Добавил:
Upload Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз: Предмет: Файл:
Color_Atlas_of_Pharmacology_3rdEd.pdf
Скачиваний:
42
Добавлен:
27.02.2016
Размер:
12.08 Mб
Скачать

 

132

Cardiac Drugs

 

 

 

 

Cardiac Drugs

 

 

 

Na+/K+-ATPases, (p.134), the Ca-antagonists

 

 

 

 

to Ca2+ channels (p.126), and antiarrhyth-

 

 

Possible ways of influencing heart function

mics of the local anaesthetic type to Na+

 

 

(A). The pumping capacity of the heart de-

channels (p.136) in the plasmalemma.

 

 

pends on different factors: with increasing

 

 

 

heart rate, the force of contraction increases

Events underlying contraction and relaxa-

 

 

(“positive staircase”); the degree of diastolic

tion (B). The signal triggering contraction is

 

 

filling regulates contraction amplitude (Star-

apropagated actionpotential(AP) generated

 

 

ling’s law of the heart). The sympathetic in-

in the sinoatrial node. Depolarization of the

 

 

nervation with its transmitter norepineph-

plasmalemma leads to a rapid rise in cyto-

 

 

rine and the hormone epinephrine promote

solic Ca2+ levels, which causes contraction

 

 

contractile force generation (but also oxygen

(electromechanical coupling). The level of

 

 

 

consumption), and raise beating rate and

Ca2+ concentration attained determines the

 

 

excitability (p.88). The parasympathetic in-

degree of shortening, i.e., the force of con-

 

 

nervation lowers beat frequency because

traction. Sources of calcium are: (a) extra-

 

 

acetylcholine

inhibits

pacemaker

cells

cellular calcium entering the cell through

 

 

(p.104).

 

 

 

 

 

voltage-gated Ca2+ channels; (b) calcium

 

 

From the influence of the autonomic ner-

stored in the sarcoplasmic reticulum (SR);

 

 

vous system it follows that all sympatholytic

(c) calcium bound to the inside of the plas-

 

 

or sympathomimetic and parasympatholytic

malemma. The plasmalemma of cardiomyo-

 

 

or parasympathomimetic drugs can produce

cytes extends into the cell interior in the

 

 

corresponding effects on cardiac perform-

form of tubular invaginations (transverse tu-

 

 

ance. These possibilities are exploited ther-

buli).

 

 

apeutically: for instance, β-blockers for sup-

The trigger signal for relaxation isthe re-

 

 

pressing excessive sympathetic drive (p.96);

turn of the membrane potential to its resting

 

 

ipratropium for treating sinus bradycardia

level. During repolarization Ca2+ levels fall

 

 

(p.108). An unwanted activation of the sym-

below the threshold for activation of the

 

 

pathetic system can result from anxiety,

myofilaments (3 × 10–7 M): the plasmalem-

 

 

pain, and other emotional stress. In these

mal Ca binding sites regain their Ca-binding

 

 

cases, the heart can be protected from harm-

capacity; calcium ions are pumped back into

 

 

ful stimulation

by

psychopharmaceuticals

the SR lumen andtheplasmalemmal ATPases

 

 

such as benzodiazepines (diazepam and

move Ca2+ that entered during systole back

 

 

others; important in myocardial infarction).

out of the cell under expenditure of energy.

 

 

Cardiac work

furthermore depends

Additionally, Ca2+ isextrudedfromthe cellin

 

 

strongly on the state of the circulation sys-

exchange for Na+ (Na/Ca exchanger).

 

 

tem: physical rest or work demand appro-

 

 

 

priate cardiac performance; the level of

 

 

 

mean blood pressure is an additional deci-

 

 

 

sive factor. Chronic elevation of afterload

 

 

 

leads to myocardial insuf

ciency. Therefore,

 

 

 

all blood pressure-lowering drugs can have

 

 

 

an important therapeutic influence on the

 

 

 

myocardium. Vasodilator

substances

(e.g.,

 

nitrates) lower the venous return and/or peripheral resistance and, hence, exert a favorable effect in angina pectoris or heart failure.

