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Calcium Antagonists
Tatyana Voyno-Yasenetskaya
312-996-9823
ATP ADP
Ca2+
Ca2+
Na+
Ca2+-ATPaseNa+ -driven Ca2+ antiport
2 mM
Ca2+
Ca2+
ATP ADP
Ca2+
MitochondriaCa2+-bindingproteins
Ca2+-ATPase
Ca2+-sequestering compartments
Regulation of Ca2+ extrusion
100 nM
R
Gq
PLC
IP3DAG
Receptor-dependent Ca2+ entry
Regulation of Ca2+ entry
Voltage-dependent Ca2+ channel Polarized
DepolarizedClosed
Open-activeOpen-inactive
1
2
SS
Subunit composition of L-type Ca2+ channel
• L-type (long-lasting)-excitation/contraction coupling of cardiac myocytes (nifedipine, verapamil, diltiazem)
• T-type (transient) - participate in pace making, highly expressed in sinusal cells (mibefradil)
• N-, P-type - expressed in neurons, are not affected by Ca2+ antagonists
ACTIVATION
INACTIVATION
SELECTIVITY
VOLTAGE SENSOR
DILTIAZEMNIFEDIPINE VERAPAMIL
P
PP
P
P
P
STRUCTURE OF THE L-TYPE CHANNEL ALPHA SUBUNIT
E/C COUPLING
4
Calmodulin
Ca2+ channels blockers
Ca2+ channels
Ca2+ (intracellular)
Ca2+ - calmodulin complex
MLCK
Myosin light chain P
Myosin-actin interaction
Contraction
Control of smooth muscle contraction and the site of action of calcium
channel-blocking drugs
Calcium Antagonists
• Bind to specific sites on the alpha1 subunit of the L-type Ca2+ channel
• Reduce the probability of channel opening rather then calcium current flow through an open channel
• Tissue selectivity is one of the most beneficial properties of Ca2+ antagonists
• In general, skeletal muscle, bronchial, tracheal, and intestinal smooth muscle and neuronal tissue are relatively insensitive to Ca2+ antagonists
SMOOTH MUSCLE
Relaxation due to Ca2+ decrease•Decrease in blood pressure
•Decrease in vascular resistance
CARDIAC MUSCLE
* Excitation/contraction* Impulse generation in sinoatrial node* Conduction in atrioventricalar node
Require Ca2+ influxDECREASE IN OXYGEN
REQUIREMENT
VASCULAR SELECTIVITY
INCREASED CORONARY PERFUSION
IMPROVED OXYGEN SUPPLY
DECREASED PERIPHERAL RESISTANCE
CONTRACTION ENERGY SAVING
IMPROVED HEART PERFORMANCE
FLOWAFTERLOAD
BP
myocardium vessels sino-atrial node
verapamildiltiazemnifedipinenimodipinefelodipinenisoldipineamlodipine
+++++++
+++++++++++++++++++
++-----
Degree of tissue selectivity of
calcium antagonist in clinical
use
Amlodipine is currently the most commonly prescribed calcium blocker for hypertension
Angina and Calcium Antagonists
• Angina is a chest pain that occurs when coronary blood flow is inadequate to supply the oxygen required by heart
• Classic angina is caused by atherosclerosis
• Angiospastic or variant angina is caused by vasospasm
Angina and Calcium Antagonists
• VASODILATIONCan be used in Prinzmetal’ anginaEffective at coronary vasospasmNot recommended in unstable angina or MI
• INCREASED OXYGEN SUPPLYMyocardial oxygen extraction is almost maximal
~75% of the available oxygen under no stress condition, thus there is no reserve to meet increased demand. The increased demand is me by increasing coronary blood flow
• DECREASE OXYGEN DEMANDThree major determinants of the myocardial oxygen
uptake are heart rate, blood pressure, and the contractile status of the myocardium
Angina and Calcium Antagonists
Calcium Antagonists
• Reduce blood pressure because of peripheral vasodilation
• Reduce heart rate, especially diltiazem and verapamil
• Decrease contractility thereby reducing the oxygen demand
Hypertension and Calcium Antagonists
• Mechanism of action is VASODILATION
• Nifedipine is used commonly because is 10 times more
selective to vascular smooth muscle cells than to myocardial
cells• Often used in patients with
contraindications to beta-antagonists
Arrhythmia and Calcium Antagonists
Arrhythmia results from• Abnormal pacemaker activity
• Abnormal impulse propagation
Aim of therapy• To reduce ectopic pacemaker
activity
• To modify impulse propagation
Arrhythmia and Calcium Antagonists
Supraventricular dysrhythmia(diltiazem,
verapamil)
• Mechanism of action is selectivity for pacemaker and nodal cells.
Blocks Ca2+-dependent conduction in AV node, thereby reducing atrioventricular conduction
• Restores synapse rhythm in 75% cases
Other Uses
• Migraine• Prevent development of atheromatous
lesions• Pulmonary artery hypertension
Side EffectsDiltiazem
• Edema• Headache
• Depresses sinoatrial nodal function because of high degree atrioventricular nodal block
Nifedipine• Dizziness is the result of acute vasodilation and rapid blood
pressure fall• Headaches is the result of vasodilation
• Ankle edema is caused by precapillary vasodilation
Verapamil• May increase digoxin level when used in combination
• Absolutely contraindicated in digoxin toxicity because will cause high grade AV block
• High rate of constipation up to 30%, presumably due to a specific interaction of verapamil with calcium channels in
smooth muscle cells of the gut• Depresses sinoatrial nodal function, may cause high degree
atrioventricular nodal block
Contraindications
• Patients with low baseline blood pressure -may develop hypotension
• Patients with decreased left ventricular systolic function - may worsen the heart failure
•Arrythmias with antegrade conduction down a bypass tract, such as
syndrome Wolff-Parkinson-White
DRUG INTERACTION
DRUG AFFECTED MECHANISM PHARMACOKINETICEFFECTCT
POTENTIALCLINICALEFFECT
Digoxin Decreasedclearance
Increased serumdigoxin concentration
Digoxin toxicity
Carbmazepine Decreasedclearance
Increased serumcarbmazepineconcentration
Neurotoxicity(dizziness,headache, ataxia)
Antihistamines Decreasedclearance
Increased exposure toactive drug
Ventriculararrhythmia
HMG-CoAreductase inhibitors
Decreasedclearance
Increased exposure toactive drug
Myopathy
Immunosuppressivedrugs
Decreasedclearance
Increased exposure toactive drug
Nephrotoxicity
Beta-blockers Decreasedclearance
Increased exposure toactive drug
Bradycardia,asystole
