TREATMENT GOALS AND TOXICITY

To remove or mitigate the underlying causes or risk factors

• by eliminating ingestion of certain drugs or other substances that can cause BRADYCARDIA (beta and calcium channel blockers or bradycardic drugs)

Treatment goals of HF

1. Weak Contractions (use INOTROPIC: force the heart to contract, kung ayaw edi huwag na)

2. Increased Workload= Increase in Volume of Fluids (use LOAD UNLEASHERS: Diuretics)

Target problem for pharmacologic treament

Digoxin

Istaroxime

Inotropic agent

Na⁺ / K⁺ ATPase Inhibitors

Mechanism of Action of Inotropic agents

Digoxin

Used in conjunction with diuretics, ACE inhibitors, β-adrenergic blockers to improve the symptoms and clinical status of patients with HF

Digitalis Glycoside

Digoxin is from?

Steroid

Lactone

2-deoxysugar

Digoxin has what type of structure included?

Ouabain: Low

Digoxin: Medium

Digitoxin (most are high): High

Lipid of solubility (oil/water coefficient) of Ouabain, Digoxin, Digitoxin (most are high)

Ouabain: 0

Digoxin: 75

Digitoxin (most are high): >90

Oral availability (percentage absorbed) of Ouabain, Digoxin, Digitoxin (most are high)

Ouabain: 21

Digoxin: 40

Digitoxin (most are high): 168

Half-life in body (hours) of Ouabain, Digoxin, Digitoxin (most are high)

Ouabain: 0

Digoxin: 20-40

Digitoxin (most are high): >90

Plasma protein binding (percentage bound) of Ouabain, Digoxin, Digitoxin (most are high)

Ouabain: 0

Digoxin: <40

Digitoxin (most are high): >80

Percentage metabolized of Ouabain, Digoxin, Digitoxin (most are high)

Ouabain: 18

Digoxin: 6.3

Digitoxin (most are high): 0.6

Volume of distribution (L/kg) of Ouabain, Digoxin, Digitoxin (most are high)

Digoxin

Drug interaction of Antibiotic causing the bacteria in the GIT contributes to the metabolism when administered orally and administration of antibiotic will kill the bacteria thus inhibiting the metabolism of the drug increasing the toxicity

POLAR: Kidneys Its renal clearance is proportional to creatinine clearance

Excretion of Digoxin

renal impairment

Adjust digoxin dosage in patients with ____

Liver

Metabolized place of digitoxin

into the gut via the bile. LIPID SOLUBLE

Excretion of digitoxin

digitoxin

Renal impairment does not significantly prolong the half-life of ___

Inhibit Na⁺/K⁺ ATPase, the membrane bound transporter often called the sodium pump; Pump responsible for the exchange of sodium and potassium.

Blocking the pump will block the entry of SODIUM into the heart muscles resulting in no positive charge ion. This could indirectly affect the calcium and sodium transporter. Since there is no entry of sodium, the calcium will stay in the heart resulting in MUSCLE CONTRACTION. Gets? Okay gets.

Cardiac glycoside MOA pharmacodynamics

Increase contractility of the heart muscle → By increasing the free calcium concentration

• (+) inotropic effect

Cardiac effect of cardiac glycosides in mechanical effects

1. Na⁺/K ⁺ ATPase inhibition

2. Reduction of calcium expulsion (calcium will stay in the heart= contraction)

Cardiac glycoside causes cardiac effect that can cause an increase in calcium concentration ithat s the result of a two-step process:

Mixture of direct and autonomic actions

Decrease in action potential

• As a result of increased potassium conductance that is caused by increased intracellular calcium

• Shortening of the action potential contributes to the shortening of atrial and ventricular refractoriness

Electrical effect of Cardiac glycoside

Digoxin: arrhythmogenic

____is an ____ drug capable of causing arrhythmia

Atrial Muscle: ↓ (PANS)

AV Node:↑ (PANS)

Purkinje System, Ventricles: ↓ (DIRECT)

Effective refractory period effect on tissues Atrial Muscle, AV Node, Purkinje System and Ventricles

Atrial Muscle:↑ (PANS)

AV Node: ↓ (PANS)

Purkinje System, Ventricles: ↓ (PANS)

