CCB

Question 1

Define inotropic?

Answer 1

Affecting the force of muscle contraction

Question 2

Uses of CCB’s?

Answer 2

• for prophylactic treatment of angina
• block’s Ca2+ entry into myocardial cells, producing a negative inotropic effect on the heart
• deprives cells in vascular smooth muscle of calcium, inhibiting smooth muscle contraction
• causes vasodilation (especially in arterial smooth muscle)

Question 3

MOA of CCB’s

Answer 3

Blocks L-type voltage-dependent calcium channels, preventing calcium entry into myocardial cells

Normally:

• rapid influx of sodium ions through the fast channel
• slower influx of calcium ions through the slow channel
• Ca2+ binding to troponin, leads to membrane depolarisation and then muscle contraction

Neutral drug species partitions across the cell membrane and blocks the Ca2+ channel from the inside

So calcium cannot gain access to the channel from the outside.

Question 4

3 classes of CCB’s?

Answer 4

DIHYDROPYRIDINES

BENZOTHIAZEPINES

ARALKYL AMINES

Question 5

Name some dihydropyridines and their pka values.

Answer 5

• nifedipine, pka is 4 (acid or base?)
• amlodipine, pka is 8.5
• nicardipine, pka is 7

Question 6

Name a benzothiazpine and its pka

Answer 6

Diltiazem

pka= 8

Question 7

Name some aralkyl amines and their pkas

Answer 7

verapamil, pka is 9

bepridil, pka is 10

Question 8

Which enantiomer of verpamil is more potent?

Answer 8

R enantiomer is 2.5-20 times more potent than s

Both enantiomers are active

Question 9

How can CCB be a potent activator and an antagonist?

Answer 9

e.g. s enantiomer is a potent activator

r enantiomer is an antagonist

• it binds to the channel in different states- open, activated

Question 10

What are the bioavailabilities of verapamil, nicardipine, diltiazem, nifedipine and amlodipine

Answer 10

verapamil 10-30%

nicardipine 15-40%

diltiazem 30-60%

nifedipine 50-60%

amlodpine 60-65%

Question 11

Low bioavailabilities?

Answer 11

around half of the tablet does not get to the targeted system

It is not because they are not well absorbed, they are rapidly and completely absorbed after oral administration

therefore, first pass metabolism is extensive

as it passes from the intestines to the liver, liver metabolises it

Question 12

What other problem is encountered with CCB?

Answer 12

binding to plasma protein is high

e. g.. 70-80% of diltiazem is protein bound
- very little free drug is found in th eplasma
- most CCB’s are attached to surface of proteins such as albumin
- therefore drug interactions arise as a consequence- these compete with the protein surface, resulting in more free drug in the plasma

Question 13

What does the duration of action range from?

Answer 13

4-8 hours

Question 14

Why is amlodipine administered in a much smaller dose compared to other CCB’s?

Answer 14

• 5-10mg/day
• low dosage due to high bioavailability
• the higher the bioavailability, the more drug eaches the system and is not metabolised by the liver

Question 15

Name the metabolite of verapamil

Answer 15

Norverapamil

N-demethylation of middle hydrogen

However, the metabolite still has 20% activity

Metabolism does not always remove the activity, sometimes just reduces it

Question 16

What enzymes are CCB’s metabolised by?

Answer 16

CYP3A4

Question 17

What cannot be consumed within 2 hours before or 4 hours after administration of CCB’s?

Answer 17

grapefruit juice

contains furanocourmarin, bergamottin

these inhibit CYP3A4

blocking CYP3A4 stops the metabolsim of CCB, resulting in higher levels of CCB