In this assignment, I will be explaining the physiological action of Herceptin. I will also be explaining the mechanism whereby one significant side effect may be caused by the other. I will also identify Trastuzumab (Herceptin), is a drug which is prescribed for some types of breast cancer. It is a humanized IgG1 kappa monoclonal antibody that selectively binds with high affinity to the extracellular domain of the human epidermal growth factor receptor 2 protein, HER2. It contains the antibiotic gentamicin, which is not detectable in the final product. Herceptin was designed to target an abnormal protein, HER2, which makes tumours grow. Approximately one quarter of breast tumours have the mutation that causes high HER2 levels. Patients that test positive for this mutation are likely to respond well to trastuzumab, as it can shrink tumours, slow disease progression and increase survival. Unlike most chemotherapy drugs Herceptin kills just cancer cells leaving healthy cells intact. Herceptin is only given to women with HER2-positive breast cancer and is effective in women with metastatic and earlier stages of disease. It can shrink down and get rid of cancer that has spread beyond the breast to other parts of the body and can also helps shrink down a medium to large sized cancer in the breast before surgery. Herceptin reduces the risk of cancer returning after surgery in women with medium-sized cancer (two centimeters or larger) or if the lymph nodes are involved (no matter what size the cancer is).
The way in which Herceptin works is by stopping or slowing down the growth of certain breast cancer cells by blocking the chemical signals they need to grow. When HER2 receptors are turned on and get excited, they transmit to the cells to grow. With too many receptors, breast cancer cells pick up too many growth signals and start growing too much and too fast. One of the ways in which Herceptin work to slow down or stop the growth of the cancer cells is by blocking the receptors so they don’t pick up as many growth signals.
Herceptin can only be given intravenously, and the first dose that is given takes about 90 minutes. After that, it only takes about 30 minutes to get the other doses of Herceptin, which is usually given weekly. There are some studies that are looking at whether Herceptin may be given every three weeks instead of weekly.
Unlike standard chemotherapy, which you take for a limited time, Herceptin is taken indefinitely in order to keep metastatic breast cancer under control.
The administration of Herceptin can result in serious infusion reactions and pulmonary toxicity. Fatal infusion reactions have been reported. In most cases, symptoms occurred during or within 24 hours of administration. Herceptin infusion should be interrupted for patients experiencing dyspnea or clinically significant hypotension. Patients should be monitored until signs and symptoms completely resolve. Herceptin should be discontinue for infusion reactions manifesting as anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome.
The most common adverse reactions in patients receiving Herceptin, are fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia. Adverse reactions requiring interruption or discontinuation of Herceptin treatment include Chronic Heart Failure (CHF), significant decline in left ventricular cardiac function, severe infusion reactions, and pulmonary toxicity. These side effects generally become less severe after the first treatment. Other side effects, including low white or red blood cell counts are seen in some women receiving Herceptin in combination with chemotherapy, but are rarely seen in women taking Herceptin alone.
I have identified the enclosed trial that evaluate the efficacy and safety of herceptin after excision of early stage breast cancer and completion of chemotherapy.
This trial is an international, intergroup, open – label phase three randomised trial. This means that participants are assigned randomly to either the real treatment drug group or to the group that is given the placebo. These trials in my view provide more validity to the resutls as it removs the possibilty of bias. The trial involved women with HER2 positive, early stage invasive breast cancer, who have all completed surgery with or without radiotherapy (locoregional therapy) as well as a minimum of four courses of chemotherapy.
In this clinical trial, the researchers found that the drug Herceptin (generic name, trastuzumab) can significantly reduce the recurrence of breast cancer in women with an aggressive form of the disease, when given in combination with chemotherapy.
In the studies, breast cancer patients who received Herceptin along with standard combination chemotherapy had a 52 percent decrease in disease recurrence compared to patients treated with chemotherapy alone. Herceptin appears to only work in women whose breast cancers are classified as “HER-2 positive,” meaning that they make too much of a protein called HER-2, found on the surface of cancer cells.
The studies involved over 3,300 women with HER2 postive breast cancers. Patients were randomly selected to receive either standard chemotherapy (with the drugs doxorubicin and cyclophosphamide) followed by treatment with the drug paclitaxel, or the same form of standard chemotherapy followed by treatment with the drugs paclitaxel and Herceptin. Most patients who enrolled in the studies had breast cancers that had spread to their nearby lymph nodes.
Women who were treated with chemotherapy and Herceptin were significantly less likely to experience a recurrence of their disease.
One of the risk factors that may have contributed to Bill’s Coronary Artery Disease is his heavy smoking.
Coronary artery disease (CAD) is a condition in which plaque builds up inside the coronary arteries that supply your heart muscle with oxygen-rich blood. The mechanism whereby smoking is believed to contribute to heart disease is that smoking increases the levels of carbon monoxide that is inhaled. Long term inhalation of carbon monoxide will contribute to the damaging the blood vessels and therefore reducing the amount of oxygenated blood being supplied to the heart. Cigarette smoke also produces toxins in the blood stream, and this can contributes to the development of plaque in the arteries (atherosclerosis). As plaque causes narrowing of the arteries, oxygen-rich blood can’t reach your heart muscle therefore blood flow to the heart will be decrease and could cause angina.
