Antihypertensives I and II

Question 1

What are the two direct vasodilators?

Answer 1

Hydralazine

Minoxidil

Question 2

Are the direct vasodilators working on veins or arterioles?

Answer 2

Arterioles

Question 3

What is the major effect of arteriolar vasodilation?

Answer 3

Decreased afterload

Question 4

What other effects result from the arteriolar vasodilation?

Answer 4

Nonpostural fall in BP
LV filling pressure high
Reflex increase in cardiac work and HR
Reflex increased plasma renin

Question 5

The reflex increase in cardiac work & HR and reflex increase in plasma renin caused by direct vasodilators can ultimately result in ______

Answer 5

Increased BP (not the goal of vasodilators)

Must block these two reflexes from occurring using a beta blocker and a diuretic
(Therefore direct vasodilators are 3rd or 4th line antihypertensives)

Question 6

Which is the more potent direct vasodilator?

Answer 6

Minoxidil

Question 7

What is a potential side effect of minoxidil?

Answer 7

Hypertrichosis (hair growth, rogaine)

Question 8

What is a potential side effect of hydralazine?

Answer 8

Lupus-like syndrome (malaise, arthralgia, vasculitis)

Question 9

How is minoxidil activated?

Answer 9

Gets sulfated in liver

Therefore cannot be given by injection

Question 10

What are the channels opened by minoxidil?

Answer 10

ATP-sensitive K+ chanels (K-ATP)

Question 11

What causes K-ATP channels to open and what does the opening do to the membrane potential?

Answer 11

Decreased ATP, increased ADP causes channel opening (decreased metabolic state)

K+ leaves the cell, membrane hyperpolarizes, reduces energy demand of the cell

Question 12

What happens to the K-ATP channels in cardiac myocyte that is hypoxic/ischemic?

Answer 12

Hypoxia/ischemia –> ATP decreases, ADP increases –> K-ATP channels open –> AP duration decreases, contractility decreases –> energy demand decreases

Question 13

What happens to smooth muscle cell that is hypoxic?

Answer 13

Hypoxia –> ATP decreases, ADP increases –> K-ATP channels open –> muscle hyperpolarizes –> Ca2+ channels close –> relaxation of vascular smooth muscle
–> increased blood flow

Question 14

What causes the production of adenosine?

Answer 14

Decrease in ATP, increase in ADP

Question 15

What is the mechanism of action of adenosine?

Answer 15

Opens K-ATP channels causing vasodilation

Question 16

What happens to K-ATP channels in pancreatic beta cells when there is an increase in blood glucose?

Answer 16

Increased blood glucose –> Increased ATP, Decreased ADP –> K-ATP channels close –> Ca2+ channels open
–> insulin release increases

Question 17

What is the mechanism of action of sulfonylureas?

Answer 17

Inhibit K-ATP channels, causing insulin release

Thereby acts as a glucose lowering agent

Question 18

What is the mechanism of action of diazoxide?

Answer 18

Opens K-ATP channels, causing decreased insulin release

Question 19

What are the two subunits of the pancreatic Beta cell K-ATP channel?

Answer 19

SUR1

Kir 6.2

Question 20

What inhibits the SUR1 subunit of K-ATP channel?

Answer 20

Sulfonylureas

Question 21

What activates the SUR1 subunit of K-ATP channel?

Answer 21

Diazoxide

ADP

Question 22

What inhibits the Kir 6.2 subunit of K-ATP channel?

Answer 22

ATP

Question 23

What type of K-ATP channels (VSM, cardiac, pancreatic) is minoxidil selective for?

Answer 23

VSM

Question 24

What type of K-ATP channels (VSM, cardiac, pancreatic) is adenosine selective for?

Answer 24

Cardiac

VSM

Question 25

What type of K-ATP channels (VSM, cardiac, pancreatic) is diazoxide selective for?

Answer 25

Pancreatic | VSM

Question 26

What is unique about the K-ATP channels involved in the cardioprotectant mechanisms of diazoxide and adenosine?

Answer 26

They are mitochondrial K-ATP channels

Question 27

Describe the concept of ischemic preconditioning

Answer 27

A previous short period of ischemia protects the heart when a longer period of ischemia occurs

Question 28

What occurs in the early phase (<3 hrs) of ischemia to be protective?

Answer 28

Mitochondrial K-ATP channels open --> closure of mitochondrial permeability transition pore --> sustained mitochondrial function

Question 29

What occurs in the late phase (24-48 hrs) of ischemia to be protective?

Answer 29

Reperfusion injury salvage kinases (RISK) --> gene transcription --> increased expression of protective proteins like heat shock proteins and superoxide dismutase

Question 30

What is the role of adenosine in ischemic preconditioning?

