13 Oct 2020
Vaccination is acquisition of a specific response of the immune system to pathogens within the body. It is achieved by the introduction of a substance that will bring about an immune response. This then leads to immunisation to the pathogen. Immunisation is associated with lower incidence of disease in a population with reduced complications of disease when it does develop. Factors such as herd immunity can provide further protection to a population as the ability of a pathogen to propagate across a population is impeded by immune individuals. Immunity is commonly mistaken as binary, rather than highly variable over time. Comprehensive vaccination programmes greatly reduce the burden of disease on public health and can improve the average number of quality years lived in a population significantly.
Vaccines can degrade rapidly if not stored in correct conditions. This can render them ineffective when administered which poses a risk to health. Ensuring that the quality of a vaccine is not compromised means maintaining the cold chain from manufacture to administration. Different vaccines have varying sensitivity to heat and therefore different storage conditions; these different storage conditions can produce significant logistical issues to rolling out vaccination. Temperatures of storage areas must be monitored and there should not be any deviations from the defined temperature range. Some vaccines require very cold storage which in turn necessitates the use of expensive and uncommon freezers. In developing countries these issues are magnified. Even if a vaccine is highly effect it may be unfeasible for widespread use if the logistics of its supply and storage are too challenging. Consideration must also be given to the cost versus the risk of infection.
There are a few broad classes of vaccines:
- Whole pathogen vaccines
- Live attenuated
- Inactivated
- Conjugate
- Toxoid vaccines
- Subunit vaccines
- Nucleic acid vaccines
- DNA
- RNA
- Recombinant vector
Live attenuated vaccines
Live attenuated vaccines are live viruses or bacteria that have been weakened so that they generate an immune response but do not cause disease. They are often created by replicating the pathogen in cells that they do not typically infect for many generations. This leads to maladaptation of the pathogen to its intended host.
MMR vaccine is a combination vaccine which provides protection against infection with measles, mumps and rubella. These are serious diseases which can cause permanent disability and death. Three weakened live strains are included in the vaccine. It is given as two doses. The first is usually around one year of age; this is because maternal antibodies have subsided at this time which can render the vaccine ineffective by working against the active components of the vaccine. A second dose is given before the child starts school – typically at 3 years and 4 months old.
BCG vaccine is a vaccine against the bacteria that cause tuberculosis. It is not part of the NHS routine vaccinations but is given to people that are deemed as high risk. This can be due to a parent or grandparent being born in a country where there is a high rate of tuberculosis, or being born in areas of the UK where tuberculosis rates are higher than the rest of the country. The vaccine contains a live weakened form of the bacteria.
##Inactivated vaccines
Inactivated vaccines are vaccines that are produced by producing a large number of the virus and then physically or chemically inactivating them. The whole ‘killed’ pathogen or parts of the pathogen, when introduced to the body, will induce the intended immune response. The vaccine for influenza is an example of an inactivated vaccine.
Influenza vaccine is given annually and is offered to at-risk groups and healthcare professionals. At-risk groups include the elderly and those that suffer from conditions that increase the likelihood of adverse effect from complications of influenza. Proteins that cover the surface of the virus are included in the vaccine and promote an effective immune response when the vaccinated person comes into contact with annual flu.
Conjugate vaccines
Some pathogenic bacteria have very poor immunogenicity and can be vaccinated against by conjugation of the bacteria with an antigen with greater ability to induce immune response. The pneumococcal vaccine is a conjugate vaccine that is given at 8 and 16 weeks of age with a further booster at 1 year. This will change to two doses given at 12 weeks and 1 year. This vaccine is also given to those over the age of 65 just once, unless they also have an underlying health condition. Typically a higher valent pneumococcal vaccine is given over the age of 65 which provides protection to a greater number of strains of pathogenic bacteria.
Toxoid vaccines
Toxins that cause diseases such as diphtheria and tetanus are purified and inactivated by chemical means. This disrupts the structure of the protein and its ability to cause symptoms in the individual. Two toxoid vaccines form part of the combination vaccine DTP.
