Cardio-tonic drugs, cardiac glycosides and Drugs used in heart Failure DR BUSARI. A.A (MB.BS, M.Sc., MMCP, FWACP) Consultant Nephrologist & Lecturer Dept. Of Pharmacology, Therapeutics and Toxicology

Cardio-tonic drugs Cardiostimulatory drugs (also called "cardiotonic drugs") Enhance cardiac function by increasing heart rate (chronotropy) myocardial contractility (inotropy), May increase electrical conduction (dromotropy) within the heart and augment relaxation (lusitropy).

Cardio-tonic drugs The cardiac effects of these drugs make them suitable for Heart failure Cardiogenic shock and hypotension.

Classes of Cardiostimulatory Drugs Beta-agonists Digitalis compounds Phosphodiesterase inhibitors PDEI Calcium sensitizers

Beta-agonists Beta-agonists are sympathomimetic drugs that bind to beta-adrenoceptors located in cardiac nodal tissue, the conducting system, and contracting myocytes. β1 receptors induces positive inotropic, chronotropic output of the cardiac muscle, leading to increased heart rate and blood pressure, secretion of ghrelin from the stomach, and renin release from the kidneys.

Beta-agonists β2 receptors β3 receptors induces smooth muscle relaxation in the lungs, gastrointestinal tract, uterus, and various blood vessels increases heart rate and heart muscle contraction. β3 receptors are mainly located in adipose tissue. It induces the metabolism of lipids.

Beta-1 adrenergic receptor agonists β1 agonists: stimulates adenylyl cyclase activity; opening of calcium channel. Causing cardiac stimulation; used to treat cardiogenic shock, acute heart failure, bradyarrhythmias. Selected examples are: Dobutamine, Dopamine Isoproterenol (β1 and β2) Xamoterol epinephrine (non-selective)

Beta-1 adrenergic receptor agonists

Phosphodiesterase inhibitors PDEI These drugs mimic sympathetic stimulation and increase cardiac output. are used clinically for short-term treatment of cardiac failure Examples Amrinone Milrinone Enoximone.

Cardiac glycosides Cardiac glycosides are organic compounds containing a glycoside (sugar) that act on the contractile force of the cardiac muscle. Important class of naturally occurring drugs whose actions include both beneficial and toxic effects on the heart.

Cardiac glycosides Found as secondary metabolites in several plants, but also in some insects, such as the milkweed butterflies. From ancient times, humans have used cardiac-glycoside-containing plants and their crude extracts as arrow coatings, homicidal or suicidal aids, rat poisons, heart tonics, diuretics and emetics.

Examples of plants producing cardiac glycosides Cardenolide type: Digitalis lanata and Digitalis purpurea – digoxin, digitoxin Strophanthus – ouabain g/k/e-strophanthin Nerium oleander - oleandrin Lily of the Valley (Convallaria majalis) Antiaris toxicaria Asclepias sp. Calotropis gigantea Bufadienolide type: Drimia maritima Kalanchoe daigremontiana and other Kalanchoe species – daigremontianin and others

Sources of plants

Chemistry of cardiac glycosides All of the glycosides - of which digoxin is the prototype – combine a steroid nucleus linked to an unsaturated 5 membered lactone ring at the 17 position and a series of sugars at carbon 3 of the nucleus.

Chemistry of cardiac glycosides Because they lack an easily ionisable group, their solubility is not pH dependent. Steroid nucleus with lactone ring is essential for myocardial action.

Chemistry of cardiac glycosides

Chemistry of cardiac glycosides Example of the chemical structure of oleandrin a potent toxic cardiac glycoside extracted from the Oleander bush.

CVS effect of Cardiac Glycosides in Heart Failure Mechanical and Electrical effect (+ve) inotropic. (-ve) chronotropic →Binding to Na pumps in the plasma membrane of central & peripheral nervous system → (-) of symp.

CVS effect of Cardiac Glycosides in Heart Failure Nervous outflow → Stimulate Baroreceptor → ↑ Vagal tone of heart ( by acting on central vagal nucleus) →↓ Firing of SA node → ↓ A-V Conduction → ↓ Heart rate.

CVS effect of Cardiac Glycosides in Heart Failure ↓Automaticity & Conduction Velocity at the AV nodal tissue → Use in Heart failure with arrhythmia. Chance of Heart block is side effect ↑ Automaticity- at high dose-causes arrhythmia.

