Pharma - Cardiac

Question 1

Adenosine?

Answer 1

Adenosine
Description

MOA (Mechanism of Action)

▪Adenosine stimulates adenosine A1 receptors in the AV node, which results in:
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Increased outward K+ currents
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Decreased inward Ca+2 currents
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Decreased inward Na+ currents (If)
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These ionic actions hyperpolarize the cell (i.e., make the inside of the cell more negative because there are fewer positive ions inside the cell) and render it refractory for a prolonged period (a few seconds or more).
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Essentially, the AV node is completely turned off for a brief period of time, creating a third-degree heart block for a few seconds. Through this action, tachycardias that originate in the atria can be diagnosed more easily because all the QRSs are absent from the ECG for a few seconds.
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Because the AV node is turned off, any reentry circuit that was originating inside or travelling through the AV node will be terminated. Through this action, reentry circuits can be treated and normal sinus rhythm resumes (Figure 11-8).

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Adenosine has a half-life of about 10 seconds. It must be given as an intravenous push (quickly) with a saline flush (otherwise it will be metabolized in the arm veins before it gets to the heart, where it exerts its effects).
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Caffeine acts on the same adenosine A1 receptor and can block the action of adenosine.

Indications

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Adenosine is used for the diagnosis and treatment of supraventricular tachycardias (SVTs).

Contraindication

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None of major significance.

Side Effects

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Because the half-life of adenosine is very short, side effects usually last for only a few minutes.
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Dyspnea (shortness of breath) is caused by adenosine agonism in the bronchioles.
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Angina and feelings of extreme discomfort and unpleasantness may occur. Adenosine is liberated when there is a deficiency of ATP, which occurs when there is a deficiency of oxygen; adenosine is one of the mediators of symptoms when myocardial ischemia occurs.
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Nausea may occur.
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Transient complete heart block is common (and in fact is the method by which adenosine is diagnostic for SVTs). Therefore ECG monitoring is required during adenosine administration.

Important Notes

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Diagnostic for SVT: If the HR is so fast that you cannot determine what the underlying rhythm is, then adenosine will temporarily shut down the AV node, which will block conduction that leads to ventricular activity. This gives the observer an opportunity to assess the underlying atrial activity.
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Treatment for reentry tachycardias: When adenosine is given, the AV node is turned off for a few seconds. This is usually sufficient to completely abolish a reentry tachycardia (which almost always uses the AV node as part of its pathway).
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If a patient’s heart converts to sinus rhythm after the administration of adenosine, then a diagnosis of reentry tachycardia is confirmed.
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If a patient’s heart resumes the SVT after an ECG pause, then the rhythm is probably atrial fibrillation, flutter, or tachycardia or sinus tachycardia and should be diagnosable while the ventricles are temporarily stopped.
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Patients sometimes refuse the drug if they have had it before because of the severity of the unpleasant sensation.
Evidence

Adenosine versus Verapamil for Supraventricular Tachycardia
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A Cochrane review in 2006 (eight trials, N = 577 patients) found that both drugs were 90% effective in treating SVTs and that there were no differences in efficacy; however, adenosine converted heart rhythm to sinus rhythm a little bit faster than verapamil did. Adenosine caused unpleasant side effects in about 10% of patients, and verapamil caused hypotension in 2% of patients.
FYI Notes

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Adenosine is an endogenous nucleotide (i.e., occurs naturally) that is part of the well known ATP molecule. In the body, adenosine is liberated during ischemia and in fact is a mediator of the symptoms of cardiac ischemia.
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Warn the patient how terrible he or she will feel for about 3 minutes.
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Sometimes adenosine has absolutely no effect (caffeine blocks its effect).

Question 2

Doxorubucin?

Answer 2

TOXIC FOR HEART

Anthracyclines
Description

Anthracyclines are cytotoxic anticancer agents that work by damaging DNA and by generation of free radicals. This class is also grouped under a larger class of antitumor antibiotics (but are never used as antibiotics).
 Prototype and Common Drugs

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Prototype: doxorubicin
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Others: daunorubicin, idarubicin, epirubicin, aclarubicin, mitoxantrone
MOA (Mechanism of Action)

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The anthracyclines are believed to exert their cytotoxic effects through a variety of mechanisms.
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Topoisomerase II (Top II) plays a key role during DNA synthesis, nicking and resealing the DNA helix so that it does not become tangled during replication.
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The anthracyclines prevent the resealing step from occurring by intercalating into and inhibiting the DNA–topoisomerase II complex after the nicking phase. This results in a large number of DNA fragments, eventually prompting the cancer cell to undergo apoptosis (Figure 20-2).