Subunit vaccines
Recombinant protein vaccines Take the gene for the antigen and express it in something else. Harvest, concentrate and inject. Receptor binding domain vaccines Similar to recombinant protein but only involves the part of the antigen that forms a complex with human cells. Hep B and HPV vaccines
DNA vaccines
DNA plasmid grown in large quantities. Injected and electroporation utilised to get DNA into cell. When present in nucleus of cell protein is translated and expressed.
RNA vaccines
Encapsulate mRNA in lipid nanoparticles. This mRNA can code for just the antigen or it can be self-replicating and code for both the antigen and itself. Production is entirely in vitro which is good for scalability. However, storage requirements for these vaccines are typically -80C which presents a challenge for distribution.
Recombinant vector vaccines
Use another non-pathogenic virus to insert gene for desired antigen. This causes some cells in the vaccinated person to produce the antigen. May be replication competent or incompetent. Potential problems with pre-existing antibodies rendering the vector useless. Can be circumvented by using a virus that isn’t prevalent in humans. Advantage good T cell response due to activation of innate immune response. Disadvantage can prove problematic in those with reduced immune response. Ebola vaccine.
13 Oct 2020
Rheumatoid arthritis and osteoporosis are two distinct conditions with differing mechanisms of onset. However, there are links between the two conditions, patients with RA are at an increased risk of developing osteoporosis. Both conditions can impede locomotion and compromise an individual’s ability to care for themselves if their conditions are severe
Rheumatoid arthritis is a long-term condition that affects the joints of the body. It causes inflammation, pain and loss of motion. It is a progressive condition which seriously impacts on quality of life. It is an autoimmune disease which is caused by the body attacking the lining of joints. Its exact causation is currently unknown but it is thought to involve genetic and environmental factors.
It can impede the ability of an individual to use medical devices themselves which can cause exacerbations of other conditions that the patient may suffer from. An example of this could be the successful use of inhalers to manage asthma or COPD.
Symptoms of rheumatoid arthritis can also include lethargy, fever, sweating, poor appetite and weight loss. It can contribute to the development of other conditions such as depression, cardiovascular disease and infections.
Medicinal intervention aims to relieve suffering caused by the disease and to modify the progression of the disease. Non-steroidal anti-inflammatory drugs are useful as analgesia to manage the pain associated with rheumatoid arthritis, they can also alleviate some of the stiffness experienced from this condition.
Aspirin and ibuprofen are commonly used to provide pain relief for sufferers of rheumatoid arthritis. Non-steroidal anti-inflammatory drugs may have side-effects including gastrointestinal discomfort, hypersensitivity, rash and skin reactions. Aspirin can cause bleeding due to its anti-coagulant effect and patients should be adequately counselled so that they understand this risk. Patients must understand that these drugs will only treat the symptoms of the condition and are not associated with an improvement in the progression of the disease.
Methotrexate, sulfasalazine, leflunomide and hydroxychloroquine are first-line treatments for the slowing of the progression of rheumatoid arthritis. These drugs are classified as disease modifying anti-rheumatic drugs (DMARD). They do not treat symptoms but they do slow the progression of the disease. As rheumatoid arthritis is a long-term progressive condition this can improve quality of life by reducing the rate at which symptoms worsen.
Methotrexate is most commonly used of these and is often given in combination with biological treatments if it does not achieve adequate clinical effect as a monotherapy. Blood tests must be done regularly when taking methotrexate. A weekly dose of methotrexate is given on the same day each week. Folic acid is often given as a co-medication on the days in which methotrexate is not taken.
Side effects of methotrexate treatment can include anaemia, diarrhoea, drowsiness, fatigue, gastrointestinal discomfort and increased risk of infection. Patients must be counselled adequately and understand that they must immediately report signs of blood disorders, liver toxicity and respiratory effects. These can be life-threatening complications of methotrexate treatment.
Sulfasalazine is another non-biological treatment option for the management of rheumatoid arthritis. Compliance can be an issue with this medication as it takes many months of treatment before the emergence of clinical effect. Side effects of this medication can include gastric disturbance, nausea, diarrhoea, dizziness, fever, headache, skin reactions and vomiting.
Biological treatments are newer developments in the treatment of rheumatoid arthritis. These are complex medicinal products that act specifically on biological processes to achieve their clinical effect.
