1. DIHYDROPYRIDINES
& THEIR EFFECT ON
CALCIUM CHANNELS.

2. DIHYDROPYRIDINES
 Normally, we consider Dihydropyridines as group of
L-Type Calcium channel blockers like
 Amlodipine
 Felodipine
 Nifidipine etc.
 But actually Dihydropyridine is a GENERAL group
of molecules which contain drugs having pyridine
group in them.

3. BUT THAT’S NOT ALL…
….the most important and interesting part
of the discussion starts here.
Dihydropyridines may be AGONISTS as well as ANTAGONISTS of Calcium
Channels!!

4. DERIVATIVES OF DIHYDROPYRIDINES
(TO WHICH WE ARE FAMILIAR)
Dihydropyridine Ring
Amlodipine
Nifedipine Nimodipine
Felodipine

5. OTHER DERIVATIVES OF DIHYDROPYRIDINES
Dihydropyridine
Ring
Amlodipine
Nifedipine
Nimodipine
Felodipine
Bay K8644
A
N
T
A
G
O
N
I
S
T
S
A
G
O
N
I
S
T
S

6. COMPARISON OF DHP AGONIST & ANTAGONISTS
 Contains drugs which
block influx of Ca++ into
cell.
 Decreases force of cardiac
contraction & dilatation of
blood vessels.
 Negative ionotropic effect
 Examples;
 Amlodpine
 Felodipine
 Nifedipine
 Contains drugs which
allow influx of Ca++ into
cell.
 Increase the force of
cardiac contraction &
contraction of blood
vessels.
 Positive ionotropic effect
 Examples;
 Bay K8644
CC Antagonists CC Agonists
*CC = Calcium Channel

7. NOW LETS SEE THE PHYSIOLOGY OF
CA++ CHANNELS

8. HVA= High Voltage Activated
LVA= Low Voltage Activated
L-Type = Long Lasting aka DHP(Dihydropyridine) receptors
T-Type= Transient Receptors (Lasting only for short time)
P-Type = Purkinje (Neurons in cerebellum)
N-type= Neural/ Non-L (throughtout CNS, PNS)
R-Type = Residual type

9. BASIC DIFFERENCE BETWEEN T & L TYPE
 Long Lasting
 Aka DHP receptors
 HVA
(High Voltage Activated receptors)
 Found in
 Skeletal muscle
 Smooth muscle
 Bone (osteoblasts),
 Ventricular myocytes (responsible
for prolonged action potential in
cardiac cell; also termed DHP
receptors)
 Dendrites and dendritic spines of
cortical neurons
 Short acting
 T for ‘transient’
 LVG
(Low Voltage Gated)
 Found in
 Neurons
 Cells that have pacemaker activity
 Bone (osteocytes)
L-type Ca++ Channels T-Type Ca++ Channels

10. NOW LETS TAKE A LOOK ON L-TYPE CALCIUM
CHANNELS…
…according to Rang & Dale’s Pharmacology, 6th Edition.

11. TO BE BRIEF OR IN SHORT…
 According to Rang & Dale’s Pharmacology, 6th
Edition, Ca++ Channels exist in 3 modes:
 Mode 0
 Mode 1
 Mode 2
 These modes of Calcium channels are classified
upon their opening probability, whenever a
depolarizing current arrives and tries to activate
them.

12. SO, WHEN A DEPOLARIZATION IMPULSE
ARRIVES…
 Calcium Channels in Mode 0 = Remain closed.
 Calcium Channels in Mode 1 = Open briefly and
there is a low opening probability.
 Calcium Channels in Mode 2 = Open for a
prolonged time and there is very high opening
probability.
 NOTE: Under normal conditions, the channel
spends most of there time in modes 1 and 2, and
only rarely enters mode 0.

13. NOW LETS LOOK AT THE FOLLOWING TABLE* :
*Table extracted from Rang & Dale’s Pharmacology, 6th Edition.
This table represents the results of an experiment done on cardiac muscles…
The traces are patch clamp recordings of the opening of single calcium channels (downward
deflections) in a patch of membrane from a cardiac muscle cell.
A depolarizing step is imposed…
When the channel is in mode 1 (centre), this causes a few brief openings to occur;
In mode 2 (right), the channel stays open for most of the time during the depolarizing step;
In mode 0 (left), it fails to open at all.
Under normal conditions, the channel spends most of its time in modes 1 and 2, and only rarely enters
mode 0

14. NOW LETS LOOK AT THE FOLLOWING TABLE* :
*Table extracted from Rang & Dale’s Pharmacology, 6th Edition.
This table represents the results of an experiment done on cardiac muscles…
Just NOTE where the DHP antagonists and DHP agonists show their actions upon.
ON THE OTHER HAND…
DHP agonists like Bay K8644 attach to Ca++ channels in Mode 2, who have High opening
probability and spend approximately 30% of time in this mode.
…which means channel will remain open for a longer time and there will be a considerable
Ca++ influx. Hence, POSITIVE IONOTROPIC EFFECT.
DHP antagonists like Amlodipine attach to Ca++ channels in Mode 0, who have Zero opening
probability and spend less than 1% of time in this mode.
…which means channel will remain close and there will be no Ca++ influx. Hence, NEGATIVE
IONOTROPIC EFFECT.

15. TO SUMMARIZE THE CONCLUSION:
 CCBs always have Negative ionotropic effect.
 CCBs are of two types:
 Phenylalkylamine (Verapamil, Diltiazem)
 Dihydropyridines (Amlodipine, Felodipine, etc)
 CCBs effect mainly on Cardiac & Smooth Muscle.
 More preferentially,
 Verapamil act on Cardiac muscles (Mainly used for Arrhythmias)
 Diltiazem acts on both Cardiac & Smooth Muscles (for Angina)
 DHPs acts on Smooth Muscles. (for Hypertension)
 CCBs reduce the contractility of heart so are not given to
patients of Heart Failure; except Amlodipine which can be
given in Stage A patient.

16. TO SUMMARIZE THE CONCLUSION:
 Calcium Channels are of many types. (T, L, P/Q, N, R)
 L-type channels stay in three distinct modes 0, 1 & 2.
 Dihydropyridines can be agonists (Bay K8644) as well as
antagonists (Amlodipine, felodipine, etc).
 Their attachment affinity to the specific mode of channel
describes their effect of action.
 Dihydropyridines of the antagonist type bind selectively to
channels in mode 0, thus favoring this non-opening state,
ending up in smooth muscles relaxation and reduced cardiac
contractility.
 Whereas agonists bind selectively to channels in mode 2,
favoring this prolonged-opening state, ending up in smooth
muscle contraction and increased cardiac contractlity.

17. THANKS A LOT FOR YOUR PATIENCE
Compiled, composed & researched by:
Omaid Hayat Khan
Pharm-D, rPh.