exam 2 lecture 5 Flashcards
what are ion channels
Proteins that form pores on plasma membrane
Three ways ion channels are categorized
gating (opening and closing mechanism)
ion selectivity
Pharmacology
which ion channel is most selective
K channels
two tyoes of ion chnnnales that are categorized by gating
Ligand gated
voltage gated
are ion channels active or passive
Passive
Difference between ion channels and trasnporter
ion channels are pores that respond to stimulus (voltage, Ach) to open them. The ions will pass through the channel and flow down their electrochemical gradient. NO ENERGY REQUIRED
What determines direction of flow for ions
Concentration gradient
Electrical gradient
membrane potential
98 mv
excitable cells have what kind of potential across the membrane? why is that?
Excitable cells have a negative inward potential across the membrane
This is due to selective permeability of resting membrane to K
Levels of K inside and outside of cell
High inside cell (155mm)
low outside (4mm)
Levels of Na inside and outside of the cell
Low inside the cell (12)
high outside
how is gradient Na and K gradient maintained
By active trasnport of Na out and K into cell.
Levels of free Ca2+ inside vs outside of the cell
Free Ca2+ is very low inside cell (100nm)
High outside of cell (1.5mm)
15,000 fold difference
what is the role calcium channels play in myscle contraction
When Na rushes into the cell and depolarizes it, Ca channels open. And they stay open, FOR A LONG TIME(broad action potential). This is where contraction occurs (broad part of calcium channels opening)
why is K channel so selective?
because of its selectivity filter. potassium ion makes contact with carbonyls that strip the water of ion as it passes through filter. (it is called a long pore due to long narrow passage)
Open vs closed shape of K channel
V is closed
/\ is open
most important target for calcium channel blockers
Ca v 1.2
what will happen if we block Ca influx through Ca v 1.2
It will inhibit contraction of cardiac and vascular muscle
what is the use of calcium channel blockers
Used to block Ca V 1.2 channels in vasculature and create VASODILATION to relax smooth muscle.
effect of calcium channel blockers on BP and Angina
Lower BP and relieve angina
Use of blocking of channels in cardiac muscle and SA/AV node
It is ANTIARRHYTHMIC
what is CICR
calcium inducedd calcium release
Explain CICR mechanism
Ca2+ influx via Ca v 1.2 induces release of Ca from intracellular stores via RYR2 in SR
what does RYR2 do
indices release of calcium stores in SR
Use of Ca release in SR
Drives contraction of muscle
how does epinephrine affect Ca V 1.2
Epinephrine binds to B receptor in heart andgenerates phosphorylation of Ca V 1.2 and increases Ca influx.
Leads to
1. greater contraction force
2. increased AV nodal action potential (Increased HR)
difference in vascular smooth muscle contraction and cardiac muscle and skeletal muscle for Ca required
extracellular Ca is required for vascular smooth muscle and cardiac muscle. Not for Skeletal muscle
how does volatage gated calcium channel lead to vascular smooth muscle contraction
-Calcium comes in
-releases calcium from stores by activating RYR2, increasing intracellular Ca concentration
-Ca binds calmodulin and activates Myosin LC kinase
-myosin LC kinase phosphorylates myosin LC
- Phosphorylated Myosin lc combines with actin and initiates contraction
how does volatage gated calcium channel lead to cardiac muscle contraction
-Calcium comes in
-releases calcium from stores by activating RYR2, increasing intracellular Ca concentration (these two steps similar in vascular muscle)
-In cardiac muscle (and skeletal muscle) Ca ions are released from SR and bind Troponin C
- Ca binding by troponin C causes displacement of tropomyosin, allowing actin to bind to myosin. leading to contraction
how does volatage gated calcium channel lead to skeletal muscle contraction
Extracellular Ca not required. Ca V 1.1 and RYR 1 used instead of 1.2 and RYR 2
-Ca ions are released from SR and bind TroponinC
- Ca binding by troponin C causes displacement of tropomyosin, allowing actin to bind to myosin. leading to contraction
similarity and difference of vascular, cardiac and skeletal contraction
vascular and cardiac have similar 1st 2 steps
–Calcium comes in
-releases calcium from stores by activating RYR2, increasing intracellular Ca concentration
Cardiac and skeletal have similar last 2 steps
-Ca ions released from SR and bind troponin C
- Ca binding of troponin c causes displacement of troponin C allowing myosin and actin to bind
Skeletal muscle extracellular Ca not required, but is required for cardiac and vascular muscle.
skeletal uses CaV 1.1 and RYR 1,
Cardiac and vascular use CAV 1.2 and RYR 2
Name the 3 calcium channel blockers
Dihydropyridines
Phenyalkylamines
Benzothiazepines
Indication and use of CCB (Calcium channel blockers)
HTN, arrythmia, angina
Name DHP drugs (how to recognize the name)
-dipine
Amlodipine
Nimodipine
Clevidipine
Nifedipine
KNOW STRUCTUREE FOR DHP (dihydropyridine)
Has
KNOW STRUCTURE FOR AMLODIPINE AND NIMODIPINE
Why is amlodipine special
Ether group side chain and primary amine
Use of ether group side chain in amlodipine
Give it characteristics of very slow onset and very long duration of action
Why is Nimodipine special
It has an ether group and is EXTREMELY hydrophobic
What is the use of extreme hydrophobia of Nimodipine
Nimodipine can be used to relax the vascular muscle within an area of hemorrhage (bleeding) to try and restore blood flow due to its hydrophobia.
