Exam 2 - Medchem 753, Inotropics Kioussi Flashcards
Describe the 7 steps of Cardiac Excitation-contraction coupling
- Membrane depolarization of Gap Junction
- Opening of Voltage gated Na channels
- Inactivation of Na channels, opening of K channels, opening of Ca channels
- Ca enters into the cell and triggers the release of Ca from SR through the Ryanodine channel
- Calcium binds to troponin complex to activate contractile apparatus
- Relaxation and removal of Ca from the cells via the Ca uptake Sarcoplasmic Reticulum
- Na gradient maintained by Na/K pump
Describe the process of Sarcolemmal Na-Ca exchange during cell depolarization and Repolarization
- Ca enters through L channels
- Ca activates myofilaments
- Ca released from Sarcoplasmic Reticulum
- Ca exits via NCX
- ATPase and NCX compete
- Ca enters SR
- Systole occurs
Describe the process of Muscle movement from Troponin, Tropomysin, Actin and Ca
- Ca binds to troponin, pulling the tropomyosin away and exposing the myosin binding site.
- 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 - The ADP and phosphate release causes the myosin head to change position and actin filament to move
- Binding of ATP causes myosin head to return to the resting position.
What cellular actions are regulated by voltage-activated Ca channels
Contraction
Secretion
Neurotransmission
Gene Expression
Describe the make up of Ca-channels
They are composed of 4-5 subunits, with an a1 subunit incorporating the conduction pore
Where is the site of pharmacological activity for Ca channels?
The A1 subunit
What are the different types of Voltage-activated calcium channels?
- 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
What is the role of DHPRs?
Control contraction both in the heart and in the skeletal muscle cells
What is the function of Ca-Channel Antagonists?
Prevent the release of internal calcium stores into cell cytosol, so that the heart does not respond to calcium ion signal.
What are CCBs often used to treat?
High BP Angina Abnormal heart Rhythm Pulmonary Hypertension Raynauds Cardiomyopathy Subarachnoid hemorrhage Migraine Heart failure
What is the danger of high dose CCB use?
Increased risk of MI, GI hemorrahge and mortality
What is the mechanism of action for CCBs?
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).
What drugs allow use-dependent binding and target cardiac cells?
Diltiazem (Benzothiazepines)
Verapamil (Philakylamines)
What drug allows for voltage-dependent binding and targets smooth muscle?
Nifedipine (Dihydropyridines)
What are Dihydropyridines used to treat?
Hypertension
Angina Pectoris
What are Verapamil and Diltiazem used to cover?
HTN Angina Supraventricular arrhythmias - A Fib - A Flutter - Paroxysmal Supraventricalar Tachycardia
What is the effect of depression of the SA node and AV node by Verapamil, Diltiazem, and Nifedipine
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
Which drug has the largest hemodynamic effects on afterload between Verapamil, Diltiazem and Nifedipine?
Nifedipine - most
Verapamil/Diltiazem (less)
What is the effect on BP, HR and VR of Verapamil
BP - lower by decreasing systemic vascular resistance
VR - Reduces arterial pressure by dilating peripheral arterioles and reducing peripheral resitance
HR - minimal changes
What is the effect on BP, HR and VR of Diltiazem?
BP - potent Vasodilaor,
VR - Vasodilates; reduces peripheral resistance and afterload
HR - Decreases HR via strong depression of AV node conduction
What is the effect on BP, HR and VR of Nifedipine?
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
What are the most common side effects of Ca-channel antagonists?
Abdominal pain constipation drowsiness fatigue heart palpitations flushing (hot flashes) headaches nausea sore throat Edema of hands, feet, legs
What is the major benefit of calcium sensitizers?
Hemodynamic and symptomatic improvements w/o increasing cAMP and intracellular calcium concentrations
What is the mechanism of action for Pimobendan and levosimendan?
They both prolong binding of Ca to troponin, which allows actin to be available longer for myosin
What is the effect of levosimendan on Katp channels?
Opening of Katp channels of smooth muscle cells, which causes a vasodilatory effect
Opening of Katp cjannels in cardiac mitochondria
Which classes of Inotropic drugs are cAMP dependent?
Phophodiesterase inhibitors
Glucagon
Which classes of Inotropic drugs are cAMP independent?
Digoxin
Calcium Channel Blockers
Levosimendan (calcium channel sensitizer)
