L13- Direct Vasodilators

Question 1

What are the direct vasodilators? How do they work?

Answer 1

Hydralazine (prototype - uknown mechanism)

Minoxidil (KCO)

Selectively dilate the small arteriole resistance vessels (more artierolar dilation than venodilation)

Question 2

Compare and contrast venodilation vs arteriodilation

Answer 2

Venodilation - Decreased preload!!! Postural fall in BP; decreased LV filling pressure and pulmonary BP.
Caused by Organic nitrates

Used for Pulmonary congestion and MI

Arteriodilation - decreased afterload!!! Non-postural fall in BO, increased LV filling pressure, Increased PRA for salt and water retention, Reflex increase in cardiac work and HR

Caused by Hydralazine
Used for weak pump or poor organ perfusion

Question 3

What is pseudotolerance? Why can it develop in arteriodilation?

Answer 3

Reflexive increase in CO, HR, and salt/water retention

Increased CO as a response to initial decrease in BP from direct vasodilators

These drugs are usually used in conjunction with a beta blocker (to block sympathomimetic effect) and a Diuretic (to block PRA increase)

Question 4

Similarities between Hydralazine and Minoxidil?

Answer 4

both have reflex increase in CO, HR, Salt water retention [Pseudotolerance]

Both are used in combination with beta-blockers and diuretics for HTN

Question 5

Hydralazine metabolism, dosing/usage, Adverse effects

Answer 5

Hydralazine is inactivated by Acetylation in the Liver

[*Slow acetylators have higher blood levels for same dose]

Effective PArenterally and iused via IV injection for ecclampsia in pregnancy

Side Effect = Lupus-Like Syndrome with malaise, arthralgia, vasculitis and production of anti-nuclear antibodies

Question 6

Minoxidil metabolism and uses and side effects

Answer 6

More potent dilator and so needs loop diuretic

Activated by Sulfonation in liver so NOT given parenterally but rahter only oral (not good in emergencies)

Side Effect = Hypertrichosis - hair growth (ingredient used in Rogaine!)

Question 7

What are the ATP-sensitive K+ channels?

Answer 7

Found in cardiac myocytes, SM, pancreatic beta cells

When low ATP and high ADP, channels open and hyperpolarize the membrane to make it more negative and shorten myocardial AP to reduce the energy demands on the heart

Question 8

What are the classes of drugs act on the K-atp channels?

Answer 8

**KCO = openers; Minoxidil and Diazoxide **

• Used to treat HTN, Hyperinsulinema, Hypoglycemia or Sulfonylurea OD

**Indirect KCO = Adenosine **

• Adenosine release from hypoxic tissues opens this channel via the adenosine receptor as a cardio-protectant

**Channel Inhibitors = Sulfonylureas **

• Oral glucose lowering agents that increase insulin release

Question 9

What happens with K-ATP channel activation in iscemic myocytes?

Answer 9

With Hypoxia, ATP levels go down which opens the K-ATP channel and causes hyperpolarization to shorten the AP and therefore decrease AP duration and contractility

….to decrease energy demand on the heart

Question 10

What happens with activation of the K-ATP channels in SM?

Answer 10

reduced flow –> tissue hypoxia –> Decreased ATP –> KATP channels open –> Vascular SM relax –> ‘resistance arterioles’ dilate –> increased blood flow

Question 11

How does the K-ATP channel work in the pancreas?

Answer 11

Glucose transporter brings in glucose which gets metabolised to increase cellular ATP and closes the K-ATP channels

–> slight membrane depolarization opens L-type Calcium channels

–> Ca influx causes vesicular fusion and Insulin release

Question 12

How do sulfonylureas work?

Answer 12

Inhibit K-ATP channel to incrase Insuline release

Question 13

Describe the relationship between sulfonylureas and Diazoxide?

Answer 13

Sulfonylureas inhibit K-ATP channel causing greater insulin release

Diazodie opens the K-ATP channel and decreases insulin release

Question 14

What happens in ischemic Pre-conditioning?

Answer 14

Delay of Infarct development by 1 or more preceding cycles of ischemia and reperfusion

Acute Phase - opening of K-ATP channels

Delayed Phase - Reperfusion injury salvage kinases (RISK) to activate gene transciption of protective Heat Shock Proteins and Superoxide Dismutase

Question 15

What is the role for adenosine in ischemic pre-conditioning?

Answer 15

Adenosine on to A2 receptors leads to indirect opening of the K-ATP channel and vasodilation of vascular SM

Adenosine onto A1 receptors leads to activation of PKC to open channels in mitochondria and leads to production of RISK

decreased ATP from ischemia leads to increased adenosine release

Question 16

What are the difference effects of adenosine on A1 vs A2?

Answer 16

A2 = vasodilation, coronary hyperemia, Ischemic preconditioning, Anti-inflammatory

A1 = decreased HR, AV conduction, ischemic preconditioning, Bronchoconstriction

Question 17

How is adenosine used in the nuclear stress test?

Answer 17

the nuclear stress test uses radio-nucleotide to show perfusion of the heart

Adenisone IV used to dilate artioles in normoxic myocardium and divert flow from the hypoxic region

Poorly perfused regions take up less radio-nucleotide and Adenosine dilates the small vessels in the normocardiac region for a better defined imaged of ischemia

Question 18

What is remote ischemic pre/post conditioning?

Answer 18

Transient ischemia of the arm liberates circulating effector to induce remote cellular adaptation to a subsequent extended and potentially lethal period of iscemia in remore tissues

Question 19

What are cardioprotective strategies for reducing lethal reperfusion injury?

Answer 19

Ischemic Post-conditioning

during reperfusion eith do repeated occlusions via IV balloon or IV infusion of adenosine to protect the size of infarct and improve outcomes

Question 20

What are Adenosine receptor antagonists?

Answer 20

Methylxanthines = caffeine and Theophylline (adenosine receptor antagonists and PDE inhibitors)