overview of calcium channel blocker

8/6/2019 Overview of Calcium Channel Blocker

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Presentation on

Overview of Calcium ChannelBlocker


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Presenter

Md. Faruq Hossain

ID: 2008-3-70-078

Khadija Akter Sweety

ID: 2008-3-70-082


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Calcium channel blockers are medicines that slow the

movement of calcium into the cells of the heart and

blood vessels. This, in turn, relaxes blood vessels,

increases the supply of oxygen-rich blood to the heart,

and reduces the heart's workload.

Voltage sensitive Calcium channels mediate the entry of

extracellular Ca2+ into smooth muscle and cardiac

myocytes and sinoatrial and atrioventricular nodal cells

in response to electrical depolarization.

Defination


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History

In 1967, Fleckenstein suggested that negative inotropiceffect result from inhibition of excitation-contractioncoupling and that the mechanism reduced movement ofcalcium into myocytes.

A derivative of verapamil,gallopamil and other compounds

such as nifedipine,also were shown to block the movementof calcium through cardiac myocyte calcium channel.

In 1969, the term calcium antagonists were given a noveldrug designation.

in 1975 ,in an extensive search for other calciumantagonists, a considerable number of substances wereidentified e.g. nifedipine, nimodipine.

In 1975, Japanese pharmacologists introduced diltiazem to

this group.


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Classification


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Classification

Dihydropyridinecalcium channelblockers are often used

to reduce systemicvascular resistance andarterial pressure, but arenot used to treat angina.

Example: AranidipineAzelnidipine


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ClassificationNon-Dihydropyridine:

Phenylalkylamine calciumchannel blockers are

relatively selective formyocardium

reduce myocardial oxygendemand

reverse coronary vasospasm,

and often used to treat angina.Example: Gallopamil Structural formula of Verapamil


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Classification

Benzothiazepine calciumchannel blockers are anintermediate class between

phenylalkylamine anddihydropyridines in theirselectivity for vascularcalcium channels.

Example: DiltiazemStructural formula of Diltiazem


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Classificationy Nonselective:

y While most of the agents listed above are relatively

selective, there are additional agents that areconsidered nonselective.

y Example: mibefradil, bepridil and fendiline.


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Clinical Applications

Pulmonary hypertension

Reynauds syndrome

Subarachnoid hemorrhage

Migraine headaches

Angina pectoris

Hypertension

Treatment of supraventricular

arrhythmias

- Atrial Flutter

- Atrial Fibrillation

- Paroxysmal SVT


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Clinical ApplicationsAngina pectoris:

Angina is not a disease itself but is the primary symptom

of coronary artery disease. It is typically experienced aschest pain, which can be mild, moderate, or severe.

Variant angina:

The probable mechanism by which calcium channel-blocking agents work in variant angina is the decrease

of the inappropriately stimulated tone of arterialsmooth muscle during coronary vasospasm.

Verapamil, nifedipine and diltiazem are all effective intreatment of coronary spasm.


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Chronic stable angina:

Nifedipine is the safest choice among the calcium channelblockers for combination with beta blockers. It has alsobeen shown that nifedipine, along with verapamil anddiltiazem, has additional therapeutic effects when usedwith propranolol for patients with chronic stable angina.

Unstable angina pectoris:

Studies of the long-term effectiveness of calcium channelblockers in patients with unstable angina appear to reduce

the number of patients, who require bypass surgery forrelief of angina.

Verapamil has become the treatment of choice in re-entrantsupraventricular tachycardia


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Clinical Applications Atrial Fibrillation:

For patients with atrial fibrillation verapamil has beenshown to be effective in controlling the ventricularresponse quickly and safely.

Wolff-Parkinson-White Syndrome:

By prolonging AV nodal conduction in the presence ofsupraventricular tachycardia, verapamil may increase

anterograde conduction over the accessory pathway,raising ventricular rate. Rapid AV conduction cancause degeneration of atrial fibrillation or flutter into

ventricular fibrillation and sudden death.


