Cardiovascular - Drugs & Vasculature Flashcards Preview

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Flashcards in Cardiovascular - Drugs & Vasculature Deck (13):
1

What types of receptors should drugs target to effect vasculature?

VASOCONSTRICTION:

 alpha-1 & alpha-2 adrenergic receptors - bound to norepinephrine, these cause vascoconstriction of arterioles in all organs of the body, as well as abdominal veins

AT1 receptors - bound to angiotensin II (vasopressin), these cause vasoconstriction in the RAA system

ETA receptors - bound to endothelin-1, these cause vasoconstriction (opposite to NO, which like endothelin is produed by endothelial cells)

5-HT2 receptors - bound to 5-HT (seratonin), these cause vasoconstriction, important in clotting

TxA2 receptors - bound to thromboxane, these cause vasoconstriction & encourage platelet aggregation; like 5-HT, important in clotting

VASODILATION:

ß2 adrenergic receptors - bound to epinephrine, these cause vasodilation of arterioles in the coronary circulation, increasing blood flow to heart muscles during fight or flight or exercise, as well as to working skeletal muscles in the same situations.

 M3 cholinergic receptors - bound to acetylcholine (Ach), these cause endothelial cells in blood vessels to release nitric oxide (NO), which causes vasodilation. These receptors are found in the genitals, skeletal muscle, coronary circulation and other organs.

A2 receptors - when bound to adenosine, cause vasodilation

D1 receptors - bound to dopamine, precursor to adrenaline, cause vasodilation

PGI2 receptors - when bound to prostacyclin, cause vasodilation & increased vascular permeability

ANPA receptors - when bound to atrial natrurietic peptide, the RAA system is blocked; can act as vasodilator

 

 

2

What effect would an alpha-1 adrenergic receptor antagonist have on vascular tone in a hypertensive animal? 

Hypertension means high blood pressure, so resistance in blood vessels would be high. 

Alpha-1 adrenergic receptors are found in arterioles in every organ, as well as in abdominal veins. When bound to norepinephrine, tney cause vasoconstriction. Excessive stimulation of alpha-1 receptors could be a feature of hypertension. 

An antagonist of alpha-1 receptors would reduce the vasoconstriction, ie., reduce vascular tone throughout the body. In effect, an alpha-1 antagonist is a vasodilator.

An example of an alpa-1-selective agonist is:

Prazosin

3

What would be the effect of a drug that acted as an antagonist to AT1 receptors? What are some examples?

AT1 receptors are found in the vasculature (arterioles) and they bind angiotensin II, released during the RAA-system to conserve blood-plasma levels. 

Angiotensin II is a very strong vasoconstrictor, so an antagonist at its receptor (blocks receptor) would result in reduced or no vasoconstriction (possibly vasodilation instead). 

ATi-receptor blockers are:

1. Saralasin
(peptide analogue)

2. Losartan (non-peptide analogue)

4

What would be the effect on vascular tone of drugs that acted as agonists for ß2-adrenergic receptors? What are some examples?

ß2-adrenergic receptors are located in the arterioles of coronary circulation and working skeletal muscle. When bound to their natural ligand, norepinephrine, they cause vasodilation, resulting in increased blood flow to the heart muscles and skeletal muscles during flight or fight response.

Agonists of these receptors would induce vasodilation.

Examples:

Clenbuterol  - a sympathomimetic drug that stimulates production of cAMP, which relaxes vascular smooth muscle

- Relatively weak vasodilator but a better brochodilator
 

5

When ß-2 adrenergic receptors stimulate adenylate cyclase to produce cAMP inside a cell, what is the effect on vascular smooth muscle?

Unlike alpha 1 & 2 receptors or ß-1 adrenergic receptors, when  ß-2 receptors bind to norepinephrine or agonists such as dopamine, dobutamine or clenbuterol, they set off an inhibitory cell-signalling cascade in which the increased cAMP levels actually closes inward Ca++ channels, produces calmodulin to bind to intracellular Ca++ (so Ca++ doesn't bind to troponin-C) & increases extrusion of Ca++. The result is vasodilation. 

