotropy and/or chronotropy of the heart, increased venous pooling.
3. Direct vasodilators: cause vasodilation of resistance and/or capacitance vessels by relaxing the SM in their walls. Does not use SNS.
4. Blockade of the angiotensin-renin-aldosterone pathway, leading to less arterial resistance and increased sodium excretion.


Diuretics (medical term)



Thiazides work by

selectively poisoning the pump/channel or feedback loop in the kidney to trick it into excreting sodium.


Where sodium goes...

water and chloride follow


What is likely to increase with use of a diuretic?

Serum uric acid (can precipitate gout)


Effects of diuretics in the short term... how long does it take to equilibrate?

Due to volume receptor reflexes, the initial decrease in volume will cause SM constriction, increased PVR, increase in the renin/angiotensin system. However, after about 6-8 weeks, CO returns to nml while PVR declines.



Loop diuretic. Trade name Lasix (think lasts six hours). Most potent and effective medicine, causing a brisk and rapid diuresis with lots of sodium loss. Poisons a pump in the thick ascending limb, causing a direct net excretion of sodium and potassium and an indirect excretion of magnesium and calcium. Lasix can also cause metabolic alkalosis.


Side effect of furosemide

Increase in calcium-containing renal stones, as the urine has a higher concentration of calcium.


Chlorothiazide, chlorthalidone, hydrochrolothiazide (HCTZ)

Thiazide diuretics. Poisons a pump in the distal convoluted tubule that reabsorbs NaCl. Indirectly causes increased loss of potassium, but a decreased loss of calcium. Can cause metabolic alkalosis.


How aldosterone effects the renal collecting duct cells

Two sites of action:
1. on interstitial side: increased action of ATP-dependent pump that moves sodium into the interstitium and potassium into the collecting duct cell.
2. on lumenal side: opening and closing of channels that promote sodium diffusion into the collecting duct cell, and potassium diffusion into the lumen of the collecting duct.



Potassium-sparing diuretic, mineralocorticoid. Competitively inhibits the ATP-dependent Na+/K+ pump on the interstitial side of the collecting duct cell, causing sodium to stay in the urine and potassium to stay in the blood. Requires activation by the liver, and takes a few days to a week to start working.

As a synthetic steroid, spironolactone also have activity at androgen and estrogen receptors. Side effects include gynecomastia.



Potassium-sparing diuretic, mineralocorticoid. Competitively inhibits the ATP-dependent Na+/K+ pump on the interstitial side of the collecting duct cell, causing sodium to stay in the urine and potassium to stay in the blood. Better specificity for the pump than spironolactone with a better side effect profile.



Potassium-sparing diuretic. Inhibits the pump on the luminal side of the collecting duct cell, causing sodium to stay in the urine and potassium to stay in the blood.


Why pair beta-blockers with a diuretic?

Typically, the body has reflexes to compensate for a drop in blood pressure. Beta-blockers and diuretics work in tandem to allow the blood pressure to be reduced.


Three sites of action sympathetic HTN drugs act on:

1. Centralling acting sympathoplegics (brain): methyldopa, clonidine
2. Adrenergic neuron-blocking agents: Guanethedine, reserpine
3. Adrenoreceptor antagonists: beta-blockers (propranolol, metoprolol, atenolol, labetalol, carvedilol, esmolol), alpha-blockers (1st group prazosin, terazosin, doxazosin; 2nd group phentolamine, phenoxybenzamine)


Methyldopa, clonidine

Alpha-agonists, primarily alpha-2-agonist activity. Decrease sympathetic outflow from the brainstem, while allowing the brainstem to retain their ability to respond to input from the baroreceptors (resulting in less postural hypotension than some other drugs). Interfere with the brain's ability to make or release NE, or the ability of NE to bind to downstream receptors.



Alpha-agonist with CNS activity. Interferes with the brain's ability to make NE by replacing precursors of NE with breakdown products of the drug, resulting in the synthesis of an altered neurotransmitter (AM-epi or AM-dopa). This alternate NT is stored and released the same as NE, and stimulated central alpha-2-receptors when released. This results in decreased sympathetic tone, manifesting mainly as decreased BP. Main uses include to treat Parkinson's dz, and to control HTN in pregnant women.


Side effects and toxicity of methyldopa

Sedation, nightmares, depression, vertigo, lactation. Positive direct Coombs test in 10-20% taking for more than a year. Hepatitis and drug fever (both reverse with cessation)



Centrally acting alpha-agonist with higher affinity for alpha-2 than alpha-1. Reduces sympathetic tone while increasing parasympathetic tone, resulting in decreased BP and HR, as well as circulating catecholamine levels. It is important to remember the decrease in HR effect, as it can cause cardiogenic shock if another HR lowering drug is added (such as a beta-blocker, verapamil, dilitiazem). Short half life, and must be given QID PO or with a patch.