Infliximab is a monoclonal antibody which is used in the treatment of rheumatoid arthritis. A monoclonal antibody is a manufactured protein which provides a targeted response. Infliximab is used in the treatment of rheumatoid arthritis because it inhibits the actions of a protein called tumour necrosis factor alpha. This is a cell signalling protein which is responsible for the mediation of a number of cell functions that lead to cell death. Blockade of this protein with infliximab is associated with impeded disease progression and a reduction in symptoms of the disease.
As infliximab is a chimeric monoclonal antibody it can generate a dangerous immune response in patients that it is given to. Patients are more susceptible to infection when they are receiving treatment with infliximab and they must report any signs of infection to a doctor immediately.
Osteoporosis is a disease characterised by a reduction in bone density which increases the risk of fractures. The disease is typically diagnosed after a minor fall in which a fracture occurs. It is a disease that is associated with advanced age and occurs with more frequency as age increases.
Women are at a higher risk of osteoporosis as oestrogen affects the development of bone. Following menopause, and the associated drop in oestrogen production, there is a more rapid loss of bone. Other potential contributing factors can include smoking, alcohol, hyperthyroidism, genetic causes, long-term treatment with some medications, eating disorders and a sedentary lifestyle. The presence of the disease can be confirmed by measuring the bone density of a patient and comparing this to the bone density of a healthy adult. This scan is called a DEXA scan and utilises low energy x-rays.
There are a number of medications that are used in the treatment of osteoporosis. Vitamin D and calcium are necessary for adequate bone density. Dietary and lifestyle factors increase a patient’s risk of developing osteoporosis through the deficiency of one, or both, of these substances.
Colecalciferol can be given to increase the levels of vitamin D in the patient. This is especially useful if a patient is unable to adequately access the sun as the body synthesises this substance when exposed to sunlight. Older people in care home settings may not have adequately access to the outdoors and using this medication can avoid the development of vitamin D deficiency which can lead to osteoporosis. Side effects of this medication can include abdominal pain, headache, hypercalcaemia, hypercalciuria, nausea and skin reactions.
Calcium supplementation can form an important response to osteoporosis. If dietary intake of calcium is insufficient then osteoporosis will develop due to the body’s diminished ability to replace lost bone. This deficiency can be tackled with medication such as calcichew tablets. These are tablets which contain calcium and can be used to replenish low levels of this substance in the body. Side effects of these medications may include constipation, diarrhoea, hypercalcaemia and nausea.
Biphosphonate medications can be taken to slow the rate of bone loss and try to prevent fractures and progression of osteoporosis. Risedronate can be taken once weekly as a tablet. Patients must be adequately counselled with this medication as it can cause irritation to the oesophagus if taken incorrectly. Patients must be told to sit upright or stand for 30 minutes after taking the medication. They should not take any food or water for between 30 minutes and 2 hours after taking the medication.
Denosumab is a monoclonal antibody that prevents the formation of osteoclasts which decreases the rate at which bone is lost. It is a subcutaneous injection that is given infrequently to treat osteoporosis. It is regarded as a safe medication and reduces risk of fracture and improves bone density. Side effects can include skin infections and low blood calcium levels.
A doctor will assess the suitability of different treatment options for each patient and develop a plan in consultation with other healthcare professionals to treat osteoporosis.
13 Oct 2020
Cancer is the condition of uncontrolled cell reproduction. It is a leading cause of death as the longer someone lives, the greater their chance of developing cancer will be; one in two people will develop cancer during their lifetime. The developments of antisepsis and anaesthesia allowed for the treatment of cancer to begin, and from the mid-1800s the ability to treat cancer has been subject to rapid evolution. This has changed the narrative of cancer treatment from one of palliation to that of cure.
