CCB

Question 1

what are CCBs?

Answer 1

they are antagonists which stop the entry of calcium into cells and tissues

Question 2

how many different types of channels are there?

Answer 2

4 types of channels, L-type channel is one we focus on

Question 3

what is the l-type channel responsible for?

Answer 3

principally responsible for inward movement of Ca2+ into skeletal, cardiac and smooth muscle

Question 4

what do CCBs treat?

Answer 4

Treats angina, hypertension and atrial fibrilation

Question 5

what are the 3 classes of CCBs?

Answer 5

1,4-Dihydropyyridines (negative inotropic effect; vascular smooth muscle)
•Benothiazepines(negative ionotropic and chronotropic effect)
•Phenylalkylamines(negative chronotropiceffect)

Question 6

is there structural similarity between the 3 classes?

Answer 6

no- which suggests a distinct activity profile for each

Question 7

what is the MOA od CCBs?

Answer 7

do not block but bind in their open form at specific sites

Question 8

what does each class contain?

Answer 8

an amine-–Water soluble hydrochloride salt for oral administration

Question 9

are they hydrophobic or hydrophillic?

Answer 9

Predominantly hydrophobic

Question 10

how are they absorbed?

Answer 10

rapidly 75-95% of dose but they have a low bioavailability due to first pass metabolism

Question 11

what kind of reactions are these drugs prone to?

Answer 11

–Amlodipine (aromatic hydroxylation; dihydropyridineoxidation)
–Verapamil (N-demethylation/ O-demethylation)–Diltiazem(hydrolysis)

Question 12

does plasma protein binding occur?

Answer 12

yes extensive plasma protein binding

Question 13

what does calcium channels in the heart consist of?

Answer 13

Calcium channel in heart consists of a1, a2,band d subunits

Question 14

what differs in skeletal ?

Answer 14

it has an extra gamma subunit

Question 15

why does selectivity and sensitivity for antagonists usually occur?

Answer 15

Selectivity and sensitivity for antagonists occurs (mainly) in amino acid sequences of transmembrane segments

Question 16

what is 1,4-Dihydropyridines selective for?

Answer 16

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)

Question 17

what are benzothiazepines selective for?

Answer 17

–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

Question 18

what are phenylalkylamines selective for?

Answer 18

–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

Question 19

why is the slow release of nifidipine better?

Answer 19

as the normal one had to be administered quite frequently and it has more bioavailability

Question 20

why is amlodipine administered as racemate, maleate salt ?

Answer 20

–S-isomer x1000 more active than R-isomer
–64-90% orally bioavailable
–t1/2~ 35-50 h

Question 21

what is the more reactive form of Diltiazem?

Answer 21

Vasodilatory activity resides primarily in cis-form (x10 more active than trans)

Question 22

what is the MOA of diltiazem?

Answer 22

Same mode of action as verapamil–antihypertensive–antianginal

Question 23

what is the first pass metabolism like for diltiazem?

Answer 23

Extensive first-pass metabolism–Sometimes prescribed as an inhibitor of CYP3A4

Question 24

what class of drug us diltiazem?

Answer 24

Benzothiazepine

Question 25

what is Verapamil administered as?

Answer 25

Administered as racemate(hydrochloride salt), pKa8.7

Question 26

what is the more active form of verapamil?

Answer 26

S-isomer is more active at calcium channels

Question 27

what is the metabolite of verampamil?

Answer 27

•Norverapamilis the active metabolite–bioavailability of S-isomer is 2-3 fold less than R-isomer (stereoselectivemetabolism)

Question 28

what are the main metabolic processes in verapamil?

Answer 28

N-and O-dealkylation

Question 29

how is verapamil eliminated?

Answer 29

Elimination viakidneys (~70-80%) and faeces (~20-30%)