Exam 2 - Medchem 753, Inotropics Kioussi

Question 1

Describe the 7 steps of Cardiac Excitation-contraction coupling

Answer 1

1. Membrane depolarization of Gap Junction
2. Opening of Voltage gated Na channels
3. Inactivation of Na channels, opening of K channels, opening of Ca channels
4. Ca enters into the cell and triggers the release of Ca from SR through the Ryanodine channel
5. Calcium binds to troponin complex to activate contractile apparatus
6. Relaxation and removal of Ca from the cells via the Ca uptake Sarcoplasmic Reticulum
7. Na gradient maintained by Na/K pump

Question 2

Describe the process of Sarcolemmal Na-Ca exchange during cell depolarization and Repolarization

Answer 2

1. Ca enters through L channels
2. Ca activates myofilaments
3. Ca released from Sarcoplasmic Reticulum
4. Ca exits via NCX
5. ATPase and NCX compete
6. Ca enters SR
7. Systole occurs

Question 3

Describe the process of Muscle movement from Troponin, Tropomysin, Actin and Ca

Answer 3

1. Ca binds to troponin, pulling the tropomyosin away and exposing the myosin binding site.
2. ATP is hydrolyzed when myosin head is unattached, creating ADP and Phosphate
   3 ADP and phosphate are bound to myosin while its head attaches to actin
3. The ADP and phosphate release causes the myosin head to change position and actin filament to move
4. Binding of ATP causes myosin head to return to the resting position.

Question 4

What cellular actions are regulated by voltage-activated Ca channels

Answer 4

Contraction
Secretion
Neurotransmission
Gene Expression

Question 5

Describe the make up of Ca-channels

Answer 5

They are composed of 4-5 subunits, with an a1 subunit incorporating the conduction pore

Question 6

Where is the site of pharmacological activity for Ca channels?

Answer 6

The A1 subunit

Question 7

What are the different types of Voltage-activated calcium channels?

Answer 7

• L Type (cardiac, skeletal, smooth muscle, neurons, endocrine and bone;
  CaV1.2 a1 Cardiac or Smooth muscle) aka DHPRs
• T Type
• N Type
• P/Q Type
  -R Type

Question 8

What is the role of DHPRs?

Answer 8

Control contraction both in the heart and in the skeletal muscle cells

Question 9

What is the function of Ca-Channel Antagonists?

Answer 9

Prevent the release of internal calcium stores into cell cytosol, so that the heart does not respond to calcium ion signal.

Question 10

What are CCBs often used to treat?

Answer 10

High BP
Angina
Abnormal heart Rhythm
Pulmonary Hypertension
Raynauds
Cardiomyopathy
Subarachnoid hemorrhage
Migraine
Heart failure

Question 11

What is the danger of high dose CCB use?

Answer 11

Increased risk of MI, GI hemorrahge and mortality

Question 12

What is the mechanism of action for CCBs?

Answer 12

Increase the time that Ca channels are closed, causes relaxation of arterial smooth muscle and causes a significant reduction in afterload but not preload.

lowers BP, work on Systole (afterload), but not diastole (preload).

Question 13

What drugs allow use-dependent binding and target cardiac cells?

Answer 13

Diltiazem (Benzothiazepines)

Verapamil (Philakylamines)

Question 14

What drug allows for voltage-dependent binding and targets smooth muscle?

Answer 14

Nifedipine (Dihydropyridines)

Question 15

What are Dihydropyridines used to treat?

Answer 15

Hypertension

Angina Pectoris

Question 16

What are Verapamil and Diltiazem used to cover?

Answer 16

HTN
Angina
Supraventricular arrhythmias
- A Fib
- A Flutter
- Paroxysmal Supraventricalar Tachycardia

Question 17

What is the effect of depression of the SA node and AV node by Verapamil, Diltiazem, and Nifedipine

Answer 17

Verapamil - Strong SA and AV depression
Diltiazem - Strong Depression of SA node, and Depression of AV node
Nifedipine - weak depression of SA node, no depression of AV node

Question 18

Which drug has the largest hemodynamic effects on afterload between Verapamil, Diltiazem and Nifedipine?

Answer 18

Nifedipine - most

Verapamil/Diltiazem (less)

Question 19

What is the effect on BP, HR and VR of Verapamil

Answer 19

BP - lower by decreasing systemic vascular resistance
VR - Reduces arterial pressure by dilating peripheral arterioles and reducing peripheral resitance
HR - minimal changes

Question 20

What is the effect on BP, HR and VR of Diltiazem?

Answer 20

BP - potent Vasodilaor,
VR - Vasodilates; reduces peripheral resistance and afterload
HR - Decreases HR via strong depression of AV node conduction

Question 21

What is the effect on BP, HR and VR of Nifedipine?

Answer 21

BP - decreases arterial blood pressure, and elicits sympathetic reflexes with tachycardia and negative inotropy.
VR - Incraes selective dilation of arterial resistance vessels
HR - Heart rate and CO are modestly increased

Question 22

What are the most common side effects of Ca-channel antagonists?

Answer 22

Abdominal pain
constipation
drowsiness
fatigue
heart palpitations
flushing (hot flashes)
headaches
nausea
sore throat
Edema of hands, feet, legs

Question 23

What is the major benefit of calcium sensitizers?

Answer 23

Hemodynamic and symptomatic improvements w/o increasing cAMP and intracellular calcium concentrations

Question 24

What is the mechanism of action for Pimobendan and levosimendan?

Answer 24

They both prolong binding of Ca to troponin, which allows actin to be available longer for myosin

Question 25

What is the effect of levosimendan on Katp channels?

Answer 25

Opening of Katp channels of smooth muscle cells, which causes a vasodilatory effect
Opening of Katp cjannels in cardiac mitochondria

Question 26

Which classes of Inotropic drugs are cAMP dependent?

Answer 26

Phophodiesterase inhibitors

Glucagon

Question 27

Which classes of Inotropic drugs are cAMP independent?

Answer 27

Digoxin
Calcium Channel Blockers
Levosimendan (calcium channel sensitizer)