Ques. 02 a
Creatine kinase (CK) is an enzyme that is found in muscles tissues and the brain. In normal circumstances, very little CK is found circulating in the blood. Therefore, any elevated levels that may be present is indicative of damage to either muscle or the brain; possibly from a myocardial infarction (heart attack), muscle disease, or stroke.
During a heart attack, heart muscle cells die and burst open, letting certain proteins, (creatine kinase- CK) out in the bloodstream. Higher than normal levels of these proteins in the bloodstream is evidence of a heart attack. CK-MB shows an increase above normal in a person’s blood test about six hours after the start of a heart attack. It reaches its peak level in about 18 hours and returns to normal in 24 to 36 hours. The peak level and the return to normal can be delayed in a person who’s had a large heart attack, especially if they don’t get early and aggressive treatment. High CK levels can mean that you’ve had muscle damage in your body whereas high levels of CK-MB can mean that you’ve had a heart attack.
Streptokinase which is also known as a thrombolytic drug, is a protein that is extracted from the cultures of streptococci and activates plasminogen (Moore etal. 2003). The actions of streptokinase is to attack the substance called fibrin in your blood that causes clotting. As soon as streptokinase gets into your bloodstream, it takes just a few seconds to reach your coronary arteries. The drug then starts dissolving the clot that is blocking your artery, and allows the blood to flow to your heart again.
Streptokinase should not be used beyond four days after it is first administered because, according to the British National Formula (BNF) Prolonged persistence of antibodies to streptokinase can reduce the effectiveness of subsequent treatment.
Quest 04 Aspirin – Side effect – Gastro-intestinal Discomfort
Aspirin inhibits cyclooxygenase (prostaglandin synthetase) thereby reducing the synthesis of prostaglandins and thromboxanes. These effects are thought to be how aspirin produces analgesia, antipyrexia, and reduces platelet aggregation and inflammation. Most cells can synthesize new cyclooxygenase, but platelets cannot. Therefore, aspirin causes an irreversible effect on platelet aggregation. The most common adverse effect of aspirin at therapeutic doses is gastric or intestinal irritation with varying degrees of occult GI blood loss occurring. This is because prostaglandins role is to regulate the stomach acid as well as maintaining the gastric mucosa. Therefore, since aspirin inhibits prostaglandins then it is highly likely to have such adverse effect on gastro – intestinal effects.
Heart failure is the heart’s inability to pump enough blood to meet the metabolic demands of the body (MacKlin 2001). Heart failure may be caused by various different heart conditions, and the symptoms will include fluid retention, breathlessness, and tiredness. In most cases medication can usually ease symptoms, and can often improve the prognosis.
The heart is combined of four chambers – two atria and two ventricles. The walls of the heart chambers are made mainly of special heart muscle. Each heartbeat starts with a tiny electrical impulse near the top of the heart which spreads through the heart muscle, and makes it contract (squeeze). In someone with normal healthy heart, during each heartbeat a set amount of blood enters the heart and is pumped out again. However, as Bill is suffering from chronic heart failure, his heart cannot cope with the pumping action of filling up with blood in each heartbeat. Therefore his heart is unable to sufficiently perfuse and oxygenate his body in order to maintain homeostasis, this will result in fluid retention, oedema, breathlessness and exercise intolerance. When Bill’s heart begins to fail, compensatory neurohormonal activity will begin and this will activate the sympathetic nervous system as well as the renin-angiotensin-aldosterone system. The sympathetic nervous system is activated by impulses sent to baroreceptors and chemoreceptors located mainly in the aortic arch and the carotid sinus (Addison and Thomas 1998, Albert 1999). Therefore, it is fair to say that Bill’s first symptom would be shortness of breath or breathlessness. When the left ventricle fails to eject sufficient volumes of blood into the systemic circulation there is an increase in LVEDP, which results in the elevation of pressure in the pulmonary vasculature and may lead to pulmonary oedema (Piano et al 1998).
Patients with right-sided heart failure, or congestive heart failure, may develop systemic oedema, which may ranges from mild ankle oedema to gross oedema of the legs, abdomen, sacrum and scrotum (Addison and Thomas 1998, Watson et al 2000). Diuretics are the first-line treatment for patients with heart failure as it helps to relieve the symptoms of shortness of breath and oedema (Dougherty 2004). Frusemide which is also known as a Loop dieuretics, inihibits the NA+/K+/CI co transporter in the membrane of the loop of henle in the nephron of the kidney and therefore changes the sodium balance in the kidney (class notes 2007). This is prescribed for Bill’s chronic heart failure treatment because, it is one of the main treatment for oedema (water retention) caused by heart failure. It works in the loop of Henle by increasing the secretion of sodium and water. Potassium secretion is increased in the distal tubule of the nephron (Davies et al 2000, Downie et al 1999).Bill’s heart has become less efficient at pumping his blood around his body, therefore fluid is leaking out of his blood vessels, which is causing swelling in the tissues of his lungs and ankles. Furosemide also prevents the build up of his fluid by increasing the amount of urine which is being produced by the kidneys and make Bill pass urine more often.