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VentricularArrhythmias:Calcium channel blockers are not effective in treatingventricular arrhythmias except when these arrhythmiasoccur in the context of coronary vasospasm with resultantmyocardial ischemia.

Hypertension (high blood pressure):

Calcium channel blocking agents are not usually the firstdrugs prescribed for the management of hypertension.

Nifedipine is effective in the therapy of chronic arterialhypertension.

Nifedipine may be of particular value in patients withhypertension who also have angina or congestive heartfailure.



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Other uses of calcium channel-blocking agents

Nifedipine and diltiazem are both widely used forRaynaud's syndrome.It is also used for migraine headache prophylaxis,

especially when agents such as propranolol andamitriptylene have proved ineffective.

Nifedipine has also been used in the setting ofsubarachnoid hemorrhage to prevent cerebral

vasospasm.CCBs are as effective as ACE inhibitors in reducing blood

pressure, but they may not be as effective as ACE

inhibitors in preventing the kidney failure caused byhigh blood pressure or diabetes.Verapamil used to improve left ventricular outflow

obstruction and symptoms in patients withhypertrophic cardiomyopathy.


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Using electrophysiological and pharmacological techniques,

three different types of VGCCs which

they called:

L-type (for long lasting, large channels),

Ttype (for transient, tiny channels) and

Ntype (for neuronal, neither L nor T).

They are classified according to their activation and inactivationkinetics, their conductance,

their ion specificity and their sensitivity to drug and toxin.

Types of Voltage Gated Calcium Channels


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L-type channels

These are widely distributed in many tissues particularly

in heart, smooth and skeletal muscles. They are highlysensitive to the dihydropyridines e.g. nifedipine,

phenylalkylamines e.g. diltiazem.

N-type channels

Thses N-type channels generally seemed to be sensitive

to W-contoxins and in certain instance may be coupled to

transmitter release whereas selective antagonists of L-type channels do not normally modify neurotransmitter

release.


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Calcium channel blockers work by inhibiting Ca"+movement across the cell membrane duringdepolarization in smooth and cardiac muscle. Thisaction blocks muscle contraction and results indecreased myocardial contractility and decreasedsmooth muscle cell tone (vasodilation).1 Generationand conduction of impulses in the sinoatrial (SA)and atrioventricular (AV) nodes of the heart dependon the movement of ca++ through membranechannels.


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CCBs Mechanisms of Action

The effects of calcium antagonists are membranepotential (voltage) dependent. The binding and effects

of calcium antagonists are stereoselective.While the (R)-enantiomers ofBay, K-8644 and 202-791

(two recently synthesized experimental 1,4-dihydropyridine derivatives), act like calcium

antagonists, the (S)-enantiomers are calcium agonists.


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CCBs Mechanisms of ActionCalcium antagonists exhibit different binding affinities.

Depending on the membrane potential (voltage) and thefrequency of channel opening, it is thought that calcium

antagonists bind with highest affinity to channels in the

inactivated state. The channels can exist in one of threedistinct states; mode 0, 1, and 2.

When a channel is in mode 0, it does not open in responseto depolarization. In mode 1, depolarization produces a

low opening probability and each opening is brief. Inmode 2, depolarization produces a very high openingprobability and single openings are prolonged.


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The different binding sites ofCCBs result in differingpharmacological effects

Voltage-dependent binding (targets smooth muscle)

Use-dependent binding (targets cardiac cells)

Cell

membrane

E1K

out

inF

+20

-80

mV E2H

DiltiazemVerapamil

E1

F

E1

out

K

in

+20

-80

-30E2

H

E1

Nifedipine

CellmembranemV


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CCBs Mechanisms of ActionIt was found that only the L-type channels were sensitive

to calcium channel-inhibiting drugs. L-type calcium

channels are different in various tissues with respect totheir affinities for calcium antagonists. CCBs bind tothe receptors with higher affinity under depolarizedrather than polarized conditions.


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CCBs: Pharmacokinetics

Absorption:

All calcium antagonists are rapidly absorbed from the small

intestine.

Onset of action of these drugs occur within 1-2 hours. Significant

first pass effect with bioavailability .

