Download Ca 2+

Calcium Antagonists
Tatyana Voyno-Yasenetskaya
[email protected]
312-996-9823
Regulation of Ca2+ extrusion
Ca2+-ATPase
Na+ -driven Ca2+ antiport
Ca2+
Ca2+
2 mM
Na+
ATP
ADP
100 nM
ADP Ca2+-ATPase
ATP
Ca2+
Ca2+-sequestering
compartments
Ca2+
Ca2+-binding
proteins
Ca2+
Mitochondria
Regulation of Ca2+ entry
Receptor-dependent Ca2+ entry
R
Gq
PLCb
IP3
DAG
Voltage-dependent Ca2+ channel
Closed
Open-inactive
Polarized
Depolarized
Open-active
Subunit composition of L-type Ca2+ channel
SS
a2
g a1 d
b
• 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
STRUCTURE OF THE L-TYPE CHANNEL4
ALPHA SUBUNIT
ACTIVATION
SELECTIVITY
NIFEDIPINE
DILTIAZEM
VERAPAMIL
P
P
P
P
P
P
INACTIVATION
E/C COUPLING VOLTAGE SENSOR
Control of smooth muscle contraction
and the site of action of calcium
channel-blocking drugs
Ca2+ channels
Ca2+ channels
blockers
Ca2+ (intracellular)
Calmodulin
Ca2+ - calmodulin complex
MLCK
Myosin light chain
Myosin-actin interaction
Contraction
P
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+ influx
DECREASE IN OXYGEN
REQUIREMENT
VASCULAR SELECTIVITY
INCREASED
CORONARY
PERFUSION
FLOW
IMPROVED
OXYGEN SUPPLY
DECREASED
PERIPHERAL
RESISTANCE
AFTERLOAD
BP
CONTRACTION
ENERGY SAVING
IMPROVED HEART PERFORMANCE
Degree of tissue selectivity of
calcium antagonist in clinical
use
myocardium
verapamil
diltiazem
nifedipine
nimodipine
felodipine
nisoldipine
amlodipine
+
+
+
+
+
+
+
vessels
+
+
++
+++
++++
++++
++++
sino-atrial node
+
+
-
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
• VASODILATION
Can be used in Prinzmetal’ angina
Effective at coronary vasospasm
Not recommended in unstable angina or MI
• INCREASED OXYGEN SUPPLY
Myocardial 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 DEMAND
Three 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 betaantagonists
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 Effects
Diltiazem
• 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
PHAR MACOKINETIC POTENTIAL
EFFECTCT
CLINICAL
EFFECT
Digoxin
Decreased
clearance
Decreased
clearance
Incr eased serum
digoxin con centration
Incr eased serum
carbmazepin e
conc entration
Incr eased expo sure to
active drug
Incr eased expo sure to
active drug
Incr eased expo sure to
active drug
Incr eased expo sure to
active drug
Carbmazepine
Antihistami nes
HMG-CoA
reduc tase inhibit ors
Immuno suppressive
drugs
Beta-blockers
Decreased
clearance
Decreased
clearance
Decreased
clearance
Decreased
clearance
Digoxin toxicit y
Neurotoxicit y
(dizzines s,
head ache, a taxia)
Ventricular
arrhy thmi a
Myop athy
Nephrotoxicit y
Bradyc ardia,
asystole