Block 6 - anti-arrhythmic drugs and vasodilators

Question 1

Describe the 3 basic forms of cardiomyocytes that coordinate heart contractions and relaxations.

Answer 1

1 - pacemaker nodal cells (SA and AV); auto-rhythmically produce the heartbeat (note, the AV node is slower)

2 - conductive fibers (Purkinje, bundle of His, etc.); carry and coordinate impulses that are produced by the pacemakers; can produce auto-rhythm if the pacemakers do not, so they are called “latent pacemakers”

3 - contractile (working muscle) cells; these are the only cells that contain myosin-actin organized into sarcomeres; can produce auto-rhythm when injured but normally do not

Question 2

What is the main difference between the 3 types of cells?

Answer 2

the type and distribution of the voltage gated sodium channels

Question 3

Name and describe the type of voltage gated sodium channel found in pacemaker cells

Answer 3

Pacemakers only contain gated HCN channels that only respond to HYPER-polarization
(meaning a more negative membrane potential)

Question 4

Name and describe the type(s) of voltage gated sodium channel found in conductive cells

Answer 4

Conductive cells contain BOTH VGSCs (regular ones) and HCN channels
- it takes a VERY negative potential to activate their HCN channels though, so they normally just rely on gap junctions to activate their regular VGSCs

Question 5

Name and describe the type(s) of voltage gated sodium channel found in contractile cells

Answer 5

Contractile cells only contain channels that will cause depolarization (positive) as a response

• they are the “classic” voltage-gated sodium channels
• they will only be autorhythmic when there are altered sodium/potassium levels

Question 6

Which type of sodium channels (HCN or VGSC) will cause depolarization?

Answer 6

BOTH types will carry sodium that will cause depolarization, which will then go on to activate voltage gated calcium and potassium channels.

the difference is the potential at which they open

Question 7

Describe the role of voltage gated calcium channels in cardiac action potentials/contractions.

Answer 7

L-type VG calcium channels are called such because they stay open for a long time

• they cause a plateau after the initial repolarization of the membrane
• the increase in intracellular calcium leads to contraction of the contractile cells

Question 8

How does beta-1 activation affect VGCC opening?

Answer 8

increases the length and speed of channel opening (of L-type VGCC) due to increased levels of cAMP in the cell

Question 9

Describe the impact of the voltage gated potassium channels.

Answer 9

They work to either hyperpolarize or repolarize the membrane (making it more negative). This counteracts the work of sodium and calcium influx.

For the pacemaker cells, this drive towards hyperpolarization is also what activates the HCN channels, ultimately allowing for the auto-rhythmic activity

Question 10

How do cAMP levels impact the HCN channels?

Answer 10

The HCN channels are cAMP gated (cyclic nucleotide gates).
When there are high levels of cAMP in the pacemaker cells, the cAMP binds to the HCN channels and allows them to open at less negative potentials (like -60 vs -80mV). When the cell is repolarizing, it does not have to repolarize as much before it is able to depolarize again (thanks to the sodium influx from the HCN channels).

Question 11

How does M2 activation impact contractility?

Answer 11

M2 channels are coupled to Gi. Gi works to inhibit AC, decreasing cAMP levels, and forcing the HCN channels to repolarize to more negative levels in order to open. This makes the heartbeat slower.

Question 12

Describe the phases of an action potential in a pacemaker cell

Answer 12

Phase 4 - the membrane has hyperpolarized enough to open the HCN channels, allowing sodium influx and depolarizing the membrane

Phase 0 - once threshold is reached, the voltage gated calcium channels open, allowing calcium into the cell and causing an action potential.
at the peak, the voltage gated calcium channels close and the voltage gated potassium channels open

Phase 3 - the voltage gated potassium channels are the only ones still open, so the membrane repolarizes back to a negative membrane potential

Question 13

What is MDP? How does it relate to cAMP levels?

Answer 13

Maximum diastolic potential = the degree of negativity (via hyperpolarization) needed to trigger opening of HCN channels

• less (than normal) cAMP means there’s a more negative MDP
• more cAMP means the HCN can open at a less negative potential (doesn’t have to hyperpolarize as much)

Question 14

Why don’t the HCN channels of conductive fibers generate auto-rhythmicity?

Answer 14

They are overridden by the gap junction carrying the AP from adjacent cells (and the nodes)

Question 15

Class 0 agents block _______. What effect does this have?