Conduction velocity on tissues Atrial Muscle, AV Node, Purkinje System and Ventricles

Atrial Muscle: ↑ (DIRECT)

AV Node: ↑ (DIRECT)

Purkinje System, Ventricles: ↑ (DIRECT)

Automaticity on tissues Atrial Muscle, AV Node, Purkinje System and Ventricles

Atrial Muscle: Negligible

AV Node: ↑ PR interva

Purkinje System, Ventricles: ↓ QT interval; T wave inversion; ST segment

Before arrhythmias on Electrocardiogram Atrial Muscle, AV Node, Purkinje System and Ventricles

Anorexia

Vomiting

Nausea

Diarrhea

Effect of cardiac glycoside in the gastrointestinal tract effect

Vagal and chemoreceptor zone stimulation

Disorientation and hallucinations

• Especially in the elderly

Visual disturbances

Agitation and convulsions

Effect of cardiac glycoside in the Central Nervous System Effects

Gynecomastia

Is a rare effect of cardiac glycoside

peripheral estrogenic action

hypothalamic stimulation

Gynecomastia effect of cardiac glycoside is not certain whether this effect represents a ______ of these steroid drugs or a manifestation of _________

Positive inotropic effects - increase force contraction of heart

Deactivation of renin angiotensin-aldosterone compensation - decrease output decrease blood supply

Therapeutic effect of digoxin

tablet, injection, elixir and capsule forms

Digoxin available in what administration forms?

Narrow therapeutic index

Digoxin therapeutic index?

0.5-1.5 ng/mL

Dosage and administration of digoxin

Therapeutic plasma concentration

>2 ng/mL

Dosage and administration of digoxin

Toxic plasma concentration

0.25 (1.125-0.5) mg

Dosage and administration of digoxin

Daily dose (slow loading or maintenance)

0.5-0.75 mg every 8 hours for three doses Deslanoside

Dosage and administration of digoxin

Rapid digitalizing dose (rarely used) to achieve equilibrium within 24 hours

7 days or 1 week

Oral digoxin will take ____ before the equilibrium is achieved

Decrease potassium levels (< 3)= Increase digitalis Toxicity

• Favor digoxin binding to cardiac cells and increase its effect

• Drugs causing Hypokalemia: Thiazide and loop diuretics

Increase potassium levels = Decrease digoxin binding and decrease effect

• This is likely in patients taking potassium, or a captopril-like agent

• Drugs causing Hyperkalemia: Potassium sparing diuretics, ACE inhibitor, ARBs.

Precaution and monitoring effects of Digoxin in Potassium

Increase Calcium = Increase force of myocardial contraction

• Act synergistically with digoxin

Precaution and monitoring effects of Digoxin in Calcium ions

Decrease magnesium (hypomagnesemia) = Increase digoxin toxicity

• Inversely related to digoxin activity

Precaution and monitoring effects of Digoxin in Magnesium levels

increases with coadministration of: (anti arrhythmic drugs)

• Quinidine,

• Verapamil,

• Flecainide,

• Propafenone,

• Spironolactone

• Amiodarone

Risk of toxicity of digoxin

Quinidine

___ decreases the renal clearance of Digoxin

1. Anorexia, a common and early sign (GIT)

2. Fatigue, headache and malaise

3. Nausea and vomiting

4. Mental confusion and disorientation

5. Alteration in visual perceptions (blurring, yellowing, a halo effect)

6. Cardiac effects

Signs of toxicity of Digoxin

1. Premature ventricular contractions and ventricular tachycardia and fibrillation (arrhythmia)

2. Sinoatrial (SA) and atrioventricular (AV) block- premature ventricular depression

3. Atrial tachycardia and AV block

Cardiac effect signs of toxicity of digoxin

Administer potassium supplements

TREATMENT OF TOXICITY:

Management/Antidote If the patient is hypokalemic

lidocaine or phenytoin

TREATMENT OF TOXICITY:

Management/Antidote in Arrhythmias

Bind to digitalis glycosides to prevent absorption of digitalis in the bile

TREATMENT OF TOXICITY:

Management/Antidote if Cholestyramine used in case of toxicity

Purified digoxin fab fragment antibodies Brand name: Digibind

TREATMENT OF TOXICITY:

Management/Antidote if the Patients with very high serum digoxin levels