CHF can involve either the L, R or both ventricles. Its
characterized by backward congestion and forward insufficiency → cardiac output is lower due to
ventricular dysfunction. The dysfunction can be systolic when theres not
enough force to eject the blood (e.g. MI), or it can be diastolic, when the
ventricle cant relax to allow normal filling (e.g. hypertrophy). Positive
inotropic drugs, such as digitalis have better results with systolic dysfunction
Rarely, high output failure occurs when the demands of the body are so high that even increased cardiac output is not enough (e.g. in hyperthyroidism or anemia). It also poorly responds to positive inotropics and treated by treating the underlying disease.
The main symptoms include tachycardia, ↓exercise tolerance, dyspnea, peripheral (R) & pulmonary (L) edema and cardiomegaly. In acute cases, the body tries to compensate by:
↓cardiac output → renal hypoperfusion → ↑RAA → ↑preload, afterload and remodeling.
↓cardiac output → ↓carotid sinus firing → less inhibition of the vasomotor area → ↑Sym discharge → tachycardia, ↑contractility & preload, which ↑CO, but it also causes vasoconstriction & ↑resistance → ↑afterload → ↓CO.
Myocardial hypertrophy is the most important chronic compensation. It allows maintaining performance despite pressure or volume overload, myocyte loss or decreased contractility. Later hypertrophy causes ischemia & ↓diastolic filling.
Clinically, CHF is divided to: (1) class-I: no limitations and with symptoms that occur only in much higher exercise; (2) class-II: silent limitation of normal activity causing fatigue; (3) class-III: no symptoms at rest but with fatigue at little exercise; (4) class-IV: symptoms even at rest.
Cardiac performance is determined by a 4 factor pyramid:
Preload according to Frank-Starling mechanism, the preload is increased due to ↑volume load or ↑venous tone.
Afterload the resistance facing the heart, which is elevated in CHF patients.
Contractility reduced contractility causes reduced intra-ventricular pressure → ↓pump performance. It can occur in MI and responds well to positive inotropics.
Heart rate in CHF the stroke volume diminishes but the Sym tone ↑ the ↑heart rate & CO.
and strength of the muscle. Most cause also a (+) chronotropic &
dromotropic effect, increasing the HR and the velocity of conduction. These
effects are a problem regarding the coronaries, which are less perfused. This
is the main problem of norepinephrine (NE). A better drug will be with a (+)
inotropic & (-) chronotropic effects → cardiac glycosides.
The glycosides have a steroid structure → on the D-ring theres an unsaturated lactone ring and on A-ring, at C3 theres a hydroxyl group with a sugar attached → mostly digitoxose.
The drugs are digoxin & digitoxin. Digitalis drugs block Na+/K+ ATPase. The resulted ↑Na+ concentration slows secondary exchangers such as Na+/Ca+2 antiports → Ca+2 stay in the cells and in the rER → mm. contraction. It acts both on atrial & ventricular myocytes but the direct effect is on the ventricular cells (positive inotropic). It also has an indirect effect on the CNS, where it increases Psy vagal tone, which affects the atrial myocytes & conduction (negative chronotropic).
The parasympathomimetic effect is due to increase M2-receptor sensitivity to ACh in the myocytes.
Any drug that acts on ion concentration can change rhythm so any antiarrhythmia drug can cause arrhythmia. Higher Na+ concentration → depolarization and the resting potential will be closer to the excitation point. If the cells are overloaded with Ca+2, Ca+2 outflow can occur spontaneously causing depolarization → late after depolarization. So when a sick myocyte is treated with digitalis the result can be ventricular premature beat.
Other drugs, such as nitroprusside, hydralazine, nitroglycerine & ACE inhibitors are helpful in ↓vascular tone → ↓the afterload facing the failing heart.
Pharmacodynamics these drugs are very toxic and the therapeutic index is very low.
Minor liver metabolism
By the kidney
Enter the bile and reabsorbed
Systolic CHF cardiac glycosides will contraction & ↓conduction.
Atrial fibrillation (AF) this absolute arrhythmia has an increased ventricular rate of 300-400/min → the heart contracts without blood and the pulse rate is higher than the heart rate. In pulse deficit patients give cardiac glycosides, due to its Psy effect → ↑conduction time.
Atrial flutter when the atrial rate is
200-300/min and the ratio is fixed (1:2, 1:3, etc.).
E.g.: in case of 240/min rate and ratio of 1:2 → ventricular rate of 240/min. Cardiac glycosides will reduce the rate to 80/min (Psy effect). Too much will cause bradycardia.
Cardiac glycosides disrupt the reentry mechanism in flutter & AF, allowing normal beats to take over.
