Pharmacology of CHF drugs Flashcards
Two main factors influencing cardiac output
Stroke Volume and Heart Rate
Preload is..
Left ventricular end diastolic volume
Afterload is…
force that the ventricle has to push against to eject blood
Increasing contractility will increase….
SV for a given preload
How do optimized and failing hearts compare to normal hearts in Frank-Starling curves
Optimum hearts have a steeper curve where small changes in preload result in major SV changes. Failing hearts do not respond well to increased preload, as might be seen in a CHF patient.
Relationship btw SV and afterload?
Inverse
What might make a patient very sensitive to afterload changes?
Heart Failure
Effect of inotropy on SV at a given afterload
Increases it
What is compensation (CHF)?
When heart fxn is stable. There i still underlying disease, but patient can participate in most normal activities.
What is decompensation (CHF)?
When the heart/CV cannot compensate adequately for reduced effectiveness of the CHF heart. Patient is often hospitalized. Basically – Acutely worsening CHF.
In early heart failure, how does afterload, SV, preload
Afterload – Potentially high
SV – Reduced a bit
Preload – Starts to increase
How does the body maintain SV in early heart failure (3)
- Sympathetic Discharge
- RAAS Activity
- Cardiac remodeling
How does a CHF ventricular wall compare to a healthy one
Thicker walls and increased deposition of connective tissue
How is Calcium related to CHF hypertrophy response
When the heart has more rounds of calcium enry/exit, the expression of hypertrophic memodeling genes is upregulated.
What endocrine condition can exacerbate hypertrophic CHF?
Hyperthyroidism
How does late stage heart failure change the starling curve and force-tension curve?
Starling – Preload continues to rise,
FT – Afterload increases
SV goes down
What does it mean when I say that CHF patients are afterload sensitive?
Increases in afterload bring about sharp reductions in stroke volume
Two main categories of CHF treatment strategies? Do them improve mortality rates?
Manipulate Hemodynamics (No) Inhibit Compensation (Yes)
What does someone do for a CHF patient under the “Manipulating hemodynamics” strategy
Alleviate extreme pressure problems of CHF to improve overall heart fxn. Mainly only treats symptoms.
What does someone do for a CHF patient under the “Inhibit compensation” strategy
Use agents to reverse cardiac remodeling
ACE inhibitors and beta-blockers
Four drug classes used to manipulate hemodynamics of CHF patients
Vasodilators, Diuretics, Angiotensin inhibitors, inotropic agents
Why use a vasodilator? Examples?
Dilate veins, decrease preload
Organic nitrates, hydralazine
Why use a diuretic?
Examples of diuretics?
Decrease blood volume
Furosemide, Bumetanide, Torsemide
Why use an angiotensin inhibitor?
Examples of angiotensin inhibitors?
Decrease pressure and volume
ACE inhibitors, ATII rec antag., Renin inhibitors
Why use an inotropic agents?
Examples of inotropic agents?
Stimulates contractility
Digoxin, PDE3 inhibitors, beta-arrestin agonists
Examples of chronic inotropic therapy?
Glycosides (digoxin)
Examples of acute inotropic therapy?
PDE inhibitors and beta agonists
Typically only used in decompensated, hospital/ER patients
Risk associated with PDE inhibitors?
Inducing arrhythmias long term
Problem with long term beta agonists?
Desensitization
How does Calcium move in myocyte contraction
Ca enters through L TYPE channel, triggers internal release through RYANODINE receptors.
How does Calcium move in myocyte relaxation?
- Ca ATPase pumps it out of the cell.
- SERCA pumps Ca into the SR
- NCX (Na/Ca exchanger) trades Ca out of the cell
What is oubain?
A blocker of Na/K ATPase
Oubain has what effect on Ca? Contractility? (After 25 minutes)
Increased release of Ca during contraction, increase in contraction.
Why does blocking a sodium pump jack up the Calcium levels?
Decreased Ca extrusion by NCX. This leads to more being reloaded by SERCA for intracellular stores, and thus more release in response to stimulation.
Effect of Digoxin?
