CCB Flashcards
what are ion channels?
- proteins that form pores in the plasma membrane
what is a passive ion channel?
allow ions to flow down electrochemical gradient
what are the two gradients and what is the difference?
- concentration –> flow down
- electrical –> can go against gradient
what is the membrane potential for K+, Na+, and Ca2+?
K+ –> high inside and low outside
Na+ –> low inside and high outside
Free Ca2+ –> very low inside and high outside (15,000 fold differ)
What is the type of voltage-gated family that CCBs are a part of and what is the type and location?
- L type
- Cav1.2
- cardiac, smooth muscle/Ca2+ entry triggers contraction
what does a block of channels in the vascular smooth muscle do and cause?
- vasodilation
– dec. BP
– relief of angina pectoris
what does a block of channels in cardiac muscle & SA/AV node cause?
antiarrhthmic
what happens to trigger a vascular smooth muscle contraction?
- Ca2+ induced Ca2+ release (CICR)
- Ca2+ influx via Cav1.2 releases Ca2+ via RYR2 in the SR
- extracellular Ca2+ required for contraction (vascular and cardiac smooth muscle_
what causes the contraction in vascular smooth muscle?
the phosphorylation of myosin LC to myosin LC-PO4 and actin
what causes a smooth muscle contraction?
- Ca2+ released from SR binds to troponin C
- binding to troponin C displaces tropomyosin
- when tropomyosin displaced allows myosin to bind to actin making a contraction
what about skeletal muscle? how do we have a contraction? What is it coupled to?
- coupled to Cav1.1 & RYR1
- calcium is not required
–> CCBs do not interfere with Ca2+
what are the 3 classes of CCBs?
- DHPs
- phenylalkylamines
- benzothiazepines
what are the clinical applications of CCBs?
- angina pectoris
- arrhythmia
- HTN
what do all DHPs have in common?
a dihydropyridine ring.
- 6 membered ring with an NH and H
what DHP is this?
amlodipine
what is interesting about clevidipine?
- it has 2 cleavage points (the second one is inactive)
- given IV to treat HTN, PO admin is not possible
what is the blockade mechanism like for dihydropyridines?
- Clues from a pair of enantiomers
- enantiomer blocks current and interferes with opening of gate
- enantiomer potentiates current and interferes with closing of gates
what is the tissue selectivity like for DHPs?
do not compromise cardiac function(NOT GOOD SELECTIVITY)
vascular selectivity of DHPs are…..
observed in functional (cell intact) but not binding assays
what type of block do DHPs have?
voltage dependence
- no frequency dependence
what is DHP binding like?
allosteric; outside the pore
– bind to closed channels and prevent opening TONIC BLOCK
what is the vascular selectivity like for DHPs?
- dilation of arterioles leading to decreased afterload
what DHP exhibits greater selectivity for cerebral arteries (sub-arachnoid hemorrhage use) ?
nimodipine
what is a clinical consideration for DHPs?
efficacy in angina due to the reduction of oxygen in the heart
what are the PK factors of DHPs? Onset? Tachycardia?
- all DHPs are highly bound to proteins and have reflex tachycardia EXCEPT amlodipine due to slow onset and longer duration of actions (others are fast acting)
what is important to know about nifedipine?
- prompt release of this formulation may increase heart attack due to tachycardia (rapid inc. in BP)
what drug is a phenylalkylamine?
verapamil
what are the clinical considerations for verapamil?
- it causes vasodilation = less potent than DHPs
- slows conduction through SA/AV nodes
–> reduces heart rate and force of contraction - blunted for reflex tachycardia
what kind of block does verapamil have? How does it do it?
channel has to open for drug to enter into pore–>frequency-dependent block
–> very little tonic block
what drug is a benzothiazepine?
diltiazem
what does diltiazem do?
directly inhibits the heart less than verapamil but more than DHPs
what type of block does diltiazem exhibit?
- frequency-dependent block of Ca2+ channels
what is the characteristics of verapamil block on graph?
- lonngg
- marked frequency block
- very little tonic block
what does the graph for diltiazem look like?
- some tonic block and some frequency dependence
what drug is this?
verapamil
what drug is this?
diltiazem
what are the common side effects for Diltiazem? (want %s)
- ankle edema (5-10%)
what are the common side effects for DHPs? (want %s)
- ankle edema (5-10%)
- facial flushing (10-20%)
- tachycardia (5-10%)
what are the common side effects for Verapamil? (want %s)
- ankle edema (5-10%)
- constipation (>10%)