Cancerous cells have a number of differences from non-malignant cells which gives rise to their uncontrolled proliferation. Cancer cells have six features which distinguish them from normal cells:
- Sustained growth signals: typically pathway actions will drive the growth of a cell but in a cancerous cell these become autonomous
- Inhibited growth supression: Signals that prevent unrestrained growth are inhibited
- Cell death supressed: the processes that normally govern apoptosis are suppressed so cancerous cells do not respond to external signals that mediate cell death
- Delimited cell growth: the growth potential of the cell is delimited and so cells become immortal with limitless replicative potential
- Neovascularisation: angiogenesis is promoted by cancer cells through downregulation of inhibitory pathways, this also results in neovascularisation which gives an increased supply of blood to tumours
- Metastasis occurs when cancer cells migrate to other areas of the body
Cancer therapy can be thought of as a term encompassing the surgical, radiotherapeutical and medicinal interventions to halt the progression of cancer, and to aim for remission. Combination therapy involves the use of two or more medicines to treat cancer. Using multiple drugs allows for synergistic effects between different chemotherapeutic agents. A drug that may only inhibit the progression of cancer on its own can prove to be curative if given with other agents. This is due to factors like the targeting of different malignant pathways or the initiation of programmed cell death.
Combination therapy also allows for the management of drug toxicities. By using lower doses of a range of drugs less severe side effects from those drugs will be present. Combination therapy is effective for a range of cancers and they are often referred to by acronyms. Some examples of this include: CHOP, CVP, VAMP, FOLFOX, POMP.
There is a number of criteria for the selection of anti-cancer drugs in the treatment of cancer. Cost and effectiveness strongly determine which drugs are used in the treatment of cancer. The National Institute for Health and Care Excellence (NICE) creates guidelines for use by the NHS. They determine the efficacy of a drug in the treatment of a particular condition by reviewing literature and analysing the degree of improvement to patient outcomes balanced against the cost of the drug.
As the resources of a free universal healthcare system, such as the NHS, are finite difficult decisions must be made to produce the most effective benefit for the most people. Assessments are made on an intervention’s ability to add quality years of life to a patient. This is a better evaluation of the efficacy of a given treatment than just assessing the quantity of time added as a patient can experience poor states of health which some would argue are worse than death. Discussions on medical ethics must guide the evaluation of any medical treatment.
When these principles are not followed it can lead to unsustainable expenditure on treatments which are not clinically beneficial. Controversy surrounds the Cancer Drugs Fund which is source of funding for cancer drugs that consultants can apply for. It has been criticised for undermining NICE and costing tax payer’s money - with little benefit to patients, and without extending lives.
Chemotherapy can be non-specific or specific to cancerous cells. Non-specific chemotherapy can exploit the rapid division and replication of cancerous cells. Different drugs work on different parts of the cell cycle.
| Condition |
Example regimen |
Drug classes |
Non-Hodgkin lymphoma
A cancer affecting the lymphatic system of the body. It can begin in any part of the system. Symptoms can include: painless swellings in the neck, armpit and groin, heavy sweating at night, fever with unknown origin, weight loss and itchiness |
RCHOP
Rituximab, Cyclophosphamide, Doxorubicin, Vincristine & Prednisolone |
Monoclonal antibody, Alkylating agent, Anthracycline antibiotic, Vinca-alkaloid & Corticosteroid |
Testicular cancer
This is a cancer that affects the reproductive system of men. It most commonly affects young men. Symptoms can include: a lump in the testicle, a heavy scrotum and discomfort or pain in a testicle or the scrotum. |
BEP
Bleomycin, Etoposide & Cisplatin |
Glycopeptide antibiotic, Podophyllotoxin & Alkylator-like agent |
Relapsed or refractory Hodgkin lymphoma
This is a cancer that begins in the white blood cells. If it is relapsed or refractory that means that it has returned after treatment or has not responded to treatment. Symptoms can include: painless swellings in the neck, armpit and groin, heavy sweating at night, fever with unknown origin, weight loss and itchiness. |
BRESHAP
Brentuximab, Etoposide, Methylprednisolone, Cytarabine & Cisplatin |
Monoclonal antibody, Podophyllotoxin, Corticosteroid, Antimetabolite & Alkylator-like agent |
Doxorubicin is a broad spectrum antitumour antibiotic. It belongs to the classification of anthracycline antibiotics and it was discovered as a result of the efforts to synthesise an analogue to daunorubicin. It achieves its cytotoxic effect by binding to DNA in the nucleus of cells and preventing the mitotic process. It is not specific for a phase in the cell cycle.