Answer 15

HCN channels

by blocking HCN channels, phase 4 in pacemaker cells is elongated

• this slows down the influx of sodium, so the cells reach threshold more slowly
• the result is bradycardia (aka a longer T to P segment and the cell is resting longer)

NOTE: this does not affect the rest of a healthy heart, including contractility, because contractile cells don’t have HCN channels

Question 16

For classes 1-4, what is blocked by each class?

Answer 16

NAKC

1 - N (voltage gated sodium channels)

2 - A (autonomic drugs so beta blockers and anti-muscarinics)

3 - K (voltage gated potassium channels)

4 - C (voltage gated calcium channels)

Question 17

Which cells are unaffected by class 1 drugs?

Answer 17

Pacemakers because they do not contain traditional voltage gated sodium channels.

Question 18

Describe the effects of a class 1a anti-arrhythmic drug, including its impact on an ECG. Give an example.

Answer 18

Example: Procainamide

Class 1a is unique and blocks both sodium and potassium channels.

• blocking the sodium channels causes the QRS wave to widen because it takes longer for the cells to depolarize (blocks rapid activation)
• blocking the potassium channels means there’s a prolonged depolarization (it can’t repolarize as quickly) so the QT segment is also longer (wider)

Question 19

Describe the effects of a class 1b anti-arrhythmic drug, including its impact on an ECG. Give an example.

Answer 19

Example drug - Lidocaine

Class 1b drugs act predominantly on hyper-excitable cells – meaning they only bind to OPEN channels
- they then render the channels less sensitive so they’ll require greater depolarization from subsequent action potentials in order to open

• due to the reduction in sensitivity, there’s diminished excitability in both contractile and conductive cells

***IMPORTANT: because they specifically target “hyper-excitable” cells, they are useful in diminishing ectopic beats

OVERALL EFFECT - shorten the QT segment because they block VGSCs that are already open, so the membrane repolarizes faster, but will still depolarize at (mostly) the same speed

Question 20

Describe the effects of a class 1c anti-arrhythmic drug, including its impact on an ECG. Give an example.

Answer 20

Example drug - flecainide

Blocks the VGSCs for a long period of time, so it limits the rapid activation spike (aka depolarization).
- thus, it slows conduction

On an ECG, this will be shown by a very wide (slow) QRS wave. Because this kind does not impact the VGPCs, there is no change in the repolarization. (there may be a slight increase in the QT segment just because the QRS wave is so much wider)

Question 21

Describe the effects of a class 3 anti-arrhythmic drug, including how it would look on an ECG.

Answer 21

By blocking potassium channels, the drug will cause a prolonged action potential because potassium efflux is unable to counter the calcium influx as readily

This affects ALL types of cardiac cells because they all have VGPCs.
This slows the heart rate will increasing contractility because more calcium = greater contractility (more time for calcium to come in before the channels close).

On an ECG, this would be shown as an elongated QT segment, but it does NOT affect the width of the QRS.

*NOTE: this type of drug prevents re-entry AP’s due to the long depolarization/long refractory period.

Question 22

Describe the effects of a class 4 anti-arrhythmic drug, including how it would look on an ECG.

Answer 22

Class 4 drugs are L-type VGCC blockers. By blocking the calcium channels, this decreases the pacemaker cells’ ability to depolarize
- it takes more sodium influx from HCN channels to activate VGCCs

On an ECG, the P to R segment is longer due to slow activation at the AV node. It takes longer for the ventricle to depolarize, even after a stimulus has been seen from the atria.

There’s also a decrease in the plateau phase of the contractile/conductive cells due to the diminished levels of calcium (they’re no longer efficient at countering the potassium efflux.

Finally, there’s decreased contractility due to low calcium influx.

In conclusion, they decrease contractility and heart rate to reduce work.

Question 23

Give an example of a class 4 anti-arrhythmic drug.

Answer 23

Verapamil and other non-DHP VGCC blockers.

(they block cardiac L-type VGCC more than vascular smooth muscle L-type VGCC, so they decrease contractility without vasodilation)

Question 24

Describe the effects of a class 2 anti-arrhythmic drug.

Answer 24

Beta 1 activation increases heart rate due to increased cAMP. M2 has the opposite effect.

Beta 1 blockers would have the opposite effect (decreased heart rate and decreased cAMP), so they decrease rate, conduction, and contractility (similar to VGCC blockers) because cAMP would normally work to increase VGCC sensitivity.

Question 25

How does adenosine work?