The heart muscle cells can also be reached directly. Thus, cardiac glycosides bind to the

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

 

 

 

Cardiac Drugs

133

A. Possible mechanisms for influencing heart function

 

 

Drugs with

 

 

Drugs with direct action

 

indirect action

 

 

 

 

 

 

 

Nutrient solution

 

Psycho-

 

 

 

 

tropic drugs

 

 

 

 

 

 

 

Force

 

Parasympathetic

 

 

Rate

 

 

 

 

 

Sympathetic

Cardiac

β -Sympathomimetics

 

Phosphodiesterase inhibitors

 

 

 

Epinephrine

glycosides

Rate

 

 

 

Force

 

Drugs altering

 

 

Parasympathomimetics

 

 

Catamphiphilic

 

preand afterload

 

 

Ca-antagonists

 

 

 

 

 

 

 

 

Local anesthetics

 

B. Processes in myocardial contraction and relaxation

 

Contraction

 

2+

 

-3

 

 

Membrane potential

 

Ca

 

10 M

 

[mV]

Electrical

 

 

 

excitation

 

 

 

 

 

 

0

Ca-channel

 

 

 

 

 

 

 

Sarcoplasmic

 

 

 

 

 

 

 

reticulum

 

 

 

 

 

cell

Action potential

 

 

 

 

 

 

Transverse tubule

 

Ca2+

 

 

muscle

 

 

 

 

 

 

 

 

 

 

Heart

 

Plasmalemmal

 

10-5M

 

 

-80

binding sites

 

 

 

 

 

 

 

 

 

 

 

 

 

 

t

Relaxation

Ca

2+

10

-3

M

 

Force

 

 

 

 

 

 

 

 

Na+

 

 

 

 

 

 

Ca2+

Ca-ATPase

 

 

 

Na/Ca-

 

 

 

 

 

cell

Contraction

exchange

 

 

 

 

 

 

Ca2+

 

Ca2+

 

muscle

 

Na+

 

Na+

 

 

Ca2+

 

 

 

 

 

 

 

 

Heart

 

Plasma-

 

10-7M

 

 

 

lemmal

 

 

 

 

 

 

 

binding sites

 

 

 

 

 

 

 

 

 

 

 

 

 

 

300 ms

 

 

 

 

 

 

 

t

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

134 Cardiac Drugs

Cardiac Glycosides

Diverse plants are sources of sugar-contain- ing compounds (glycosides) that also contain a steroid ring system (structural formulas, A) and augment the contractile force of heart muscle: cardiotonic glycosides, cardiosteroids, digitalis.”

The cardiosteroids possess a small therapeutic margin, signs of intoxication are arrhythmia and contracture (B). This therapeutic drawback can be explained by the mechanism of action.

Cardiac glycosides (CG) bind to the extracellular domain of Na+/K+-ATPases and exclude this enzyme molecule for a time from further ion transport activity. The high-af nity binding of CG is restricted to a particular conformation that the enzyme adopts during its transport cycle. In the resting state, Na+/K+-ATPase molecules are not binding partners. Under normal conditions only a fraction of the Na+/K+-ATPase transport activity is required to maintain the high gradients of Na+ and K+ across the plasmalemma. Low therapeutic concentrations of CG occupy onlya fraction of Na+/K+-ATPases; the decrease of the resulting pump activity can easily be compensated for by recruitment of resting ATPase molecules via a small increase of the intracellular Na+ concentration.

Attached to the ATPases there are Na+ channels which, upon binding of CG to the enzyme, lose their specificity for Na+ and are converted to nonselective, promiscuous channels: during systole, Ca2+ will easily pass through this channel owing to its huge gradient (almost 4 orders of magnitude!). This results in an increased Ca2+-influx and augmented contractile force. It should, however, be noted that the mode of action of cardiosteroids is still a matter of debate.