Based on Bill’s pathological condition,and according to the BNF, Amitriptyline is not recommended for use during the acute recovery phase following myocardial infarction and in the presence of acute congestive heart failure. The contraindication of the drug is, myocardial infarction, arrhythmias (particularly heart block), not indicated in manic phase, severe liver disease (BNF 57)
Ginkgo ( Ginkgo biloba ) is a herbal medicine. Unlike many other medicinal herbs, ginkgo leaves are not used in their crude state, they are concentrated, standardized ginkgo biloba extract (GBE). Ginkgo has been used in traditional medicine to treat circulatory disorders and enhance memory. Scientific studies throughout the years lend support to these traditional uses. Emerging evidence has also suggests that GBE may be particularly effective in treating ailments associated with decreased blood flow to the brain, particularly in elderly individuals. Laboratory studies have shown that GBE improves blood circulation by dilating blood vessels and reducing the stickiness of blood platelets. Therefore since Ginkgo has blood-thinning properties Bill should not be using it, as he is prescribed the anticoagulant aspirin and they will interact with each other and could have a detrimental effect.
St John’s wort is also a herbal medicine and is used as an antidepressant, but is available for purchase without a prescription. It contains many different chemicals which are thought to be the active ingredients. It is thought that st John’s wort works by altering the balance of some of the chemicals in the brain (neurotransmitters) such as serotonin, dopamine, gamma aminobutyric acid (GABA), and noradrenaline. Alterations in the balance of these neurotransmitters may play some part in causing depression. Although St John’s wort is said to be a hebal remedy, it does contains chemicals that may interact with other drugs and therefore should not be taken if taking warfarin, which is also an anticoagulant and Bill is prescribed aspirin so this medicine could also interact with his prescribed medicines.
The prescription and administration of medicines to older people require special care and attention (BMA/RPSGB 1999). As people grow older they experience more than one illness, this is known as multipathology (Horan 1992). As a result, they will require more medications (Corlett 1996) and may therefore be taking several different medications at the same time (Swift 1998). Commonly, an older person admitted to a nursing home may have four or five conditions including, for example, arthritis, cardiovascular disease, diabetes and bronchitis (MacLennan etal 1984). Each of these conditions will require treatment which may lead to an older person taking a selection of drugs – each drug having its own effects, side effects and possible interactions with other drugs and this leads directly to the phenomenon of polypharmacy.
Polypharmacy does not merely occur because a person is taking many drugs, but as a result of taking many different drugs, they end up with adverse effects. The risks of polypharmacy in the elderly, is that they often use medications that have no apparent indication. They may duplicate medications, as well as concurrent use of interacting medications. They are also likely to use contraindicated medications as well as inappropriate dosage. Other factors which contribute towards polypharmacy (Watson 1996) are the: Self-administration of over-thecounter medications which are not prescribed Self-administration of old drugs prescribed for previous illnesses which are no longer required Poor adherence to prescribed drug regimes. (LeSage 1991).
Addison C, Thomas K (1998) Heart failure. In Shuldham C (Ed) Cardiorespiratory Nursing. Cheltenham, Stanley Thornes.
British Medical Association/Royal Pharmaceutical Society of Great Britain (1999) British National Formulary 38. London, BMA/RPSGB.
Corlett AJ (1996) Aids to compliance with medication. British Medical Journal, 313, 926-929.
Davies M et al (2000) ABC of heart failure. Management: diuretics, ACE inhibitors, and nitrates. British Medical Journal. 320, 7232, 428-431.
Dougherty R (2004) Pharmacological treatment of chronic heart failure. In Stewart S et al (Eds) Caring for the Heart Failure Patient: A Textbook for the Health Care Professional. Hampshire, Martin Dunitz.
Downie G et al (1999) Pharmacologyand Drug Management for Nurses.Second edition. London, ChurchillLivingstone.
Horan MA (1992) Introduction – presentation of disease in old age. In: Brocklehurst JC et al Textbook of Geriatric Medicine and Gerontology 4th edition. Edinburgh, Churchill Livingstone.
LeSage J (1991) Polypharmacy in geriatric patients. Nursing Clinics of North America, 26, 273-289.
MacKlin M (2001) Managing heart failure: a case study approach. Critical Care Nurse. 21, 2, 36-48.
MacLennan WJ et al (1984) The Elderly. Berlin, Springer-Verlag.
Piano M et al (1998) The molecular and cellular pathophysiology of heart failure. Heart and Lung: The Journal of Critical Care. 27, 1, 3-19.
Swift CG (1998) Clinical pharmacology and therapeutics. In: Pathy MSJ, Principles and Practice of Geriatric Medicine 3rd edition. London, Wiley.
Watson R (1996) Mixed medicines: spotting the signs.Practice Nurse, 7, 20, 32-35.
Watson R et al (2000) ABC of heart failure: clinical features and complications. British Medical Journal. 320, 7229, 236-239.