In AF → use quinidine cardioversion, an anti-arrhythmic agent that blocks Na+ channels & M-receptors → sinus rhythm but with tachycardia. Adding digoxin will block the tachycardia → not used today.
MI since many patients have conduction blocks after MI that can lead to death. Digitalis will promote this effect due to its parasympathomimetic action.
Contractility problems since these drugs have slow onset of action (3-4hrs), and in such cases we need more rapid drugs.
Pulmonary diseases causing hypoxia since the patients are easily intoxicated.
Liver problems dont use digitoxin.
Kidney problems dont use digoxin due to ↓ elimination → ↑ activity time.
Sick sinus syndrome dont use since it reduces heart rate.
Interaction with drugs causing AV blocks such as β-blockers & Ca2+ antagonists, since digitalis may also result in AV blocks.
Digitalis intoxication dont add more digitalis since itll appear as CHF.
AV block of any type due to Psy action.
HOCM since the obstruction increases due to the ↑contractility.
K+ the most important. It behaves
like glycoside antagonist. In hyperkalemia cardiac glycosides are inhibited
while hypokalemia potentiate them.
In CHF, most patients receive diuretics, which are mostly K+ wasting, so beware using glycosides (usually extra K+ is added).
The K+ sparing drugs (as spironolactone) & ACE inhibitors will cause hyperkalemia → act against digitalis.
Ca2+ synergistic with digitalis, as opposed to K+. Hypercalcemia → ↑effect.
Mg2+ behaves like K+ and opposite to Ca2+.
Side effects depend on the level of intoxication:
Heart has an arrhythmogenic effect and can cause any ventricular arrhythmia. It starts with bigeminy, couplets, group binding, VT and eventually VF → death.
CNS causes weakness, headache, anxiety, nightmares, hallucinations and if the patient survives → delirium.
Eyes blurred vision, photophobia & color vision problems (see everything in yellow or green).
GI may cause anorexia, nausea, vomiting & abdominal pain.
Hormonal problems in men may result in gynecomastia.
3 drugs similar to digitalis:
Deslanoside given parenterally. It has an additional glucose group in the sugar chain.
Acetyldigitoxin acetylated digitoxin with same function.
Ouabain a parenteral drug with a faster onset (rapid digitalization).
Monitor K+ level hypokalemia will potentiate digitalis → ↑intoxication, so we must supply K+, but in low concentration, otherwise it can cause death → use slow infusion with normal plasma K+ concentration (K+ is a hard to detect K+illing tool, e.g. KCl).
Group I/B anti-arrhythmic drugs either lidocaine or IV phenytoin, which act on the ventricles only (used in poor hospitals).
Digitalis Ab very expensive, but can bind circulating digitalis, reducing their level (digibind).
generally will cause severe tachycardia. Must be used in cases of cardiogenic
shock or terminal CHF → act
Some special Sym agents act only on the heart with no vasoactivity → selective β1 agonists:
a. Dopamine (DA) cAMP, given IV and depending on the dose there are 3 ranges:
<2.5μg/kg/min (kidney dose) → causes vasodilation of the kidney arterioles, acting directly on D1 receptors, not on β1-receptors.
2.5-7.5μg/kg/min → the DA effect on the kidney remains but it also acts on β1-recptors → (+) inotropic effect. It also has (+) chronotropic effect → tachycardia.
>7.5μg/kg/min → this dose loses the β1 selectivity and also acts on α1-recepors → vasoconstriction.
Dobutamine does not cause
vasoconstriction, only acts as a selective β1 agonist. Theres
also less (+) chronotropic activity →
Dobutamine is frequently combined with the kidney dose of DA and in cases of very low diastolic pressure its given in combination with NE (NE acts only on β1, while E acts both on β1 & β2).
c. Prenalterol & enoximon selective β1 agonists that are not used anymore due to ↑mortality.
CPD (cyclic phospohodiesterase)
inhibitors CPD is responsible for cAMP metabolism.
If its blocked → ↑cAMP level → β-mimetic action → (+) inotropic & chronotropic effect on the heart:
Theophylline a smooth mm.
relaxant and a very weak heart stimulator (hardly used).
High dose can intoxicate the patient since it has effect on the CNS.
b. Selective CPD3 inhibitors which are found in the heart:
Amrinone → can cause thrombocytopenia & liver damage.
Milrinone → causes liver damage. Its used in case of dobutamine resistance, related to its toxicity.
Ca+2 sensitizers the newest drugs. They act inside the ventricular myocytes.
a. Pimobendan has a dual action: it increases the affinity of troponin-C to Ca2+ → easier binding and it also acts as CPD inhibitor, ↑cAMP level. Not a good drug.
b. Levosimendan reduces CPD action and have less activity on troponin-C.
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