DIHYDROPYRIDINES& THEIR EFFECT ON

CALCIUM CHANNELS.

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.

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!!

DERIVATIVES OF DIHYDROPYRIDINES(TO WHICH WE ARE FAMILIAR)

Dihydropyridine Ring

Amlodipine

Nifedipine Nimodipine

Felodipine

OTHER DERIVATIVES OF DIHYDROPYRIDINES

Dihydropyridine Ring

Amlodipine

Nifedipine

Nimodipine

Felodipine

Bay K8644

ANTAGONISTS

AGONISTS

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

NOW LETS SEE THE PHYSIOLOGY OF CA++ CHANNELS

HVA= High Voltage ActivatedLVA= Low Voltage Activated

L-Type = Long Lasting aka DHP(Dihydropyridine) receptorsT-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

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

NOW LETS TAKE A LOOK ON L-TYPE CALCIUM CHANNELS…

…according to Rang & Dale’s Pharmacology, 6th Edition.

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.

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.

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

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.

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.

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.

THANKS A LOT FOR YOUR PATIENCE

Comments, Suggestions, Questions and

Corrections are always welcomed…

Compiled, composed & researched by:

Omaid Hayat KhanPharm-D, rPh.