Overview of Calcium Channel Blocker
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Transcript of 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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Clinical Applications
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.
Clinical Applications
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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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CCBs: Pharmacokinetics
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
CCBs: Pharmacokinetics
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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