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Flashcards in L13- Direct Vasodilators Deck (20)
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What are the direct vasodilators? How do they work?

Hydralazine (prototype - uknown mechanism)

Minoxidil (KCO)


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




Compare and contrast venodilation vs arteriodilation

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


What is pseudotolerance? Why can it develop in arteriodilation?

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) 


Similarities between Hydralazine and Minoxidil?

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


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


Hydralazine metabolism, dosing/usage, Adverse effects

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 


Minoxidil metabolism and uses and side effects

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!)


What are the ATP-sensitive K+ channels?

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


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

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 


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

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


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

reduced flow --> tissue hypoxia --> Decreased ATP --> KATP channels open --> Vascular SM relax --> 'resistance arterioles' dilate --> increased blood flow 


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

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


How do sulfonylureas work?

Inhibit K-ATP channel to incrase Insuline release 


Describe the relationship between sulfonylureas and Diazoxide?

Sulfonylureas inhibit K-ATP channel causing greater insulin release


Diazodie opens the K-ATP channel and decreases insulin release 


What happens in ischemic Pre-conditioning?

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


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

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


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

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


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




How is adenosine used in the nuclear stress test?

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 


What is remote ischemic pre/post conditioning?

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 


What are cardioprotective strategies for reducing lethal reperfusion injury?

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 


What are Adenosine receptor antagonists?

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