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Flashcards in Cardiovascular - Drugs & Heart Deck (13):

What are the THREE sites of action of cardiac drugs that work to increase chronotropy & inotropy or decrease them? 

1. Cell-membrane receptors:

Specifically, these drugs would affect:

ß1 adrenergic receptors, which increase strength & speed of contraction of cardiac myocytes

ß2 adrenergic receptors, which dilate arterioles of coronary circulation & skeletal muscles

M2 cholinergic receptors, which decrease strength & speed of heart-muscle contraction

2. Cell-membrane ion channels: 

Specifically, these drugs would affect: 

Fast Na+ channels, through which extracellular sodium ions enter cardiac muscle cells very quickly once cell membranes reach threshold. They inactivate very quickly. At rest, voltage-gated sodium channels are closed, K+ channels open.

K+ channels, which are open at rest. Less K+ leaves during the plateau phase, when Ca2+ is entering the cell. During repolarisation phase, more K+ channels open & thus more K+ leaves the cell, along with Ca2+, so inside of cell can become negative again. 

3. Enzymes inside cardiac muscle cells: 

Phosphodiesterase III (PDE III) - Breaks down cAMP by degrading the phosphodiester bond following normal stimulation of cAMP. In heart, PDE III ↓ cAMP ↓ Ca2+. If PDE is switched off or down-regulated, then cAMP can stay active in the cell longer, causing more contraction of myocytes as Ca2+ channels stay open.




What are examples of heart drugs that ANTAGONISE cell-membrane receptors, ß-1 & ß-2 adrenergic receptors? What are their effects?

Class II anti-dysrhythmics antagonise ß-adrenergic receptors. These are also called ß-blockers.

Non-selective ß-blockers (antagonise ß-1 & ß-2):

Propranolol, Sotalolol

These are anti-chronotropic & anti-inotropic, and they can cause vasoconstriction of coronary arterioles & arterioles in skeletal muscle

ß-1-selective antagonists:

Atenolol - negative chronotrope & negative inotrope without any effect on coronary circulation or skeletal muscle (ie., no effect on ß-2 receptors)



What are examples of heart drugs that AGONISE cell-membrane receptors, ß-1 & ß-2 adrenergic receptors? What are their effects?

Drugs that agonise ß-1 & ß-2 adrenergic receptors end up mimicking the effect of their natural ligands, norepinephrine & epinephrine. Their effects would chronotropic and inotropic, as well as vasodilatory for the coronary circulation and working skeletal muscle if they are non-selective. 

Non-selective ß-adernergic receptor agonist:

Isoprenaline - increases heart rate (ß-1 effect); vasodilation in skeletal muscle ( ß-2 effect)

Sympathomimetics (mimic norepinephrine):

Dobutamine - ß-1 -selective therefore chronotropic AND inotropic

Dopamine - natural precursor of noradrenaline - good for shock & low-output heart failure; both ß-1 & ß-2 effects)



What are exampes of heart drugs used to treat low blood pressure that target the M-cholinergic receptors?

Low heart rate and low blood pressure usually mean predominance of parasympathetic-nerve activity on the heart. Ach released from parasympathetic neurons especially in the SA, AV nodes and the atria bind to M2-cholinergic receptors to slow HR, SV & CO. Antagonising these receptors help reverse these effects:

Muscarinic receptor antagonists:
Atropine - non-selective for M2 & M3, thus HR, SV & CO increase (M2 effect), but vasoconstriction in arterioles to skeletal muscle & other organs occurs (M3 effect);

- pre-med for anaesthesia &
surgery when vagal stimulation is
potential problem;
- treatment of bradycardia in
incomplete heart block



M2 cholinergic receptors, when bound to their natural ligand Ach, activates the Gk receptor. What does this mean and what happens to the cell membrane?

First, M2 cholinergic receptors are found on the cell membranes of cardiac muscle cells, particularly the SA node, AV node & atrial muscles, which are innervated by parasympathetic neurons. They have the overal effect of decreasing HR, SV & CO, and thus blood pressure.

The activated (bound) receptors, which are G-coupled-protein receptors, achieve these effects by opening potassium channels, enabling more potassium to flow out of cells. The cells thus become hyperpolarised, extending the refractory period (slowing HR). 