Clonidine side effects and toxicity

Dry mouth, sedation, depression (can be serious). Cannot be used with tricyclic antidepressants, as it blocks their major mechanism of action. Pts must be warned not to stop the drug suddenly, as this can cause reflexive increases in SNS output resulting in anxiety, tachycardia, HTN (including hypertensive crisis). (other thing about withdrawal once I figure it out)


Adrenergic neuron-blocking agents

Guanethedine, reserpine (these aren't clinically important! whoo hoo!)



Adrenergic neuron-blocking agent (no longer used). Blocks the release of NE from sympathetic nerve endings by replacing it in synaptic vesicles. Activity of guanethedine is blocked by drugs that prevent the uptake of catecholamines into the neuron (cocaine, amphetamine, tricyclic antidepressants). Serious list of side effects, including postural hypotension, retrograde ejaculation, hypertensive crisis when mixed with sympathomimetic cold medicines.



Adrenergic neuron-blocking agent (no longer used). Blocks the uptake of biogenic amines into synaptic vesicles (blocks VMAT transporter). Works both centrally and peripherally, and can therefore effect NE, DOPA, and serotonin. Irreversible. Causes Parkinson's like syndrome (due to dopa deletion), depression. Contraindicated in pts who have Parkinson's, depression, and peptic ulcer dz.


Adrenorecetor antagonists: alpha-blockers

1. Prazosin, terazosin, doxazosin
2. phentolamine, phenoxybenzamine



Non-selective alpha-blocker. Very short acting, reversible. Used to treat pheochromocytoma (tumor of the adrenal medulla that produces catecholamines and causes hypertensive crisis). Cause reflex tachycardia by blocking presynaptic alpha-2 receptors.



Non-selective alpha-blocker. Irreversible, prodrug. Used to treat pheochromocytoma (tumor of the adrenal medulla that produces catecholamines and causes hypertensive crisis). Cause reflex tachycardia by blocking presynaptic alpha-2 receptors.


Selective alpha-1-antagonists

Doxazosin, prazosin, tamsulosin, terazosin. Used to treat HTN (cause contraction of SM via elevation of intracellular calcium) and prostatic hypertrophy (cause relaxation of SM around the urethra). Selective alpha-1-antangonists are good because they allow the PSNS control heart as it needs to. However, there are issues the other way, since reflex tachycardia is blocked, people can have postural hypotension, especially right after starting this drug. Other side effects: parasympathetic overload, stuffy nose, urinary incontinence, poor night vision.


Which selective alpha-1-antagonist is best for treatment of benign prostatic hypertrophy?

Tamsulosin. It is more selective for the alpha-1-blockade in the prostate.


-lolol ending

beta-blockers with exclusive beta-blocking activity


-alol or -ilol ending

beta-blockers with other partial action in addition to their beta-blocking activity


Beta-blocker effect after MI

Reduce mortality


Beta-blocker effects with HF

Some reduce mortality


In severe HTN, beta-blockers prevent what, when the pt is also being treated with direct vasodilators?

Reflex tachycardia


Main purpose of beta-blockers when used in combination with other drugs:

Blockage of reflex response. Used with vasodilators and diuretics


Effects of beta-1-AGONISM

Heart: + chronotrophic, + inotropic, + dromotropic (conduction speed)
Kidney: stimulate renin release, increased ATI ro ATII in the lungs.
Other tissues: stimulate cAMP


Effects of beta-2-AGONISM

Relaxation of SM


Non-selective beta-blockers

Nadolol, propranolol, timolol, pindolol



Atenolol, bisoprolol, esmolol, metoprolol, nebivolol


beta-blockers with alpha-blocking activity

Carvedilol, labetalol



Non-selective beta-blocker, with near equal beta-1 and beta-2 activity. Largely replaced by more selective beta-blockers. Does still have uses as: migraine prevention, treatment of essential tremor, treatment of performance, social, and test-taking anxiety.



Non-selective beta-blocker. Used in eyedrops to treat glaucoma.



Beta-1 selective blocker. 100x more selective for beta-1 than beta-2. Lowers HR, force of muscle contractility, calcium influx inside cardiac myocytes, slowing of conduction through the AV node. Taken several times a day, or as slow release.



Beta-1 selective blocker. 100x more selective for beta-1 than beta-2. Lowers HR, force of muscle contractility, calcium influx inside cardiac myocytes, slowing of conduction through the AV node. Taken one a day.



