Calcium channel blockers - Hockerman Flashcards
What are ion channels?
How are they categorized?
Proteins that form pores in the plasma membrane
Categorized by
- gating (opening and closing) mechanisms
- ion selectivity
- pharmacology
Are channels active or passive
Passive!
They are not transporters, they just open and allow ions to flow through, down the electrochemical gradient
What affects the flow of ion through the channel?
Concentration gradient (i.e. distribution of ions)
Electrochemical gradient (i.e. membrane potential)
Membrane potential
- excitable cells have ..
- where is K+ high? low?
- where is Na+ high? low?
- where is Ca+ high? low?
Excitable cells have a negative inward potential across the membrane due to selective permeability of the resting membrane to K+
K+ is high inside, low outside
Na+ is low inside, high outside
Ca+ is low inside, high outside
Gradient maintained by Na+/K+ active transport and by K+ channels
What are the important parts of a Kcsa H+ gated K+ channel?
- Spans the membrane
- Gated (by helices crossing in inverted Tee Pee conformation)
- Aqueous vestibule (where ion can exist)
- Selectivity filter (GYG motif)
What are the important parts of a MthK Ca2+ gated K+ channel?
- Gate
- Hinge point with flexible amino acids that bend to allow opening of channel
- Selectivity filter
WRT to cardiac drugs, which channels are we selectively targeting?
L-type Cav1.2
Which are located on cardiac and smooth mm
In these channels, Ca2+ entry triggers contraction
A block of calcium channels in vascular smooth causes …
Vasodilation
- decrease in blood pressure
- relief of angina pectoris
Review cardiac mm and skeletal mm contraction
A block of calcium channels in cardiac mm & SA/AV node causes …
anti-arrhythmia
What are the three distinct chemical classes of calcium channel blockers?
What is the difference b/t each?
Dihyrdopyridines
Phenylalkylamines
Benzothiazepines
The binding sites are close, but not identical
Describe the blockade mechanism of dihyrdopyridines
+ enantiomer blocks current –> interferes with opening
- enantiomer potentiates current –> interferes with closing
Tissue selectivity of dihydropyridines in the results of …
What is the tissue selectivity of these
- amino acid differences in channel splice variants
- differences in membrane potential properties
More potent in relaxing sm mm - esp coronary artery
Do not compromise cardiac fxn
Not antiarrhythmics
Describe the idea that dihydropyridine is voltage-dependent
The affinity of drug for the channel is different at different voltages
Calcium channels do not have just open or closed states
- rather have different closed states that are either closer or farther from opening
- a state that is closer to opening will be held at a less negative potential and therefore the drug will have a high affinity for this channel
Clinical considerations for DHPs
- what kind of selectivity?
- what changes does the drug cause?
- do they effect cardiac fxn?
Vascular selectivity
Marked decrease in peripheral resistance (dilation of arterioles; little affect on venues)
Decreased after load
Little effect on HR or force of contraction
They do not depress cardiac fxn (except nifedipine)
Which DHP is least vascuarly selective?
Nifedipine
Nisoldipine, felodipine, nicardipine, isradipine, amlodipine all have greater vascular selectivity
