What are the direct vasodilators? How do they work?
Hydralazine (prototype - uknown mechanism)
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?
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)