Beta-1 selective blocker. Very short acting. Given IV. Used to treat tachyarrythmias, hypertensive crisis, or to treat HTN in the OR.



Mixed beta- and alpha-blocker. Activity is about 3:1 beta:alpha blockade. Produces vasodilation (peripheral alpha-1 receptors) with a lower chance of tachycardia (beta-blockade). Used to treat hypertensive emergency. First line therapy for HTN in pregnancy.



Non-selective peripheral alpha- and beta-blocker. More effective antihypertensive than beta-1 selective blockers. Good option for CHF (shown to decrease mortality).



Vasodilator. Directly causes SM to relax. Tachyphylaxis can develop, so this is best used in combination with other drug. Hydralazine and a long-acting nitrate has been shown to be very beneficial in pts with HF and HTN, especially AA pts. Slow acetylators at increased risk of lupus-like syndrome.

Side effects: HA, tachycardia, nausea, sweating, flushing, angina in pts with ischemic heart dz



Vasodilation (arteries) via opening of potassium channels, causing hyperpolarization of SM. Very potent vasodilator of arterioles, but not of veins. Used particularly with hypertensive renal failure pts. MUST be given with very large doses of loop diuretics to prevent sympathetic reflex fluid retention, edema, and CHF, and beta-blockers to prevent reflex tachycardia.

Side effects: hypertrichosis (hair growth), also sold as a topical agent for baldness.


Sodium nitroprusside

Vasodilator (arteries and veins). Administered IV in ICU, ER, OR to treat hypertensive emergencies and severe CHF exacerbations. MOA (release of NO or direct stimulation, causing increased levels of cGMP, causing SM to relax) causes decreased PVR and venous return to the heart, decreasing preload.

Side effects: CN poisoning, especially in pts with renal failure, manifesting as metabolic acidosis, arrythmias, hypotension, and death. Also hypothyroidism and methemoglobinemia.



Vasodilator. Administers IV in the ICU, ER, OR, to treat hypertensive emergencies, though mostly replaced by other drugs. Still used to treat insulin-secreting tumors in the pancreas (blocks extraneous insulin release).



Vasodilator. D1 dopamine receptor agonist, dilates arteries and veins. Administered IV only, in the ICU, ER, OR.

Side effects include HA, flushing, increased intraocular pressure. Drug should not be given to pts with glaucoma.


Calcium channel blocker types

Dihydropyridines: amlodipine, nicardipine, nifedipine, isradipine

Non-dihydropyridines: verapamil, diltiazem

CCBs work by binding the alpha-1 subunit of the voltage-gated L-type calcium channel, reducing the frequency of opening in response to depolarization. This decreases calcium influx, resulting in relaxation of muscle. In cardiac muscle, contractility is reduced, sinus node rate decreases, and AV nodal conduction decreases, as well. Skeletal muscle not significantly effected, as it has a large intracellular pool of calcium.



Amlodipine, nicardipine, nifedipine, isradipine. CCB with selectivity for peripheral tissue SM. Much more action in vascular SM than myocytes or conduction cells in the heart. Dihydropyridines are used to treat HTN, and are not useful in the treatment of arrhythmias. These four drugs are mainly different in their half-lifes. Amlodipine takes about a week to build up and is dosed once a day (need bridging drug). Nifedipine can bring BP down too quickly, and is therefore not used for chronic HTN.

Other indications for short-acting CCB: Reynaud's phenomenon, coronary vasospasm, angina.

Nifedipine used to treat HTN in pregnancy.

CCB have a negligible effect on renal perfusion, as long as the pt remains normotensive.



Verapamil, diltiazem. CCB having a stronger effect on the heart than on the peripheries (at usual doses). Used to treat arrhythmias.

Verapamil in particular suppresses HR and CO.

Diltiazem has less cardiac effect than verapamil, but is still used more often to treat arrhythmias than HTN.


Side effects of CBB

Flushing, dizziness, nausea, peripheral edema.


Four options when blocking the renin-angiotensin-aldosterone response

1. Block renin (which prevents angiotensinogen being converted to angiotensin I) (Aliskiren)
2. Block ACE (which prevents ATI being converted to ATII), (only option that interferes with bradykinin)
3. Block ATII from binding to it target receptor (angiotensin receptor blockers, or ARBs)
4. Block the endocrine response from the adrenal medulla (aldosterone) from binding and activating channels in the renal collecting duct cells (diuretics)


ACE inhibitors

Captopril, lisinopril, benazepril. Works two ways: 1. prevents the conversion of ATI to ATII. 2. increases the effects of bradykinin (causing vasodilation). Majority of drugs are prodrugs. MOA: affect the ability of the kidney to autoregulate the efferent arteriole.