What are examples of drugs that AGONISE M2 cholinergic receptors in the heart? 



↓ HR is a side-effect


What are the CLASSES of drugs that target ion channels in the cell membranes of cardiac myocytes to slow heart rate or dampen contractility? 


Class I: Target "fast sodium channels"

Class III: Target potassium channels

Class IV: Target "slow calcium channels"


How do Class I antidysrhythmics work, and what are some examples?

Class 1 antidysrhythmics target the fast sodium channels in the cell membrane of cardiac muscle cells. These voltage-dependent channels, in normal conditions, open when a cell membrane reaches threshold to let extracellular sodium rush into the cell to depolarise it. The sodium rushes out quickly also, and the channels close very rapidly.

Local anaesthetics such a lidocaine & procainamide are Class I antidysrythmics, which block the fast Na+ channels

As a result, depolarisation rate & magnitude are lower, and cell-to-cell velocity is slower in non-nodal tissue - ie., HR lowers, SV lowers, CO lowers.

Heart contractility decreases: More calcium ends up leaving through the Ca2+-Na+ exchanger, since there's less Na+ inside the cell (the exchanger works properly when there's loads of sodium inside the cell, so as it leaves, it brings in calcium)


How do Class 3 antidysrhythmics work, and what are some examples?

Class 3 antidysrhythmics target potassium channels in the cell membranes of cardiac myocytes. They are usually open at rest, closed during the plateau phase of Ca2+ influx via slow calcium channels, and open again during repolarisation. 

Amiodarone blocks potassium channels so potassium can't leave the cell: just remember that if potassium is blocked from leaving a cell, then calcium can't enter. Conversely, if potassium can't enter a cell, calcium can't leave a cell. 


How do Class 4 antidysrhythmics work, and what are some examples?

Class 4 anti-dysrhythmics target slow Ca++ channels that open during the plateau phase of a cardiac action potential to increase the influx of extracellular Ca++ into the cardiac muscle cell. These drugs block the channels, so both HR & contractility are reduced.

Examples are:



What are heart drugs that target the action of phosphodiesterase III enzyme inside cardiac muscle cells? What are their effects?

PDE III inhibitors block the action of phosphodiesterase, which normally breaks down cAMP by eroding the phosphodiester bond. In the heart muscle, cAMP triggers Protein Kinase A (PKA) to phosphorylate (open) slow calcium channels, increasing HR & contractility, & PDE III puts an end to cAMP & Ca++ activity in the cell.

PDE III Inhibitors would therefore allow cAMP to keep working, triggering PKA to lead to open Ca++ channels, so Ca++ continues to flow in. You get increased HR, SV & CO, as well as increased contractility.



Methylxanthines - eg. etamiphylline, theophylline, camsylate, propentofylline

Benzimidazole derivatives - eg. Pimobendan (Inodilator)


What are cardiac glycosides and what are they used for?

Cardiac glycosides are heart drugs used to increase heart contractility while decreasing heart rate.

The most well-known is Digoxin, or digitalis, derived from the foxglove plant. 

It works by targeting the Na+-K+-ATPase antiporter enzyme in the cell membrane. Normally, the Na+/K+-ATPase helps maintain resting potential, pumping 3 Na+ out of cells, while pumping 2 K+ into cells, thus in total removing one positive-charge-carrier from the cell. The energy for this active transport comes from the hydrolyzation of ATP to ADP (the P from ATP phosphylates the pump).

Digoxin binds to the K+-binding site on the antiporter, so K+ can't come in & Na+ can't be pumped out. As a result, cell remains depolarised. 

The failure of pumping out sodium means the Na+-Ca++ exchanger doesn't work properly. This pump works by taking in sodium and extruding calcium, which has built up in the cell from the last action potential. With increased Ca++ inside the cell, muscular contraction is increased.

However, HR is DECREASED because as SV increases, this is detected by the atrial volume receptors, which activate parasympathetic activity in the SA node to decrease heart rate. 

Digoxin is used for:

- management of congestive heart failure
esp. when there is systolic myocardial dysfunction



What is propranolol? 

It's a beta-blocker.

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