Mobilization of edema (weight loss) and lowering of heart rate are simple but decisive criteria for achieving optimal dosing. If ATPase activity is inhibited too much, K+ and Na+ homeostasisisdisturbed:the membrane

potential declines, arrhythmias occur. Intracellular flooding with Ca2+ prevents relaxation during diastole: contracture.

The CNS effects of CGs (C) are also due to binding to Na+/K+-ATPases. Enhanced vagal nerve activity causes a decrease in sinoatrial beating rate and velocity of atrioventricular conduction. In patients with heart failure, improved circulation also contributes to the reduction in heart rate. Stimulation of the area postrema leads to nausea and vomiting.

Indications for CGs are:

1 chronic congestive heart failure,

2 atrial fibrillation or flutter, where inhibition of AV conduction protects the ventricles from excessive atrial impulse activity and thereby improves cardiac performance (D).

Signs of intoxication are:

1Cardiac arrhythmias, which under certain circumstancesarelife-threatening,e.g.,si- nus bradycardia, AV-block, ventricular ex-

trasystoles, ventricular fibrillation (ECG); 2 CNS disturbances: characteristically, altered color vision (xanthopsia), and also fatigue, disorientation, hallucinations;

3 anorexia, nausea, vomiting, diarrhea;

4renal: loss of electrolytes and water; this must be differentiated from mobilization of edema fluid accumulated in front of the heart during congestive failure, an effect expected with therapeutic dosage.

Therapy of intoxication: administration of K+, which inter alia reduces binding of CG, but may impair AV-conduction; administration of antiarrhythmics, such as phenytoin or lidocaine (p.136); oral administration of colestyramine (p.160) for binding and preventing absorption of digitoxin present in the intestines (enterohepatic cycle), and most importantly injection of antibody (Fab) fragments that bind and inactivate digitoxin and digoxin. Compared with fullantibodies, fragments have superior tissue penetrability, more rapid renal elimination, and lower antigenicity.

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

 

 

 

 

 

 

Cardiac Glycosides

135

A. Cardiac glycosides

 

 

 

 

 

 

 

 

 

 

Enteral absorption

Elimination

 

 

 

 

O

 

 

 

 

 

 

Digoxin

 

HO

O

t 1 2 : 2–3 days

better control

 

 

 

 

 

CH3

 

 

 

 

 

 

CH3

H3C

 

~80%

prolonged with

 

 

O

 

OH

decreased renal

 

 

O

 

 

function

 

 

HO

 

 

 

 

 

 

 

 

 

 

 

 

 

OH

3

 

 

 

 

 

 

 

 

O

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Digitoxin

 

 

O

 

 

 

 

 

 

 

 

t 1

 

: 5–7 days

Slow waning

 

 

 

CH3

 

2

 

 

 

 

 

 

 

of intoxication

CH3

H3C

14

100%

independent

 

 

O

 

 

 

 

 

 

 

of renal

 

 

O

3

OH

 

 

 

HO

 

 

 

function

 

 

OH

3

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. Therapeutic and toxic effects of cardiac glycosides (CG)

 

Contraction

 

Arrhythmia

 

 

 

 

Time

“therapeutic”

“toxic”

 

Na+ Na/K-ATPase

 

CG

 

Na+

Na+

 

 

Coupling-

Ca2+

 

Ca2+

K+

K+

K+

 

 

Heart muscle cell

 

CG

Contracture

Dose of cardiac glycoside (CG)

CG

Na+

 

Ca2+

CG

K+

 

CG

 

C. Cardiac glycoside effects on the CNS

D. Cardiac glycoside effects in

 

atrial fibrillation

Disturbance

“Re-entrant”

of color vision

excitation in

 

atrial

 

fibrillation

 

Cardiac

Excitation of

glycoside

 

N. vagus:

Decrease in

Heart rate

 

ventricular

Area postrema:

rate

 

nausea, vomiting

 

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

Тут вы можете оставить комментарий к выбранному абзацу или сообщить об ошибке.

Оставленные комментарии видны всем.

Соседние файлы в предмете [НЕСОРТИРОВАННОЕ]