FIGURE 20-2
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As a secondary mechanism, anthracyclines produce free radicals, and these free radicals in turn damage cell membranes, proteins, and lipids. The generation of free radicals is also believed to mediate an important toxicity associated with this class (see Side Effects).
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In addition anthracyclines are DNA intercalators, meaning that they insert themselves into DNA structure, inhibiting transcription and replication.
Mechanisms of Resistance
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Drug efflux through P-glycoprotein (Pgp-170) or multidrug-resistant (MDR) gene
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Altered topoisomerase II levels
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Mutations in topoisomerase II
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Increased glutathione (a free radical scavenger)
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Increased glutathione peroxidase activity
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Decreased concentration of glucose-6-phosphate (G6P) dehydrogenase
Pharmacokinetics

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Doxorubicin is a prodrug, and idarubicin is the active metabolite.
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Doxorubicin was the first anthracycline to be encapsulated in liposomes to facilitate targeted delivery of the drug and therefore avoid cardiotoxicity (see Side Effects). One of the key mechanisms for this targeted delivery relies on the fact that the liposomes readily extravasate in tissues that have a disrupted vasculature, such as that found in tumors. Blood vessels in tumors tend to be “leaky” owing to the constant angiogenesis that is taking place. Conversely, the liposomes have difficulty exiting vessels in tissues such as the myocardium.
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The anthracyclines are eliminated through hepatic metabolism, through a variety of routes. Because of the toxicities associated with these agents, dose adjustments should be considered in patients with significant hepatic impairment.
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Idarubicin is the only anthracycline that can be given orally; the rest are available only in intravenous formulations.
Indications

Doxorubicin
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Acute leukemias
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Hodgkin’s disease
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Non-Hodgkin’s lymphoma
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Sarcomas
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Cancers of the breast, lung, stomach, thyroid
Daunorubicin
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Acute leukemia
Idarubicin
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Acute leukemia
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Breast cancer
Epirubicin
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Lymphoma
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Cancers of the lung, breast, ovary, stomach
Mitoxantrone
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Prostate cancer
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Non-Hodgkin’s lymphoma
Contraindications

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Severe cardiac disease: Anthracyclines should be used only with extreme caution and after a careful risk-benefit assessment in these patients. See Side Effects.
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Lactation: Patients should not breastfeed while using these agents.
Side Effects

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Nausea and vomiting are common side effect with cytotoxic agents, which tend to target rapidly dividing cells, including those of the GI tract.
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Alopecia: Cytotoxic chemotherapy agents tend to target tissues with rapidly dividing cells, such as those in hair follicles. The hair loss is reversible.
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Mucositis or stomatitis is an inflammatory condition of the mouth. Cytotoxic chemotherapy agents tend to target tissues with rapidly dividing cells, such as those in the oral mucosa.
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Soft tissue necrosis: If the anthracyclines become extravascular, they can damage surrounding tissue. Infusions should be carried out slowly to reduce the risk of extravasation.
Serious
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Cardiotoxicity: The free radicals generated by the anthracyclines cause peroxidation of the cardiac sarcoplasmic reticulum, leading to a Ca2+-dependent cardiac necrosis. The reason this toxicity is selective for cardiac tissue is that catalase, able to neutralize these free radicals, is not found in cardiac tissue.
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Myelosuppression: Cytotoxic chemotherapy agents tend to target tissues with rapidly dividing cells, such as those of the bone marrow. The bone marrow suppression is reversible but does predispose the patient to major complications such as infection while receiving treatment.
Important Notes

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Cardiotoxicity associated with anthracyclines can occur both acutely and chronically. Acute toxicity is characterized by abnormal electrocardiograms (ECGs) and reductions in systolic function. Chronic toxicity is cumulative and dose related. It manifests as congestive heart failure, and once it has reached this point it has a very high mortality rate. This chronic cardiotoxicity is of greater concern, and it is addressed using a number of strategies, including limitations on doses used, as well as use of liposomal formulations and adjuvant agents, as described later.
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Mitoxantrone has a chemical structure that is distinct from that of the anthracyclines, and it is believed to be less cardiotoxic than the anthracyclines. It does not generate free radicals.
Advanced
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Strategies to minimize cardiotoxicity include the use of a cardioprotective drug such as dexrazoxane. The generation of free radicals by anthracyclines is iron dependent. Dexrazoxane chelates iron that is bound in anthracycline complexes, and this prevents the formation of the free radicals that damage the myocardium. Dexrazoxane does not appear to impair the antitumor activity of the anthracyclines.
Drug Interactions
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It appears that the cardiotoxic effects of anthracyclines may be worsened by concurrent administration of trastuzumab. Trastuzumab is a monoclonal antibody that is used in the treatment of breast cancers expressing the HER2/neu receptor. A number of anthracyclines are used in treating breast cancer.
FYI

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 The anthracyclines were originally derived from the bacterium Streptomyces peucetius var caesius, and that is why they fall under a larger class of antitumor antibiotics. Other antitumor antibiotics include mitomycin and bleomycin.