Electrical activity of Cardiac Glycosides ↓ automaticity of SA node indirectly ↑ Refractory period of the AV node ↓Condution Velocity at the AV nodal Tissue Stimulate vagal Nerve

Indication/Clinical uses Heart failure Atrial arrythmia - Atrial flatter, Atrial fibrilation Paroxysmal supraventricular tachycardia

Contraindication Ventricular Tachycardia - because digitalis increase automaticity especially at high doses Heart block.

Adverse effect 1.Extracardiac On GIT→ Anorexia, nausea, vomiting Fatigue ,weakness, diarrhoea Neurological problems -Blurring of vision, confusion  Due to steroid nucleus - gynaecomastia in male

Adverse effect 2.Cardiac effect: i)All type of arrythmia (↑ Automaticity in high dose) ii) Slowing A-V nodal Conduction- Bradycardia Heart block

Toxicity Anorexia is earliest symptom Bradycardia is earliest sign ( if <60 b/min, digitalis not given) Low TI- 1-2.6nmol/L

Toxicity Treatment: Rx is different in 2 different condition (i) Stop the drug ii) Monitor K+ level( if hypokalemia administer K+, IV KCL

Toxicity (iii) If atrial arrhythmia - digoxin not given because it slows AV nodal conduction—use phenytoin which decrease arrythmia but not slow AV nodal contraction. (iv) If ventricular arrhythmia- lignocaine given, it does not slows AV nodal conduction

Toxicity If heart block – give atropine to increase HR. If patient still refractory to treatment monoclonal antibody (Fab fraction) or digoxin binding specific antibody (digibind) given to remove excess digoxin from the body.

Toxicity Effect of administration of electrolyte on effect of digoxin – K+, Ca++, Mg++ toxicity K+ and digitalis, interact in two ways- First –Hypokalemia increases the myocardial localization of digoxin. reduction in extracellular K+, cause phosphorylation cause increased phosphorylation of Na pump.

Hypokalemia And digoxin has higher affinity for the phosphorylated form. Increase K+, level can help to relieve symptoms of digoxin by dephosphorylation of Na pump. Second – abnormal cardiac automaticity is inhibited by hyperkalemia.

Hypercalcemia Ca++ facilitates the toxic actions of cardiac glycosides by accelerating the overloading of intracellular Ca++ stores that appears to be responsible for digitalis-induced abnormal automaticity. Hypercalcemia therefore increases the risk of digitalis induced arrhythmia.

Hypomagnesaemia Decreased Mg++ concentration enhances toxicities of cardiac glycosides.

Drug interaction Pharmacodynamic interaction B –blocker + digoxin= ↓ AV Conduction –so Heart Block Verapamil+ digoxin= ↓ AV Conduction –so Heart Block Digitalis+ Diuretics(Thiazide/Frusemide)= cause K+ loss

Drug interaction Pharmacokinetic interaction Verapamil+ digoxin→↑ plasma digitalis conc. by competing with digoxin for renal excretion →↑conc. of digoxin →toxicity Digitalis+Quinidine= displace digitalis from tissue binding site→↑conc. of digitalis →↑toxicity

Mechanisms of action Digitalis compounds are potent inhibitors of cellular Na+/K+-ATPase. This ion transport system moves sodium ions out of the cell and brings potassium ions into the cell. This transport function is necessary for cell survival because sodium diffusion into the cell and potassium diffusion out of the cell down their concentration gradients would reduce their concentration differences (gradients) across the cell membrane over time.

Mechanisms of action Loss of these ion gradients would lead to cellular depolarization and loss of the negative membrane potential that is required for normal cell function. The Na+/K+-ATPase also plays an active role in the membrane potential. this pump is electrogenic because it transports 3 sodium ions out of the cell for every 2 potassium ions that enter the cell. This can add several negative millivolts to the membrane potential depending on the activity of the pump.

Mechanisms of action

Mechanisms of action

Cardiac myocytes, as well as many other cells, have a Na+-Ca++ exchanger (not an active energy-requiring pump) that is essential for maintaining sodium and calcium homeostasis. By inhibiting the Na+/K+-ATPase, cardiac glycosides cause intracellular sodium concentration to increase. This then leads to an accumulation of intracellular calcium via the Na+-Ca++ exchange system.

In the heart, increased intracellular calcium causes more calcium to be released by the sarcoplasmic reticulum, thereby making more calcium available to bind to troponin-C, which increases contractility (inotropy). Inhibition of the Na+/K+-ATPase in vascular smooth muscle causes depolarization, which causes smooth muscle contraction and vasoconstriction.

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