Answer 30

Binds Adenosine receptors in the heart, causing opening of both sarcolemmal and mitochondrial K-ATP channels

Question 31

What is the role of adenosine in the nuclear stress test?

Answer 31

Dilates arterioles in normoxic myocardium, diverting flow from the hypoxic region and enhancing contrast between hypoxic and normoxic areas

Question 32

What drugs should be avoided during ischemic pre/post conditioning?

Answer 32

Sulfonylureas - inhibit K-ATP channels Methylxanthines (caffeine, theophylline) - adenosine receptor antagonists, can prevent adenosine from opening mitochondrial K-ATP channels

Question 33

What is the mechanism of reserpine?

Answer 33

Irreversibly blocks VMAT | Causes depletion of NE in storage vesicles

Question 34

When used in a large dose, what does reserpine do?

Answer 34

Sedative, tranquilizer

Question 35

When used in a lower dose, what does reserpine do?

Answer 35

Peripheral sympatholytic, causes vasodilation

Question 36

What are some of the adverse CNS effects of reserpine?

Answer 36

Increased risk of clinical depression | Exacerbation of parkinsonism

Question 37

What is the mechanism of clonidine and methyldopa?

Answer 37

Central alpha-2 agonists Decrease sympathetic outflow to cardiovascular system (inhibit NE release) Baroreceptor reflexes remain intact

Question 38

What patient population is methyldopa a first line antihypertensive?

Answer 38

Pregnant patients

Question 39

What are adverse effects of central alpha-2 agonists?

Answer 39

Drowsiness, somnolence Dry mouth Sudden withdrawal causes excess of sympathetic outflow, resulting in exacerbation of hypertension

Question 40

What is the mechanism of action of metyrosine?

Answer 40

Competitive inhibitor of tyrosine hydroxylase | Inhibits formation of NE at rate limiting step

Question 41

What is a major clinical use of metyrosine?

Answer 41

Used in management of inoperable pheochromocytomas

Question 42

What are the two categories of calcium channel blockers?

Answer 42

Dihydropyridines (DHPs) | Non-DHPs

Question 43

What drugs are the DHPs?

Answer 43

Nifedipine | Amlodipine

Question 44

What drugs are the non-DHPs?

Answer 44

Verapamil | Diltiazem

Question 45

Are the calcium channel blockers primarily arteriolar or venous vasodilators?

Answer 45

Arteriolar

Question 46

What is the action of calcium channel blockers on coronary arteries?

Answer 46

Dilates coronary arteries | Useful in coronary vasospasm

Question 47

Do DHPs or nonDHPs have cardiodepressant action?

Answer 47

NonDHPs

Question 48

At what type of L-type Calcium channels do calcium channel blockers act?

Answer 48

1.2 and 1.3 No effect on skeletal muscle or retina Main effects on cardiac muscle and vascular smooth muscle (vasodilator)

Question 49

What are the different gating modes of the L-type calcium channel?

Answer 49

2 - long-opening 1 - brief-opening 0 - rare-opening

Question 50

Which mode of the calcium channel is stabilized by calcium channel blockers?

Answer 50

0 - rare opening

Question 51

What are the different conformations of the L-type calcium channel?

Answer 51

Closed Open Inactivated

Question 52

What conformation of the calcium channel do nonDHPs bind tighter to?

Answer 52

Open Bind more tightly when channel is phasic between open and closed conformations (i.e. in cadiac muscle) Hence, better cardiodepressant effect for nonDHPs

Question 53

What conformation of the calcium channel do DHPs bind tighter to?

Answer 53

Inactive | Find more inactive state in tonically depolarized cells (always some calcium mediated contraction and tone maintained

Question 54

What happens to heart rate when cardiac L-type channels are blocked?

Answer 54

Decreases Because SA node automaticity is decreased Slows rate of upstroke of action potential

Question 55

What happens to conduction velocity when cardiac L-type channels are blocked?

Answer 55

Decreased conduction velocity Because AV node conduction is slowed Slows rate of upstroke of action potential

Question 56

What happens to cardiac contractility when cardiac L-type channels are blocked?

Answer 56

Decreased contractility | Reduced inward Ca current during plateau phase

Question 57

What are adverse effects for DHPs?

Answer 57

Hypotension, flushing, headache Reflex sympathetic activation Swollen ankles

Question 58

What are adverse effects for nonDHPs?

Answer 58

``` LV dysfunction (decreased contractility) AV block (slowed conduction) Avoid combination with beta-blockers (similar cardiodepressant effect) GI (constipation) ```

Question 59

How are calcium channel blockers metabolized?

Answer 59

By CYP450 enzyme CYP3A4 in the liver | Avoid combination with competitive substrates/inhibitors of CYP3A4 (like statins, grapefruit juice)