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Calcium Antagonists. Tatyana Voyno-Yasenetskaya Tvy@uic.edu 312-996-9823. Regulation of Ca 2+ extrusion. Ca 2+ -ATPase. Na + -driven Ca 2+ antiport. Ca 2+. Ca 2+. 2 mM. Na +. ATP. ADP. 100 nM. ADP. ATP. Ca 2+ -ATPase. Ca 2+. Ca 2+. Ca 2+. Mitochondria. Ca 2+ -binding

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calcium antagonists

Calcium Antagonists

Tatyana Voyno-Yasenetskaya

Tvy@uic.edu

312-996-9823

slide2

Regulation of Ca2+ extrusion

Ca2+-ATPase

Na+ -driven Ca2+ antiport

Ca2+

Ca2+

2 mM

Na+

ATP

ADP

100 nM

ADP

ATP

Ca2+-ATPase

Ca2+

Ca2+

Ca2+

Mitochondria

Ca2+-binding

proteins

Ca2+-sequestering compartments

slide3

Regulation of Ca2+ entry

Receptor-dependent Ca2+ entry

R

Gq

PLCb

IP3

DAG

Polarized

Voltage-dependent Ca2+ channel

Closed

Depolarized

Open-inactive

Open-active

slide4

SS

a1

a2

g

d

b

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
slide6

Ca2+ channels

Ca2+ (intracellular)

Ca2+ - calmodulin complex

P

MLCK

Myosin light chain

Myosin-actin interaction

Contraction

Control of smooth muscle contraction

and the site of action of calcium

channel-blocking drugs

Ca2+ channels

blockers

Calmodulin

slide7

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
slide8

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

slide10

VASCULAR SELECTIVITY

IMPROVED HEART PERFORMANCE

INCREASED

DECREASED

CORONARY

PERFUSION

PERIPHERAL

RESISTANCE

AFTERLOAD

FLOW

BP

CONTRACTION

IMPROVED

OXYGEN SUPPLY

ENERGY SAVING

slide11

Degree of tissue selectivity of

calcium antagonist in clinical

use

myocardium

vessels

sino-atrial node

+

+

+

verapamil

+

+

+

diltiazem

++

-

+

nifedipine

+++

-

+

nimodipine

++++

-

+

felodipine

++++

-

+

nisoldipine

++++

-

+

amlodipine

Amlodipine is currently the most commonly

prescribed calcium blocker for hypertension

slide12

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
slide13

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

slide14

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
slide15

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
slide16

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
slide17

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
Other Uses
  • Migraine
  • Prevent development of atheromatous lesions
  • Pulmonary artery hypertension
slide19

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
slide20

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