Antihypertensive Part II

Question 1

Intracellular vs. extracellular Calcium concentration

Answer 1

much higher extracellular (10.000x) than intracellular
-> osmotic drive to get into the cells through channels

Question 2

How are the Ca channels regulated?

Answer 2

-cell signaling
-membrane-voltage (voltage-dependent Ca channels VDCC: L, N, T, R)
-f.e. (T) transient Ca channels, (L) long-lasting Ca channels

Question 3

Which Ca2+ channels are targeted by Calcium channel blockers?

Answer 3

mostly the L channels

Question 4

How are smooth muscles unique in terms of contraction?

Answer 4

They can contract and stay contracted
-pyloric sphincter, bladder, or anal sphincter -> stay contracted and prevent leakage involuntarily

MLCK phosphorylates the myosin light chain -> CONTRACTION

can stay contracted until dephosphorylation by the MLCP (phosphatase)

Question 5

Where does the cell get Ca2+ from?

Answer 5

-Extracellular (through Ca2+ channels)

-Sarcoplasmic reticulum

Question 6

Which molecules cause VASODILATION?

Answer 6

-ß2-agonists (Albuterol)
-ANP
-Nitric oxide

-> activation MCLP - removes phosphorylation from myosin light chain -> RELAXATION
-> Inhibition of MCLK

Question 7

How is contractility and HR in the heart regulated?

Answer 7

-Contractility: amount of Ca2+ -> the more the harder the contraction

-heart rate: Na permeability into the SA node

Question 8

How do Calcium channel blockers reduce BP?

Answer 8

lowering Ca2+ input reduces vascular smooth muscular contraction -> lowering CO

Question 9

What are the types of CC-blocker?

Answer 9

-Dihydropyridines:
Amlodipine, Nifedipine, Felodipine

-Non-dihydropyridines (more for cardiac diseases):
Verapamil (Calan)
Diltiazem (Cardizem)

Question 10

Different effects of Dihydropyridines vs. Non-dihydropyridines

Answer 10

Dihydropyridines: greater vascular effect (Vasodilation -> BP)

Non-dihydropyridines: mostly cardiac also vascular -> Arrhythmias
ionotropy (how strong does the heart beat)
chronotropic (how fast does the heart beat, HR)
dromotropy (how fast the AP move from the SA node to the Purkinje fibers)

Question 11

Which patient population benefits from chronotropic drugs?

Answer 11

patients with arrhythmia -> the heart is too excitable
-Non-dihydropyridine CC-blockers

Question 12

Why might Amlodipine be the best CC-blocker?

Answer 12

bc its pharmacokinetic profile
-long half-life -> less fluctuations -> less frequently dosed

Question 13

All CC-blockers are subject to first-pass effect due to CYP 3A4
T or F

Answer 13

True
interaction with CYP3A4 inducer and CYP3A4 substrates

Question 14

Side effects of CC blocker

Answer 14

Non-dihydropyridines: constipation, worsening cardiac output, and bradycardia

Dihydropyridines: light-headedness, flushing, headaches, peripheral edema

Question 15

Effects of lowering body fluid volume through diuretics

Answer 15

-lower blood volume
-lowers venous return
-reduces cardiac output
-lowers blood pressure and heart work

Question 16

MOA for diuretics

Answer 16

Thiazides: Inhibit Na/Cl symporter in the distal convoluted tube

Loops: inhibit Na/K/2Cl symporter in the ascending loop of Henle

K-sparing diuretics (Mineral corticoid receptor antagonists (MRAs): block aldosterone from binding to its receptor in the collecting ducts

-> reduce in Na reabsorption -> more water excretion

Question 17

MOA of Carbon anhydrase inhibitor

Answer 17

-blockage of the CA transporter, preventing H2CO3 reabsorption
-not so often used as a diuretic
-Off-label: glaucoma

Question 18

MOA of K-sparing diuretics

Answer 18

-blocking aldosterone receptor

-blocking gene transcription responsible for upregulating Na-channels on the lumen side and Na-K-ATPase pump on the blood side

Question 19

MOA of thiazides

Answer 19

Inhibiting the Na-Cl Symporter in the distal convoluted tube

Question 20

K-sparing diuretics

Answer 20

Mineral corticoid receptor antagonists (MRAs):
-Spironolactone
-Eplerenone

Na-channel inhibitor:
-Triamterene
-Amiloride

Question 21

Which OTC drug might be prescribed with Loop diuretics?

Answer 21

Potassium supplements due to loss of K+

Question 22

Thiazide diuretics

Answer 22

-Chlorthalidone
-Hydrochlorothiazide (HCTZ)
-Indapamide
-Metolazone

Question 23

Loop diuretics

Answer 23

-Furosemide (Lasix)
-Torsemide (Demadex)

Question 24

What stimulates Aldosterone?

Answer 24

-Angiotensin II
-high K+ -> more Angiotensin II -> Aldesterone -> Na+ -> K+ exchange in the collecting duct -> K+ rxcretion

Question 25

How do alpha-2-agonists reduce BP?

Answer 25

-predominantly in the CNS
-> reduce sympathetic tone -> decrease Vasoconstriction -> decrease CO -> lower BP

-also have peripheral actions -
alpha-2 agonist binds to receptors on presynaptic nerve cells, when blocked there is no NE release

Question 26

Alpha-2-agonists

Answer 26

-Clonidine (prototype): sedation, withdrawal addictive substances, migraine, PTSD, RSD

-Guanfacine: more alpha-2-selective, ADHD

-Methyldopa: alpha-methyldopa -> alpha-dopamine -> alpha-NE

-not a first-line drug for BP anymore

Question 27

Direct acting Vasodilators

Answer 27

Hydralazine (oldest oral antihypertensive)
-vasodilates arterioles, not veins
-causes strong reflex tachycardia

Minoxidil
-restore hair loss
-opens ATP-sensitive K+ channel
-in arterioles the hyperpolarization of SM cells -> Vasodilation