Antihypertensives I and II Flashcards Preview

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Flashcards in Antihypertensives I and II Deck (59):
1

What are the two direct vasodilators?

Hydralazine
Minoxidil

2

Are the direct vasodilators working on veins or arterioles?

Arterioles

3

What is the major effect of arteriolar vasodilation?

Decreased afterload

4

What other effects result from the arteriolar vasodilation?

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

5

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

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)

6

Which is the more potent direct vasodilator?

Minoxidil

7

What is a potential side effect of minoxidil?

Hypertrichosis (hair growth, rogaine)

8

What is a potential side effect of hydralazine?

Lupus-like syndrome (malaise, arthralgia, vasculitis)

9

How is minoxidil activated?

Gets sulfated in liver
Therefore cannot be given by injection

10

What are the channels opened by minoxidil?

ATP-sensitive K+ chanels (K-ATP)

11

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

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

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

12

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

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

13

What happens to smooth muscle cell that is hypoxic?

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

14

What causes the production of adenosine?

Decrease in ATP, increase in ADP

15

What is the mechanism of action of adenosine?

Opens K-ATP channels causing vasodilation

16

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

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

17

What is the mechanism of action of sulfonylureas?

Inhibit K-ATP channels, causing insulin release
Thereby acts as a glucose lowering agent

18

What is the mechanism of action of diazoxide?

Opens K-ATP channels, causing decreased insulin release

19

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

SUR1
Kir 6.2

20

What inhibits the SUR1 subunit of K-ATP channel?

Sulfonylureas

21

What activates the SUR1 subunit of K-ATP channel?

Diazoxide
ADP

22

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

ATP

23

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

VSM

24

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

Cardiac
VSM

25

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

Pancreatic
VSM

26

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

They are mitochondrial K-ATP channels

27

Describe the concept of ischemic preconditioning

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

28

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

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

29

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

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

30

What is the role of adenosine in ischemic preconditioning?

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

31

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

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

32

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

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

33

What is the mechanism of reserpine?

Irreversibly blocks VMAT
Causes depletion of NE in storage vesicles

34

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

Sedative, tranquilizer

35

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

Peripheral sympatholytic, causes vasodilation

36

What are some of the adverse CNS effects of reserpine?

Increased risk of clinical depression
Exacerbation of parkinsonism

37

What is the mechanism of clonidine and methyldopa?

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

38

What patient population is methyldopa a first line antihypertensive?

Pregnant patients

39

What are adverse effects of central alpha-2 agonists?

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

40

What is the mechanism of action of metyrosine?

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

41

What is a major clinical use of metyrosine?

Used in management of inoperable pheochromocytomas

42

What are the two categories of calcium channel blockers?

Dihydropyridines (DHPs)
Non-DHPs

43

What drugs are the DHPs?

Nifedipine
Amlodipine

44

What drugs are the non-DHPs?

Verapamil
Diltiazem

45

Are the calcium channel blockers primarily arteriolar or venous vasodilators?

Arteriolar

46

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

Dilates coronary arteries
Useful in coronary vasospasm

47

Do DHPs or nonDHPs have cardiodepressant action?

NonDHPs

48

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

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

49

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

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

50

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

0 - rare opening

51

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

Closed
Open
Inactivated

52

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

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

53

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

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

54

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

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

55

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

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

56

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

Decreased contractility
Reduced inward Ca current during plateau phase

57

What are adverse effects for DHPs?

Hypotension, flushing, headache
Reflex sympathetic activation
Swollen ankles

58

What are adverse effects for nonDHPs?

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

59

How are calcium channel blockers metabolized?

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