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Cardiac Pharmacology: CHF & (+) Inotropic Drugs

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Cardiac Pharmacology: CHF & (+) Inotropic Drugs

Pathophysiology

CHF can involve either the L, R or both ventricles. It’s characterized by backward congestion and forward insufficiency → cardiac output is lower due to ventricular dysfunction. The dysfunction can be systolic when there’s not enough force to eject the blood (e.g. MI), or it can be diastolic, when the ventricle can’t relax to allow normal filling (e.g. hypertrophy). Positive inotropic drugs, such as digitalis have better results with systolic dysfunction than diastolic.
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.

(+) inotropic drugs

They ↑contractility 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 there’s an unsaturated lactone ring and on A-ring, at C3 there’s 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.

Digoxin

Digitoxin

Absorption

40-75%

>90%

Metabolism

No

Minor liver metabolism

Excretion

By the kidney

Enter the bile and reabsorbed

40 hours

7 days

Loading dose

0.5-1mg IV

0.8-1.2mg PO



Maintenance dose

0.125-0.5mg PO

0.07-0.1mg PO

Indications:

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.

Relative contraindications:

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 – don’t use digitoxin.

Kidney problems – don’t use digoxin due to ↓ elimination → ↑ activity time.

Sick sinus syndrome – don’t 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.

Absolute contraindications:

Digitalis intoxication – don’t add more digitalis since it’ll appear as CHF.

AV block of any type – due to Psy action.

HOCM – since the obstruction increases due to the ↑contractility.

Ion interactions:

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).

Treatment for digitalis intoxication

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).

Other (+) inotropic drugs

Sympathomimetics – generally will cause severe tachycardia. Must be used in cases of cardiogenic shock or terminal CHF → act rapidly.
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.

b.      Dobutamine – does not cause vasoconstriction, only acts as a selective β1 agonist. There’s also less (+) chronotropic activity → less tachycardia.
Dobutamine is frequently combined with the kidney dose of DA and in cases of very low diastolic pressure it’s 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 it’s blocked → ↑cAMP level → β-mimetic action → (+) inotropic & chronotropic effect on the heart:

a.       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. It’s 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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