Why is clevidipine special
half life is short and is given IV
why is clevidipine half life short? What is contraindicated
Breaks down rapidly due to esterase
Not given in patients with soybean or egg sensitivity
Tissue selectivity of DHP (vascular or smooth)
What do DHPs work well in
High degree of selectivity for relaxing vascular smooth muscle. not a strong effect on cardiac muscle.
Work well in coronary arterty
what is the reason for the vascular smooth muscle selectivity viewed in DHP
difference in membrane potential property. vascular smooth muscle tends to have a more depolarized resting membrane potential than cardiac muscle
Is DHP voltage dependent? Why?
Prefers the more depolarized vascular smooth muscle over the cardiac smooth muscle
DHP binding site
They do not bind in the pore, they bind on an allosteric site outside of pore
do DHP have tonic or frequency dependent block
Tonic
How does DHP work
Bind to closed channels and prevent opening
DHP effect on peripheral resistance
Reduction of peripheral resistance
Effect of DHP on venules and arterioles
Dilation of arterioles
Little effect on venules
Which DHPs are vasoselective
Amlodipine, nifedipine, felodipine, nislodipine, isradipine
effect of DHP on afterload and on HR or force of contraction
Decreased afterload and little effect on HR and force of contraction.
reflex tachycardia is caused by all DHPs except for
Amlodipine
Nimodipine exhibits selectivity for_________. What is it used in?
nimodiine exhibits selectivity for cerebral arteries.
Used to prevent neuropathy
how do DHPs show efficacy in angina
reduce O2 demand in heart
T/F all DHPs undergo first pass effect
T/F DHPs are highly bound to protiens
True for both
which DHP could depress cardiac function? what happens when this DHP is promptly released?
Nifedipine.
Prompt release nifedipine solutions may increase risk of subsequent heart attack
What is the only phenylalkylamine drug
Verapamil
What does phenylalkylamine do?
Causes vasodilation.
Which one causes more vasodilation (more potent) DHP or verapamil (phenylalkylamine)
DHP more potent
What can Verapamil (phenylalkylamine) do that DHP can not
Increase HR and force of contraction
is there reflex tachycardia in phenylalkylamine (verapamil)
It is blunted
is verapamil (phenylalkylamine) tonic block or frequency dependent
Frequency dependent block
What is the use of verapamil being frequency dependent
It is useful in arhythmias
Where does verapamil bind
Binds the pore (entry) not allosteric site.
In order to bind, the drug has to get inside pore to bind.
Name benzothiazepine drug
DIltiazem
is diltiazem (benzothiazepine) frequency dependent or tonic block
Exhibits both a little bit
Which one inhibits the heart rate more? DHP, Verapamil or diltiazem
Verapamil the most, diltiazem next, last is DHP
Which one causes the most vasodilation?
DHP, verapamil or diltiazem
DHP (second is diltiazem)
Which one causes tachycardia DHP, Verapamil or diltiazem
Non-amlodipine DHPs cause most tachycardia.
Second is Diltiazem
Which ones slow conduction through SA and AV node? DHP, Verapamil or Diltiazem
Verapamil (most ) and diltiazem (second)
which ones treat super ventricular arrythmias? DHP, Verapamil or Diltiazem?
Verapamil and Diltiazem
Why do verapamil and diltiazem treat ventricular arrythmias
Because they are frequency dependent
Which CCB (calcium channel blocker) suppress HR? why?
Diltiazem and Verapamil
How does DHP affect HR
increases it through reflex tachycardia
Why do diltiazem and verapamil lower HR
Due to frequency dependent kinase
DHP effect summary on HR, AV conduction, myocardial contraction and arterial vasodilation
HR- increase (only one to increase hr)
No effect on AV conduction
No effect on myocardial contraction
Best at DILATING arterial vasodilation
Verapamil summary on effect on HR, Av conduction, Myocardial contraction, Aretrial vasodilation
HR- Lowers HR (the most)
Lowers AV conduction
Lowers Myocardial contraction
Raises arterial vasodilation
Diltiazem Summary on HR, Av conduction, Myocardial contraction, aretrial vasodilation
Lowers HR
Lowwers AV conduction
Lowers Myocardial contraction
Raises Arterial vasodilation
which CCB has no effect on Myocardial contraction and AV conduction
DHP
which CCB is the best as arterial vasodilation
DHP
DHP side effets
Facial flushing, tachycardia, ankle edema (ankle edema is on all CCBs)
Verapamil side effects
Constipation and ankle edema
Diltiazem side effects
Ankle edema
