Cvs Inotropics

Endogenous opiates include morphine  Neri et al (2008) J Neurochemistry

DOPAMINE IS NECESSARY TO ENDOGENOUS MORPHINE FORMATION IN MAMMALIAN BRAIN IN VIVO

Gintzler et al 1978 PNAS

Drug effects on the heart: Inotropic drugs Prof John Finberg Pharmacology Dept

(Congestive heart failure (CHF  Chronic condition, various pathologies  Despite increased LVEDP heart cannot

sustain output sufficient for normal functioning  Increased CVP, edema, cardiac remodelling, high sympathetic tone, increased fluid volumes

CHF Increased CVP → increased preload Venodilator → increased venous capacitance → reduced preload Arteriolar vasodilator → reduced afterload and reduced cardiac work

CHF treatments  Volume

reduction, diuretics  ACE inhibitors  Venodilators  β-blockers  Arterial vasodilators  Inotropics

Drugs with inotropic effects  Adrenoceptor agonists  Digoxin  Phosphodiesterase inhibitors

CARDIAC ACTION POTENTIALS

Golan et al 2005

Stimulation of cardiac contractility by betaadrenoceptor agonists

Beta-adrenoceptor agonists Activation of cardiac beta1-adrenoceptor Activation of adenylate cyclase Increased level of cAMP Activation of pKA

Phosphorylation of L-type calcium channels and increased Ca++ entry

Increased SR Ca++ pumping

CHF; Beta receptor down-regulation

William Withering 1741-1799

Cardiac glycosides    

Digoxin, digitoxin, from Digitalis Other plants, eg Ouabain, Strophanthidin Animal tissues, eg toad skin, mammalian tissues Endogenous ouabain-like activity increases in CHF

Molecule composed of: steroid-lactone (aglycone) + sugar; pharmacological activity in aglycone sugar part gives pharmacokinetic properties

Endogenous ouabain-like activity  Mammalian tissues can synthesise

ouabain  See Murrell JR et al (2005) Circulation, 112: 1301-8 Endogenous Ouabain: Upregulation of Steroidogenic Genes in Hypertensive Hypothalamus but Not Adrenal

Effects of digoxin in CHF  Positive inotropic effect → increased CO  Reduction in CVP  Reduction in peripheral edema (improved

Starling forces in capillaries)  Reduction in sympathetic tone  Increased vagal tone → reduced SA rate + reduced AV conduction rate  Bradycardia + increased CO, improved cardiac efficiency

Digoxin pharmacological effects cardiac effects are direct + indirect  

 

Positive inotropic effect (inhibition of cardiac Na/K-ATPase) is a DIRECT cardiac effect Binds to Na/K ATPase in some CNS neurons → reduced sympathetic activity, increased baroreceptor sensitivity, increased vagal function → INDIRECT CARDIAC EFFECT Reduces automaticity in AV and SA tissue by INDIRECT effect (increased vagal activity) Increases automaticity by DIRECT effect

Mechanism of digoxin positive inotropic effect

Digoxin pharmacological effects  Extra-cardiac effects: 

  

In CHF, get vasodilation (reduced sympathetic tone) Normal subjects may show vasoconstriction Nausea, vomiting and diarrhea Altered color perception

High dose digoxin effects  Increased sympathetic activity  Increased automaticity  Reduced APD with partial depolarisation  Appearance of EAD and/or DAD  Arrythmias

Digoxin and atrial flutter/fibrillation  Flutter is made worse (reduced atrial

refractory period)  Cardiac function is improved by:  

A) reduced AV conduction B) positive inotropic effect

Digoxin toxicity  Toxicity: neurologic effects, arrythmia,

bradycardia, vomiting; effects can be treated with antibodies, Fab fraction  Low plasma

K+ increases digoxin effects by increasing binding to α sub-unit of Na/K-ATPase

Digoxin pharmacokinetics  t/2 = 36 hours  Potent drug, dose about 0.15 mg  Absorption about 75%, variable  Renal excretion, correlates with GFR  t/2 affected by other drugs, eg quinidine

Digoxin drug interactions  Care in combining with other drugs that

decrease AV conduction, eg beta-blockers and Ca++ antagonists; can → complete AV block  Pharmacokinetic interactions, eg quinidine, antibiotics (can reduce GI bacterial hydrolysis)

Digoxin: therapeutic use  Used in chronic heart failure (CHF), in

treatment resistant cases  Does not increase longevity, but improves

symptoms of CHF  Need to monitor plasma levels of digoxin,

also electrolytes

Other inotropics  Dobutamine; for short-term cardiac

support  Major effect on β1, lesser effect on β2, α1  Therapeutic doses increase contractility by β1-mediated effect, cause vasodilation by β2 effect

Phosphodiesterase inhibitors  Amrinone and milrinone  Block PDE3 (cardiac PDE)  Positive inotropic effect  Venous and arterial vasodilation  Do not improve longevity, and may even

decrease it  Limited therapeutic use