Pharmacology I
Congestive Heart Failure Drugs Objectives

Learning Objectives:

1. Blood volume: Abnormal ’es in blood volume/interstitial fluid. The heart, veins, and capillaries are dilated with blood: CHF symptoms of fluid volume overload

• Pulmonary congestion with left heart failure
• Peripheral edema with right heart failure

2. Blood pressure: the failing heart evokes 3 major compensatory mechanisms to enhance CO due to low BP. Baroreceptors trigger activation of b AR receptors in the heart, which ’s HR and force of contraction. Also a ₁ mediated vasoconstriction enhances venous return and ’s preload. (These compensatory responses the work of the heart and can contribute to further decline in cardiac function.) The subsequent ¯ in renal blood flow resulting from the ¯ BP will cause the RAA system activity to which will aldosterone which will Na⁺ and H₂O retention which leads to edema as well as ed BP. The compensatory mechanisms of ing BP will cause there to be an workload on the heart leading to a vicious cycle.
3. Hypertrophy: The heart ’s in size and the chambers dilate (Remember this info from the last test in physio) Eccentric is a result of afterload and concentric is a result of preload.

1. Reduce physical activity to ¯ myocardial work
2. Reduce dietary intake of Na⁺
3. Treatment with
   1. Vasodilators
   2. Diuretics
   3. Inotropes
4. Avoid
   1. b -blockers
   2. Ca⁺² channel blockers
   3. Certain antiarrhythmics

1. Vasodilators – used to both ¯ preload and afterload

• ACE inhibitors (captopril, enalapril): The agents of choice in CHF® superior to other vasodilators. They block the enzyme that cleaves angio I to angio II. They also ¯ the rate of bradykinin inactivation (bradykinin is a perfect vasodilator). By ¯ ing the circulating angio II levels, ACE inhibitors also ¯ aldosterone secretion which ¯ Na⁺ and water retention.
  Þ ACE inhibitors affect on the heart - ¯ vasc resistance, ¯ venous tone, ¯ BP to CO. They also blunt the usual angio II mediated increase in Epi and Aldosterone and they block the remodeling associated with hypertrophy post damage.
• Direct smooth muscle relaxants – hydralazine, isosorbide, NTG, SNP, minoxidil
  • dilation of venous blood vessels leads to a ¯ in cardiac preload by ing venous capacitance
  • arterial dilators reduce systemic arteriolar resistance and ¯ afterload.
  • Nitrates (NTG and SNP) reduce afterload. NTG can also increase coronary perfusion.

2. Diuretics- work to relieve pulmonary congestion and peripheral edema, which is useful in relieving symptoms of volume overload. They ¯ plasma volume, thus ¯ ing venous return (preload) and ¯ cardiac workload and O₂ Demand. They also ¯ afterload by reducing plasma volume, thus ¯ ing BP.

• Loop – furosemide – inhibits reabsorption of Na⁺ and Cl- from the loop of Henle and distal tubules thus ing excretion of water and Na⁺.
• Thiazides- HCTZ- ’s excretion of Na⁺ and water.

3. Positive Inotropes enhance cardiac muscle contractility, thus ing CO. Although these drugs act by different mechanisms, in each case the inotropic action is the result of an increase in cytoplasmic calcium concentration that enhances the contractility of the heart.

• Cardiac glycosides – digoxin, digitoxin
• b - agonists – dobutamine
• phosphodiesterase inhibitors – amrinone, milrinone

• Cause Na⁺ and water retention if not given with a diuretic
• Excessive vasodilation may HR
• Orthostatic hypotension
• Edema

• Hypovolemia
• Tachycardia
• Electrolyte imbalances (Hypokalemia which can increase the likelihood of dig toxicity)
• Hypotension

• Tachycardia
• BP
• PVC’s and other dysrhythmias
• MVO₂

• Relatively short ½ life (better tx of toxic reactions)
• More rapid onset of action than digitoxin – makes it useful for cardiac emergencies
• Eliminated largely unchanged in the urine
• Low volume of distribution which makes it more accessible

• Binds strongly to plasma proteins in extravascular space resulting in a large volume of distribution
• Extensive hepatic metabolism, hepatic disease may require a ¯ dose.
• Long ½ life due to protein binding.
• Long onset of action

There is a very narrow therapeutic range.
Electrolyte disturbances can occur especially hypokalemia, which can precipitate serious arrhythmias. The hypokalemia probably increases myocardial binding of cardiac glycosides, resulting in excess drug effect. Hypercalcemia and hypomagnesiumia can also occur.
Digoxin by inhibiting the Na/K/ATPase pump, affects the membrane potential and keeps the cell depolarized longer and brings the resting membrane potential closer to +. The Na⁺/Ca⁺² exchanger will then try to take more sodium out but in the process brings in too much calcium, which can cause contraction. Digoxin also alters AV nodal conduction, which is very sensitive to membrane potentials. Dig has a high affinity for the AV nodal cells and can make the membrane so less – that it can depol to the point where it can’t fire anymore and you get AV nodal block.

Know what factors can affect digitalis sensitivity of the heart and the consequences of interaction with the following drugs:
Loop and thiazide diuretics: Causes loss of K⁺ and possible dig toxicity
Verapamil, Amiodarone, Quinidine (anti-arrhythmic drugs): can all cause dig toxicity by:

1. displacing digitalis from plasma protein binding sites
2. compete with dig for renal excretion
3. Verapamil may increase dig levels by 50-75%.

Last updated 09/06/01 08:53 PM
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