Anti-hypertensive and Vasodilator Drugs

Question 0

Where do thiozide diuretics have their site of activity?

Answer 0

On the distal convoluted tubule.

more on this in renal…

Question 1

If you lower BP with a drug, how will the body try to reverse those changes?

Answer 1

With sympathetic activation, RAAS, etc.

Question 2

How do diuretics work acutely? Long term?

Answer 2

Acutely, they cause natriuresis and diuresis (…depending on the diuretic).
Long-term, the body compensates for those changes, but for some people, the diuretics continue to lower BP… perhaps by decreasing SVR somehow via NO.
(In other words, you see a restoration of volume, but not BP.)

Question 3

Why must you be careful using thiazide diuretics in the elderly?

Answer 3

Thiazides are excreted renally.
Elderly people tend to have reduced renal function, so it’s easy to get a buildup of the drug.
Combined with elderly people tending to be dehydrated to begin with, this can be bad.

Question 4

What racial/ethnic group responds particularly well to thiazide diuretics?

Answer 4

African Americans

Question 5

4 notable toxicities of thiazide diuretics?

Answer 5

Sulfa allergy
Hypokalemia
Promotes insulin resistance
Increases LDL and TGs

Question 6

What cardiac parameters do calcium channel blockers (CCBs) modify?

Answer 6

They mainly decrease SVR, but also decrease HR.

Question 7

Which calcium channels do CCBs block?

Answer 7

L-type

Question 8

Which molecule binds to Ca++ to activate contractile elements in vascular smooth muscle? In cardiac myocytes?

Answer 8

In vascular smooth muscle: calmodulin

Cardiac muscle: troponin

Question 9

Why don’t CCBs paralyze your skeletal muscles?

Answer 9

Skeletal muscles aren’t as dependent on extracellular Ca++, so CCBs don’t inhibit their contraction significantly.

Question 10

Functionally, what is the difference between dihydropyridine (DHP) and non-DHP CCBs?

Answer 10

DHPs: bind Ca++ channel in resting state.
Non-DHPs: bind Ca++ channel in active state, thus these drugs more avidly block rapidly firing (e.g. tachycardic) myocytes.

Question 11

2 non-DHP CCBs to remember?

Answer 11

verapamil (Isopten)

diltiazem (Cardizem)

Question 12

1 DHP CCB to remember?

Answer 12

nifedipine (Procardia)

Question 13

Ideal use of a non-DHP CCB?

Answer 13

Supraventricular tachycardia in a patient with pre-existing HTN or angina.
(these also dilate coronary vessels)

Question 14

Are vascular smooth muscle cells frequently depolarized to maintain tone? Thus what kind of CCB would you choose to make them relax?

Answer 14

Vascular SMCs do not frequently depolarize.

Thus a CCB that targets resting cells, i.e. a DHP CCB like nifedipine, would be a good choice to make these guys relax.

Question 15

Most notable side effect of verapamil?

Answer 15

Constipation (makes sense. inhibition of GI smooth muscle)

Question 16

Which CCB would you use to treat SVT without HTN?

Answer 16

Diltiazem - doesn’t cause much vasodilation.

Question 17

What can often happen as a response to the drop in SVR caused by DHP CCBs (such as nifedipine)?

Answer 17

Reflex tachycardia and increased contractility. (this can be bad in someone with CHF, high risk for MI, angina, etc…. can be countered by giving a beta blocker concurrently)

Question 18

Do peripheral vasodilators act through known receptors? Is the vasodilation dependent on innervation?

Answer 18

Nope and nope.

Question 19

3 sites of action of peripheral vasodilators? Example(s) of a drug that does each?

Answer 19

Venous - nitrates
Arterial - hydralazine, minoxidil (Rogaine)
Venous and arterial - nitroprusside

Question 20

DHP vasodilators (e.g. nifedipine) produce reflex tachycardia and increased contractility. Does this happen with peripheral vasodilators?

Answer 20

Yes. Peripheral vasodilators provoke a 10x greater response, including… sympathetic vasoconstriction, increased HR and contractility, and activation of RAAS.

Question 21

Does hydralazine have a preference for dilating any arteries?

Answer 21

Yes - mostly affects renal, peripheral, splanchnic, and coronary arteries.

Question 22

2 toxicities of hydralazine?

Answer 22

Too much vasodilation w. sympathetic reaction. (hypotension, flushing, sweating, palpitations, angina)
Can cause SLE (lupus)-like syndrome.

Question 23

What’s the known MoA of minoxidil?

Answer 23

Activates ATP-modulated K+ channels (apparently, preferentially in arterial smooth muscle). K+ leaves cells, making them hyperpolarized.
(but this probably isn’t the whole story)

Question 24

Notable side effect of minoxidil?

Answer 24

Hypertrichosis - i.e. excessive hair growth.

Topical minoxidil = Rogaine.

Question 25

How does sodium nitroprusside work?

Answer 25

Vascular SMCs metabolize it into NO.

Question 26

What’s the byproduct of sodium nitroprusside metabolism? How is this dealt with?

Answer 26

Cyanide is produced (by breakdown in RBCs).
Mitochondria can break this down with rhodanase to thiocyanate, using the limiting cofactor sodium thiosulfate.
Sodium thiosulfate is administered with sodium nitroprusside.

Question 27

Unusual thing you have to do with sodium nitroprusside preparations?

Answer 27

Cover them in foil, because it’s unstable in sunlight.

Question 28

What’s the “drug of choice” for hypertensive emergencies?

Answer 28

Sodium nitroprusside.

Question 29

You all know about beta blockers.

Answer 29

Sure do. All about them.

Question 30

What are 3 prototypical alpha-antagonists and their specificities?

Answer 30

Prazosin - alpha-1 and alpha-2 antagonist

Doxazosin and Terazosin - pure alpha-1 antagonists.

Question 31

Can you use alpha-antagonists for HTN?

Answer 31

Yes, but it’s really not preferred. Maybe if someone has benign prostatic hypertrophy and also HTN…

Question 32

What’s the deal with centrally acting alpha agonists? Where do they work, and why do they do what they do?

Answer 32

These act in the medulla on pre-ganglionic alpha-2 receptors.
These reduce sympathetic outflow -> unopposed vagal tone.

Question 33

2 examples of centrally acting alpha agonist?

Answer 33

Methyldopa

Clonidine

Question 34

Major problem with methyldopa?

Answer 34

Causes CNS depression - lassitude, drowsiness.

Question 35

For which patients is clonidine particularly good?

Answer 35

Diabetics with HTN and peripheral neuropathy, because it helps prevent autonomic fluctuations.

Question 36

Most adverse effects of central alpha agonism are related to what?

Answer 36

Too much vagal tone -> dry mouth, orthostatic hypotension, bradycardia, somnolence, etc.

Question 37

How do reserpine and guanethidine work? Why aren’t they used?

Answer 37

They deplete NE from synapses.

In the CNS, this effect causes severe depression and suicidality.

Question 38

How low should you try to lower blood pressure?

Answer 38

It depends.

For pts with concomitant renal disease and/or diabetes, for example, you should aim lower.

Question 39

Should lifestyle modifications be tried first to treat HTN?

Answer 39

of course

Question 40

What are 2 less effective combinations of drugs for HTN?

excluding alpha antagonists… which don’t seem to do well in combo with anything

Answer 40

Beta blockers and ACE inhibitors

Diuretics and CCBs