Vincristine is a vinca alkaloid. Vinca alkaloids were extracted from the pink periwinkle plant. Vinca alkaloids have important cytotoxic effects. They act in the M phase of the cell cycle. They induce cytotoxicity by disrupting the function of microtubules. These structures separate chromosomes during the metaphase and interrupting this process stops these cells from dividing and leads to cell death.
Cytarabine is a nucleoside analogue of deoxycytidine. It is a competitive inhibitor of the enzymes that normally metabolise deoxycytidine. Due to this it inhibits the synthesis of nuclear DNA and therefore acts in the synthesis phase of the cell cycle.
Common side effects of these chemotherapy agents include: Alopecia, anaemia, decreased appetite, eye inflammation, fever, gastrointestinal discomfort. Higher doses of doxorubicin can cause the severe side effect of cardiomyopathy, leading to congestive heart failure. Vincristine has a side effect of neurotoxicity which can lead to sensory and motor neuropathy. Cytarabine can cause severe nausea and vomiting.
Patients that are receiving chemotherapy should be counselled properly to assure adherence to their medication regimen. They should be counselled on side-effects that they may encounter, how to avoid pregnancy whilst they are receiving treatment, what they should do if they develop a fever, any interactions between other medications that they are taking or food they might eat.
Patients that are taking doxorubicin should be advised that it can cause tissue necrosis if extravasation of the drug from the venous system was to occur. They should be advised to call 999 immediately if this occurs.
Patients that are taking vincristine should appreciate the signs of cumulative sensory and motor damage. They can report this to their doctor if this occurs and then dose reduction, treatment interruption or treatment discontinuation can occur if necessary.
Patients that are taking cytarabine should be made aware of the potential for significant gastrointestinal discomfort, nausea and vomiting. They will need to tell their doctor if this happens so that medication to alleviate these symptoms can be considered and dieticians can be consulted if the patient is not able to keep food down.
References
- Mukherjee, S., 2010. The emperor of all maladies: a biography of cancer Simon and Schuster.
- Mokhtari, R.B., Homayouni, T.S., Baluch, N., Morgatskaya, E., Kumar, S., Das, B. and Yeger, H., 2017. Combination therapy in combating cancer. Oncotarget, 8(23), p.38022.
- Folkman, J., 1995. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nature medicine, 1(1), pp.27-30.
- Rodriguez, V., Bodey, G.P. and Freireich, E.J., 1973. Combination chemotherapy for lymphomas and leukemias. Disease-a-Month, 19(4), pp.1-40.
- Rosner, F., Hirshaut, Y., Grünwald, H.W. and Dietrich, M., 1975. In vitro combination chemotherapy demonstrating potentiation of vincristine cytotoxicity by prednisolone. Cancer research, 35(3), pp.700-705.
- Speth, P.A.J., Van Hoesel, Q.G.C.M. and Haanen, C., 1988. Clinical pharmacokinetics of doxorubicin. Clinical pharmacokinetics, 15(1), pp.15-31.
- Arcamone, F., 2012. Doxorubicin: anticancer antibiotics. Elsevier.
13 Oct 2020
Asthma and chronic obstructive pulmonary disease are common respiratory disorders. Effective treatment and monitoring is necessary to avoid complications that can develop due to poor oxygen saturation or exacerbation of the disorder.
Asthma is a disorder in which the bronchial tubes tighten as a result of inflammation; this then creates difficulty breathing due to the narrowing of the lumen of the airway. This happens in recurrent episodes and can be caused by a number of triggers. These triggers can include: exercise, aerosols, cold air, dust, cigarette smoke and more.
The condition often develops in childhood and can have differing severity amongst patients. Some suffers can avoid the use of medication entirely, whereas others will need a variety of medication in a treatment plan to effectively manage their condition. This can have a profound impact on quality of life and can preclude suffers from activities or occupations that they might otherwise pursue. The lowest doses of medication that control symptoms should be used so as to avoid side-effects.