6

What are ACE inhibitors and what effect do they have on vascular tone? What are some examples?

ACE inhibitors block the action of angiotensin-converting enzyme to convert angiotensin I to angiotensin II, a powerful vasoconstrictor.

So the effect would be vasodilation.

Examples:

1. Captopril - bioavailability is reduced by presence of
food in GIT
2. Enalapril - a prodrug that needs to be metabolised to Enalaprilat by the liver & is cleared by the kidney
3. Benazepril - prodrug that’s metabolised to Benazeprilat

7

What would be the effect on vascular tone of a drug that acted as an antagonist of Endothelin- converting enzyme (ECE).

ECE catalyses the formation of endothelin-1, a vasoconstrictor produced by endothelial cells.

An antagonist of ECE would result in vasodilation. 

Example:

Phosphoramidon

8

What would be the effect on vascular tone of a drug that antagonised PDE III inside vascular smooth muscle cells?

In vascular smooth muscle cells, there is a greater tendency for cAMP to cause a DECREASE in Ca++ inflow, and thus vasodilation.

PDE III degrades cAMP, which would have the effect of vasoconstriction. A drug that antagonises PDE III, then, would have the effect of prolonged vasodilation

Example: 

Methylxanthines

9

What is guanylate cyclase (GC) and what is its effect in vascular smooth muscle cells?

Guanylate cyclase is similar in action and effect to adenylate cyclase, which converts ATP to cAMP. GC converts GTP to cGMP within the vascular muscle cell. The cGMP, like cAMP, goes on to block the influx of extracellular via Ca++ channels, to reduce contraction of muscle cells. 

Thus, GC leads to more cGMP, which leads to less intracellular Ca++, and thus less contraction. In effect, anything that increases GC could be a vasodilator.

Examples:

1. Organic nitrates, eg. Glyceryl trinitrate (GTN) - organic nitrates like GTN are metabolised by blood-vessel wall to make NO, most active on venous side, to ↑"venous capacitance"


2. Sodium nitroprusside - decomposes to NO precursor, used for emergency treatment of pulmonary oedema

10

What is Clenbuterol & what is its effect on vascular tone?

Clenbuterol is a ß2-receptor agonist. When bound, as the receptor would naturally bind norepinephrine, the receptor-ligand activates adenylate cyclase's conversion of ATP to cAMP, which CLOSES calcium channels, reduced intracellular calcium, and leads to vasodilation

11

Alpha 1 & Alpha 2 adrenergic receptors in arterioles and abdominal veins cause vasoconstriction when bound to their natural ligand, norepinephrine or epinephrine. 

They work by opening voltage-dependent Ca++ channels. 

Other ligands that cause vasoconstriction by opening voltage-dependent Ca++ channels are endothelin-1 & angiotensin II 

What are some drugs that antagonise these ligands and their receptors to cause relative vasodilation?

Amlodipine

Nifedipine

12

When vascular-smooth-muscle cells are really permeable to potassium, lots of potassium leaves at the end of an action potential, along with Ca++, and the cell becomes HYPERPOLARISED. Calcium channels also can't open when potassium channels are open, so calcium can't enter or leave the cell.

Normally, this hyperpolarisation doesn't happen, because ATP inside the cells keeps the potassium channels from opening too much, and calcium channels are open so calcium can enter the cell, allowing for muscle contraction.

Drugs that antagonise the ATP end up keeping the potassium channels open, so potassium flows out and calcium CAN'T flow in. So you end up getting VASODILATION.

What are drugs that affect ATP so that it forces potassium channels to stay open and hyperpolarise the cell?

Pinacidil

Cromokalim

13

What is Hydralazine?

What is its effect on vascular tone, and what is it used for?

It's a vasodilatory drug whose mechanism of action isn't yet known, except that it does require an intact endothelium. It has a greater vasodilatory effect on arterioles, less on venous system.

It is used to treat congestive heart failure secondary to mitral-valve disease.

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