Increase in Contractility
Decreased HR and vascular sympathetic tone
How does Digoxin work?
Blocker of the Na/K ATPase
Important structural components of Glycosides?
Steroid Nucleus
Differences defined by sugar/lactone moieties
What type of glycoside is digoxin?
Cardenolides
Whats the problem with treating patients with digoxin?
There is a narrow therapeutic window before toxicity.
Because of this loading doses must be monitored closely.
Specific types of toxicity commonly associated with digoxin?
Psychiatric – Delirium, Fatigue, Malaise, Confusion
GI – Anorexia, Nausea and Vomiting, Ab Pain
Respiratory – Increased response to hypoxia
CV – Pro-arrythmic (atrial tachy, AV block)
Pharmacological interaction of digoxin and beta-blockers + Ca Channel Blockers
BB+CCB will depress the heart and oppose digoxin action
Pharmacological interaction of digoxin and Kaliuretic diuretics
Increased K elimination will lower overall K, promoting digoxin action. This will raise the risk for arrythmias.
Examples of beta-AR agonists used in CHF patients? Problems with using these drugs?
Dobutamine, Dopamine
Prone to desensitization, can cause HTN
Examples of Phosphodiesterase 3 inhibitors?
Problems with these drugs?
Milrinone, Amrinone
Pro-arrhythmic, decreased survival
Three classes of drugs used to inhibit compensation in CHF patients?
- RAA System Inhibition
- Aldosterone Antagonists
- beta-AR blockers
Pros of RAA drugs?
Pro – Alleviated pressure and volume problems (helping preload+afterload). Some stop/reverse remodeling
Types of RAA drugs?
ACE inhibitors, ATII rec. agonist, Aliskiren (a Renin inhibitor)
Pros of Aldosterone antagonists? Example?
Decrease blood volume + Reverse hypertrophy
Spironolactone (K sparing)
Perks of beta-AR blockers? Examples?
Inhibitorn of sympathetic overactivity in CHF. Can decrease remodeling+mortality in CHF.
Carvedilol, Metoprolol, Bisoprolol
What does Spironolactone actually do?
It blocks the Na+H2O reabsorption caused by aldosterone and inhibits angiotensin IIs ability to increase preload.
Six things that aldosterone does that we want to block in CHF
Na/H2O retention K and Mg Loss Reduced Myocardial NE uptake Reduced baroreceptor sensitivity Myocardial fibrosis, fibroblast proliferation Alterations in Na+ channel expression
Why use a beta-AR blocker in CHF?
Counter CHF compensation (increased adrenergic tone, heightened catecholamines, hypertrophic remodeling)
Four effects of vasopressin?
Water Retention
Vasoconstriction
Enhanced platelet aggregation
VSM and Myocyte Proliferation
Two main ADH receptor antagonists used in CHF
What receptors do they block?
Tolvaptan (V1A, V2)
Conivaptan (V2 selective)
Why would you choose to give a vasopressin receptor antagonist?
Hyponatremia in HF and SIADH
Used in Acute Care Settings
Adverse effects of Vasopressin Receptor Antagonists in CHF?
Hypotension, Osmotic demyelination, CYP3A substrate
What is Neprilysin?
A synthetic analog for Hyman type B Natriurietic Peptide
Human Type B Natriurietic Peptide release is associated with…
Increased blood volume and stretch
What does human type B Natriuretic Peptide do?
Activated membrane bound GC in VSMC+Endothelial cells. This will dephosphorylate MLC, leading the VSMC relaxation.
What does Neprilysin inhibition do?
- Increases levels of vasoactive peptides
- Counters neurohumoral vasoconstriction, Na retention, and remodeling.
- Investigational for CHF
Effect of inotropes on preload problems.
They don’t help. They only help with low output symptoms, not congestive symptoms.
Effect of ACE inhibitors on a starling curve?
Reduction of both preload and afterload (because blood volume and pressure are both reduced).
Effect of a diuretic on a starling curve?
Only help with congestive symptoms and not low output symptoms. Help pulmonary edema, but not stroke volume.