Chronic obstructive pulmonary disease (COPD) is the name of a collection of disorders where long term breathing problems and poor airflow are present. This is due to inflammation and damage within the lungs. It is typically caused by smoking, but some people that have never smoked can be affected. This can be due to a genetic cause of the disease. Asthma can lead to the development of COPD due to the narrowing of airways and inflammation that can be caused by asthma. Symptoms of COPD usually do not present until later in life and can include: increasing breathlessness, a persistent chesty cough, frequent chest infections and persistent wheezing.
COPD is a life limiting disorder as airflow obstruction is progressive. Exacerbations of the disorder are a frequent cause of hospitalisation. Due to the poor respiratory health of patients with COPD hospital acquired pneumonia can be a significant complication during hospitalisation which further worsens prognosis for these patients. An effective regimen with good patient compliance can reduce the risk of admission and therefore acquired infections.
Salbutamol is an intermittent therapy for asthma. One or two puffs of a metered dose inhaler containing this medication is used up to four times a day to help to relieve the symptoms of asthma when they are present. Patients should use this medication when they begin to notice symptoms such as wheezing, shortness of breath and tightness in the chest. It works by relaxing the muscles of the airways to the lungs.
Fluticasone is a regular preventer therapy which is taken twice daily. Doses of between 100 micrograms to 500 micrograms are given for adults. It works by reducing inflammation in the airways as well as reducing sensitivity to things that may trigger the symptoms of asthma. It is also used in the long term management of COPD to help provide relief from the symptoms of the disorder, as well as to try and reduce the number of exacerbations of COPD.
Montelukast is a leukotriene receptor antagonist. 10mg is taken once daily in the evening. It achieves its clinical effect by blocking the action of leukotriene on receptors contained within the lungs which results in decreased inflammation and relaxation of the muscle of the airways.
Long acting antimuscarinic receptor antagonists can be used in the treatment of asthma or COPD. Tiotropium is an example of a drug of this class. It is taken once daily and works by blocking the effect of a neurotransmitter on muscle. This relaxes the muscle and provides relief from constricted airways. It also provides a reduction in mucous secretion which can help patients with productive chesty coughs.
Common medicines for both these disorders are inhaled corticosteroids. These steroids share a large amount of side effects which can include: arrhythmias, dizziness, headache, hypokalaemia (with high enough doses), nausea, palpitations and tremor.
Antimuscarinic receptor antagonists cause many of the same side-effects: arrhythmias, dizziness, headache and nausea. However, due to their effect on muscarinic receptors they commonly cause dry mouth.
Proper inhaler technique is crucial to effective administration of medicines for these conditions. If a patient has poor technique then these local effect medications will not reach their intended area, or will do so in sub-optimal quantities to provide the intended clinical effect. With some inhaler devices a patient must have adequate lung function to deliver the drugs effectively to their lungs. This can be an issue, especially with patients with more advanced COPD. Some inhaler devices are able to deliver medications with greater velocity so that the patient themselves do not need to inhale with such force.
A patient should be assessed with spirometry to see which inhaler is suitable for them. Spirometry is a test that is used to monitor lung function and measures how much air a patient can inhale and exhale, and the force that they can generate as they perform these functions.
Patients will need to have a discussion with their doctor about how well their condition is managed. Patients will initially be started on a short-acting beta-2 agonist, such as salbutamol, to offer some relief of symptoms.
If this does not adequately control their condition then they will be offered maintenance therapy of an inhaled corticosteroid, such as fluticasone. If their asthma is still uncontrolled then there should be the addition of a leukotriene receptor antagonist to their treatment plan. The patient’s response to this treatment should be reviewed after 4 to 8 weeks.
If this therapy does not offer control of asthma, then a long-acting beta-2 agonist should be used. Salmeterol and formoterol are examples of drugs in this class. They are often given in a combination inhaler such as seretide or fostair.
Patients should be cautioned about the use of their medicines if they suffer from some conditions. A patient with an existing arrhythmia may not be suitable for corticosteroids due to the potential for these medicines to cause arrhythmias. Patients with diabetes need to monitor their blood glucose levels carefully as some of these medications can influence these levels. Patients with hypertension or cardiovascular disease can face adverse effects due to the effect of drugs used in treatment of asthma and COPD.