CCB Flashcards
what are CCBs?
they are antagonists which stop the entry of calcium into cells and tissues
how many different types of channels are there?
4 types of channels, L-type channel is one we focus on
what is the l-type channel responsible for?
principally responsible for inward movement of Ca2+ into skeletal, cardiac and smooth muscle
what do CCBs treat?
Treats angina, hypertension and atrial fibrilation
what are the 3 classes of CCBs?
1,4-Dihydropyyridines (negative inotropic effect; vascular smooth muscle)
•Benothiazepines(negative ionotropic and chronotropic effect)
•Phenylalkylamines(negative chronotropiceffect)
is there structural similarity between the 3 classes?
no- which suggests a distinct activity profile for each
what is the MOA od CCBs?
do not block but bind in their open form at specific sites
what does each class contain?
an amine-–Water soluble hydrochloride salt for oral administration
are they hydrophobic or hydrophillic?
Predominantly hydrophobic
how are they absorbed?
rapidly 75-95% of dose but they have a low bioavailability due to first pass metabolism
what kind of reactions are these drugs prone to?
–Amlodipine (aromatic hydroxylation; dihydropyridineoxidation)
–Verapamil (N-demethylation/ O-demethylation)–Diltiazem(hydrolysis)
does plasma protein binding occur?
yes extensive plasma protein binding
what does calcium channels in the heart consist of?
Calcium channel in heart consists of a1, a2,band d subunits
what differs in skeletal ?
it has an extra gamma subunit
why does selectivity and sensitivity for antagonists usually occur?
Selectivity and sensitivity for antagonists occurs (mainly) in amino acid sequences of transmembrane segments
what is 1,4-Dihydropyridines selective for?
Selectivity for Ca2+ channels in vascular smooth muscle; minimal effect in myocardium
–S5/6 helix of domains III and IV of a1 (2 AAs in IIIS5, 7 in IIIS6, 4 in IVS6)
–(this receptor is not available on domain II)
what are benzothiazepines selective for?
–Selectivity for Ca2+ channels in cardiac muscle
–A site on a1 allostericallylinked to the 1,4-dihydropyridine receptor (4AAs in each of IIIS6 and IVS6)
–Enhances activity of a 1,4-dihydropyridine with its receptor
–Synergistic effect
what are phenylalkylamines selective for?
–Selectivity for Ca2+ channels in cardiac muscle
–Receptors located at S6 helix and C-terminal chain of III and IV of a1 (4AAs in each of IIIS6 and IVS6)
–Prevents binding of 1,4-dihydropyridines to their receptor
why is the slow release of nifidipine better?
as the normal one had to be administered quite frequently and it has more bioavailability
why is amlodipine administered as racemate, maleate salt ?
–S-isomer x1000 more active than R-isomer
–64-90% orally bioavailable
–t1/2~ 35-50 h
what is the more reactive form of Diltiazem?
Vasodilatory activity resides primarily in cis-form (x10 more active than trans)
what is the MOA of diltiazem?
Same mode of action as verapamil–antihypertensive–antianginal
what is the first pass metabolism like for diltiazem?
Extensive first-pass metabolism–Sometimes prescribed as an inhibitor of CYP3A4
what class of drug us diltiazem?
Benzothiazepine
what is Verapamil administered as?
Administered as racemate(hydrochloride salt), pKa8.7
what is the more active form of verapamil?
S-isomer is more active at calcium channels
what is the metabolite of verampamil?
•Norverapamilis the active metabolite–bioavailability of S-isomer is 2-3 fold less than R-isomer (stereoselectivemetabolism)
what are the main metabolic processes in verapamil?
N-and O-dealkylation
how is verapamil eliminated?
Elimination viakidneys (~70-80%) and faeces (~20-30%)