The bioavailability is likely to increase in overdose.

Verapamil has two enantiomers with different kinetics and activity.

The S isomer is more active but has a shorter half life and lower

bioavailability than the R isomer.

Distribution:

All CCBs have large volumes of distribution and moderate CNS

penetration


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Metabolism & Elimination:

All CCBs are metabolised in the liver to less active or

inactive metabolites.The half life of nifedipine, verapamil and diltiazem in

therapeutic use is short (3-8 hours). Newer

dihydropyridine drugs have considerably longer half lives.

There is no data on the half life in overdose.There may be significant enterohepatic circulation.


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Agent

Oral

Absorption

(%)

Bioavail-

Ability

(%)

Protein

Bound

(%)

Elimination

Half-Life

(h)

Verapamil >90 10-35 83-92 2.8-6.3*

Diltiazem >90 41-67 77-80 3.5-7

Nifedipine >90 45-86 92-98 1.9-5.8

Nicardipine

-10035 >95 2-4

Isradipine >90 15-24 >95 8-9

Felodipine-100

20 >99 11-16

Amlodipine

>9064-90 97-99 30-50



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Possible Side Effects

Breathing difficulty, coughing, or wheezingIrregular or fast, pounding heartbeat

Skin rash

Slow heartbeat (less than 50 beats per minute; this is a

concern with bepridil, diltiazem, and verapamil only)Swelling of ankles, feet, or lower legs (more common with

amlodipine, felodipine, and nifedipine)

Bleeding, tender, or swollen gums

Chest pain (may appear about 30 minutes after medicine istaken)

Painful, swollen joints (a concern with nifedipine only)

Trouble seeing (a concern with nifedipine only)


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Constipation

DiarrheaDizziness or lightheadedness (more common with

bepridil and nifedipine)

Dry mouth (more common with amlodipine)

Flushing and feeling of warmth (more commonwith nicardipine and nifedipine)

Headache (more common with amlodipine,

felodipine, isradipine, and nifedipine)

Nausea (more common with bepridil andnifedipine)


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Calcium channel blockers and antibiotics

might be a bad combination in the elderly

patients.

Calcium channel blockers prescribed to lower blood

pressure and macrolide antibiotics to treat infections can

combine to sharply reduce blood pressure in the elderly,leading to an increased risk of hospitalization and other

problems. The combination of drugs probably reduces

blood pressure in younger patients as well, but

represents a bigger risk in the elderly, who are already at

increased risk of falls, said Dr. David Juurlink of the

Sunnybrook Research Institute in Toronto.


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Calcium channel blockers may interact with a number of

other medications.

Diuretics (water pills). This type of medicine may causelow levels of potassium in the body, which may increasethe chance of unwanted effects from some calcium

channel blockers.

Beta-blockers, such as atenolol ,propranolol, andmetoprolol used to treat high blood pressure, angina,

and other conditions. Taking any of these drugs withcalcium channel blockers may increase the effects ofboth types of medicine and may cause problems if eitherdrug is stopped suddenly.


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Drug Interactions

Digitalis heart medicines. Taking these medicineswith calcium channel blockers may increase theaction of the heart medication.

Medicines used to correct irregular heart rhythms,

such as quinidine, procainamide. The effects ofthese drugs may increase if used with calciumchannel blockers.

Anti-seizure medications such as carbamazepine.

Calcium channel drugs may increase the effects ofthese medicines.

Grapefruit juice may increase the effects of somecalcium channel blockers.


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Calcium Channel Blocker Acts As Male

Contraceptive

Procardia (Nifedipine) appears to have contraceptivepotential, and the calcium channel blocker also

appears to cause reversible male infertility.

Investigators noted the cholesterol content of the

membrane was significantly reduced. Cholesterolsynthesis significantly increased in sperm treated with

nifedipine.

These drugs act by changing the cholesterol content

of the membrane.Men should wait approximately 3 months before

attempting to impregnate their partner in order for

new sperm to generate that have been unaffected by

the calcium channel blocker.


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Thank you

overview of calcium channel blocker

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