Answer 25

It acts similarly to M2 because it is also coupled with a GPCR with Gi. It basically acts as a potent beta blocker/M2 agonist.

Question 26

What happens when an anti-muscarinic drug is used?

Answer 26

It will increase nodal-derived (pacemaker-derived) heartbeat by blocking M2’s effects (aka enhancing B1’s effects)
- thus increasing conduction and contractility

ex. atropine

Question 27

Define arrhythmia

Answer 27

Altered impulse formation or altered impulse conduction that disrupts how the heart beats.

Question 28

What is given to treat autonomic NS dysfunction?

Answer 28

If tachycardia - can be treated with adenosine (has an M2 agonist effect) or a class 2 beta blocker

If bradycardia - can be treated with an M2 blocker (atropine)

Question 29

What is given to treat pacemaker dysfunction?

Answer 29

If there’s tachycardia that does not affect the contractile cells (if it’s only affecting HCN channels), then class 0 HCN blockers can be used

Question 30

if there are multiple areas firing impulses at the same time, this is referred to as ________

Answer 30

fibrillations

Question 31

What class of drug is useful in treating ventricular fibrillations?

Answer 31

Class 1 - all sodium blockers make the cells less excitable, so by slowing the spontaneous action you can slow the ability to activate adjacent cells

Question 32

How do anti-hypertensive drugs work?

Answer 32

Decrease cardiac output and/or vasodilate (because MAP = TPR x CO)
- this can be done by either decreasing the contractility, the blood volume, or both

Question 33

List 3 ways diuretic drugs can decrease blood volume.

Answer 33

• decrease ANGII formation
• AT-1 blockers
• Aldosterone blockers

Question 34

Non-DHP L-type VGCC blockers target cardiac contractile myocytes to decrease calcium concentration.

What do DHP L-type VGCC blcokers do?

Answer 34

they target vascular smooth muscle and decrease calcium levels there (not in the heart itself)

Question 35

All smooth muscle contractions are regulated by _________. Describe how.

Answer 35

Myosin light chain (MLC)

MLC is phosphorylated by MLC kinase. Once that happens, it moves from the binding site and allows myosin-actin cross bridge formation.

Unphosphorylated MLC (by MLC phosphatase) blocks myosin-actin interactions.

Question 36

What ion is responsible for activating MLCK?

Answer 36

Calcium

Question 37

Smooth muscle GPCRs that are coupled with _____ work to increase intracellular calcium levels.

Answer 37

Gq

Question 38

What effect do PKG and PKA have on vascular smooth muscle?

Answer 38

Both relax smooth muscle because they activate MLC phosphatase, thus inactivating MLCK

Question 39

How do PKG and PKA get activated?

Answer 39

PKA is activated by Gs coupled GPCRs (Gs activates AC, which makes cAMP, which activates PKA).

PKG is activated by the NO pathway. Endothelial GPCRs with Gq activation turn on PLC, leading to calcium influx into the epithelial cells. This influx activates eNOS (endothelial NO synthase), making NO.

NO leaves the endothelium and acts on the smooth muscle. Once at the smooth muscle, NO activates GC, GC forms cGMP, and cGMP activates PKG.

Question 40

Describe the activity of DHP L-type VGCC blockers (that are specific for vascular smooth muscle), including the suffix they end with and how they work.

Answer 40

They decrease vascular smooth muscle calcium levels

• this gives them vasodilation activity because calcium that would be needed for contraction (via MLCK activity) is not present
• drugs in this class have the suffix -dipine

ex. amlodipine

Question 41

Drugs that inhibit ___, ___, ___, or ___ all work to inhibit the synthesis and/or actions of Angiotensin II

Answer 41

A0 (angiotensinogen), A1 (angiotensin 1), A2 (angiotensin 2), or aldosterone

Renin, ACE, AT1, Aldosterone

Question 42

Explain how the renin-angiotensin system normally works.

Answer 42

1 - a drop in blood pressure or volume is detected by the kidneys

2 - RENIN is released from the kidneys

3 - Renin reacts with angiotensinogen in the blood to form ANGIOTENSIN 1

4 - ACE (angiotensin-converting enzyme) is released from the lungs; it then acts on A1 to form angiotensin 2

5 - Angiotensin 2 then has two actions

• acts on adrenal glands to stimulate the release of aldosterone (which acts on the kidneys to stimulate the reabsorption of water and salt; potassium is excreted)
• acts directly on the blood vessels via the AT1 receptor, stimulating vasoconstriction

Question 43

Describe the MOA of Aliskirin

Answer 43

Aliskirin is a renin inhibitor

- it blocks renin and thus decreases the amount of ANGII in the body

Question 44

How is renin release normally controlled?

Answer 44

Renin is normally released from the juxtaglomerular cells of the nephron in response to:

• Beta 1 GPCR activation (so B1 blockers help decrease renin release)
• Low blood pressure
• Low glomerular filtration osmolarity (blood volume)

Question 45

Describe the MOA of ACE inhibitors, including benefits, side effects, and the associated suffix.

Answer 45

ACE inhibitors block ACE (angiotensin converting enzyme) in the lungs

• this decreases the amount of ANGII, giving diuretic effects
• side effect is there is more bradykinin (because ACE normally inactivates it); bradykinin is a vasodilator and also activates cough sensory neurons - resulting in ACE-inhibitor cough

benefits:

• vasodilation and diuretic effect
• does not result in reflex sympathetic activation or alter cardiac output profoundly
• kidney protection

suffix: ____pril

Question 46

Describe the MOA of angiotensin II receptor blockers.

Answer 46

The GPCR of AT1 is activated by ANGII. Drugs of this class block ANGII from binding at this receptor.

Normally, the GPCR is activated and Gq is released to act on the vascular smooth muscles, which causes vasoconstriction — ARBs block this.
AT1s are also expressed on adrenal glands, and the Gq induced increases in calcium cause aldosterone release, which in turn raises blood volume. — ARBs block this.

Thus, ARBs cause both vasodilation (by blocking AT1 at the smooth muscle) and a diuretic effect (blocking aldosterone release).

Question 47

The suffix associated with ARBs is

Answer 47

___sartan.

Question 48

Other than blocking aldosterone release, how can aldosterone’s effect be blocked?

Answer 48

by blocking its receptor (mineralocorticoid receptor)

Question 49

Give an example of a drug that blocks aldosterone’s receptor and the effects it causes.

Answer 49

Spironolactone

It lessens aldosterones actions:

• increases secretion and excretion of water, sodium, and chlorine, thus lowering blood volume to lower MAP
• increases serum potassium (can be a side effect of all RAAA drugs)

Question 50

How is vasodilation induced in vascular smooth muscle?

Answer 50

Agonists for vascular GPCRs coupled with Gs increase cAMP (and thus PKA) to induce vasodilation

Question 51

Explain how PGE2 analogues work to treat erectile disorder.

Answer 51

Example - alprostadil

• binds to EP4 GPCR-with-Gs
• activates AC, which increases cAMP
• cAMP activates PKA, which activates MLC phosphatase
• MLC phosphatase dephosphorylates MLC, and induces vasodilation

Question 52

Drugs that increase smooth muscle NO (skipping the endothelia) are used to treat…

Answer 52

hypertension and angina (coronary vasodilation)

Question 53

What is nitroprusside and how does it work?

Answer 53

It’s an NO donor, making it a potent vasodilator to lower blood pressure.

It lowers BP within seconds, with the effects disappearing within 1-10 minutes after continuous IV infusion

Question 54

What are the down sides to nitroprusside?

Answer 54

It contains iron, cyanide groups, and a nitroso-moiety.
It is rapidly metabolized in RBCs to NO and cyanide

Toxicity could cause:
1 - excessive hypotension
2 - cyanide poisoning if
high rates of infusion are given for more than an hour

Question 55

What are nitrates used to treat?

Answer 55

Angina pectoris

Question 56

Nitroglycerin is converted to ____ and is used to treat ______. How is it converted?

Answer 56

NO

Angina pectoris

Conversion requires mitochondrial enzymes (mtALD) in smooth muscles. It works on all types of smooth muscles, but there’s no direct effect on cardiac or skeletal because they lack the enzyme.

NOTE - it also decreases platelet aggregation (platelet cGC –> GMP)

Question 57

What drug can be used to stimulate GC independent of NO? What is it used for?

Answer 57

Riociguat

Pulmonary hypertension

Question 58

How do drugs like tadalafil, avanafil, and sildenafil work?

Answer 58

They are phosphodiesterase (PDE)-5 inhibitors that prevent the breakdown of cGMP.

Thus, they enhance NO effects but do NOT produce them.

Question 59

What are PDE-5 inhibitors used for?

Answer 59

they are used for PED, but they do not induce the erection just help maintain it