Flashcards in WEEK 10 Deck (145):
What is FVC?
The forced vital capacity
Forced = exhale as hard & long as possible
Vital = total volume minus the residual volume
Capacity = sum of more than one volume
This is where the graph plateaus i.e. the total amount of air exhaled
What is FEV-1?
The forced expiratory volume in 1 minute
What is the FEV-1/FVC ratio a measure of? What are the normal values?
Of airflow obstruction
> 0.7 is normal
With OBSTRUCTIVE pulmonary disease what change is made to the following (i) FVC (ii) FEV-1 (iii) FRC (iv) RV (v) TLC?
(i) normal or slightly decreased
With RESTRICTIVE pulmonary disease what change is made to the following (i) FVC (ii) FEV-1 (iii) FRC (iv) RV (v) TLC?
(ii) normal or slightly decreased
What does hypoxia tend to result from?
What are 4 common obstructive lung diseases?
List the 11 differences between asthma & COPD.
- non smoking related, allergic, tends to be younger pts, intermittent, not progressive, eosinophil filtration, diurnal variation, good corticosteroid and bronchodilator response, preserved FVC and TLC, normal gas exchange
- smokers, non-allergic, over 50s, chronic, progressive decline, neutrophils, no diurnal variation, poor corticosteroid and bronchodilator response, reduced FVC and TLC, impaired gas exchange
How is asthma diagnosed? What are the symptoms associated with asthma?
It is diagnosed clinically
Symptoms: wheeze, breathlessness, chest tightness, cough
- especially likely if diurnal variation in symptoms and history of atopy
- also if their symptoms arise in response to allergen, exercise or cold air
What are the 3 pathophysiological components of asthma?
Airway narrowing/obstruction (which is reversible)
Airway inflammation (from eosinophils)
What 3 non pharmacological treatment interventions has SIGN declared as effective?
1. Achieve and maintain a normal BMI if overweight
2. Breathing exercise programmes
3. Stop smoking (pt and household members)
What is COPD? What is it characterised by?
Common, preventable and treatable disease that is characterised by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airway and lung to noxious particles/gases
What is the epidemiology of COPD?
Indoor/outdoor pollution from biomass fuels
Alpha 1 antitrypsin deficiency ( think if early onset COP i.e. early 40s)
What is the pathophysiology of COPD?
1. Inflammation and fibrosis of the bronchial
2. Hypertrophy of submucosal glands and hypersecretion of mucous
3. Loss of elastic, parenchymal lung fibres (emphysema)
What is the clinical presentation of COPD? (HINT: there's 7 points)
1. Insidious (gradual) onset
2. Usually 50s or 60s
3. Chronic cough
4. Sputum production (worse in morn)
5. Increasing (over time) shortness of breath
6. Diminishing exercise tolerance
7. History of exposure to risk factors
What are the clinical observations of a (i) pink puffer (ii) blue bloater?
(i) pink, pursed lips (alveoli tend to collapse), barrel chest due to air trapping, use of accessory muscles and decreased breath sounds
(i) blue = cyanosed
bloater = signs of RHF
When do you give domiciliary oxygen therapy?
Patients with a pO2 < 7.3-8 kPa
Must have stopped smoking
Must be breathed for >15 hours/day to improve mortality
What is the various grades on the MRC breathlessness scale?
1. Not troubled by strenuous exercise
2. Short of breath when hurrying on the level or walking up a slight hill
3. Walks slower than most ppl on level, stops after a mile or so, or stops after 15 mins walking at own pace
4. Stops for breath after walking 100yrds or after a few minutes on level ground
5. Too breathless to leave the house, or breathless when undressing
Define (i) case series (ii) cross-sectional survey (iii) case control study (iv) cohort study (v) RCT.
1. CASE SERIES - tracks subjects with a known exposure i.e. pts who have received a similar treatment, or examines their medical records for exposures and outcomes
2. CROSS SECTIONAL SURVEY - analyses data collected from a population, or a representative subset, at a specific point in time
3. CASE CONTROL STUDY - compares patients who have a disease or outcome of interest (cases) with patients who do not have the disease or outcome (controls), and looks back retrospectively to compare how frequently the exposure to a risk factor is present in each group
4. COHORT STUDY - one or more samples followed prospectively and evaluations with respect to a disease/outcome are conducted to determine which initial exposure characteristics (risk factors) are associated with it.
5. RCT - splits participants into treatment and control group, the only expected difference between the groups in a RCT is the outcome variable being studied.
What are the advantages and disadvantages of a cross sectional survey?
- cheap and simple
- ethically safe
- useful for planning purposes
- cause and effect?
- volunteer bias
- unequal distribution of cofounders
What are the advantages and disadvantages of a cross sectional survey?
- cheap and simple
- ethically safe
- useful for planning purposes
- cause and effect difficult to obtain
- volunteer bias
- unequal distribution of confounders
What are the advantages and disadvantages of a case control study?
- Simultaneously look at multiple risk factors
- Good for studying rare conditions or diseases
- Useful as initial studies to establish an association
- Retrospective study which relies on patient recall to determine exposure (recall bias) or patient records
- selection of control group is difficult
What are the advantages and disadvantages of a cohort study?
- ethically safe
- subjects can be macthed
- can show cause precedes the effect
- easier and cheaper than a RCT
- high drop out rate (follow up must be as complete as possible)
- exposure may be linked to hidden confounder
- blinding is difficult
- outcome of interest may take a long time to occur
What are the advantages and disadvantages of a RCT?
- unbiased distribution of confounders
- Clearly identified populations
- randomisation helps statistical analysis
- more likely to be 'blinded'
- expensive (time and money)
- volunteer bias (pop may not be representative)
- ethical issues if treatment group are seen to respond badly or better than expected
Define (i) single blind (ii) double blind (iii) crossover (iv) placebo controlled
(i) subjects didn't know which treatment they were receiving
(ii) neither subjects nor investigators aware of treatment subjects receive
(iii) each subject received both the intervention and control treatment often separated by washout period
(iv) control subjects receive placebo
What are the 5 problems associated with RCTs?
1. IMPOSSIBLE to do with treatments for v.rare diseases (no. pts limited)
2. UNNECESSARY when treatment produces a 'dramatic' benefit
3. STOPPING TRIALS EARLY - interim analyses of trials are now commonly undertaken to assess whether the treatment is showing benefit and if the trial can be stopped early
4. RESOURCES as costs of RCTs substantial in money, time and energy
5. GENERALISABILITY - often carried out on specific types of pts for a relatively short period of time
What are the advantages and disadvantages of an expert (narrative) review?
- comprehensive survey
- answers a specific question
- expert bias
What is a systematic review?
It attempts to identify, appraise and synthesise all the empirical evidence that meets pre-specified eligibility criteria to answer a given research question
- researches condusing SRs use methods aimed at minimising bias, in order to produce more reliable findings that can be used to inform decision making
What are systematic reviews viewed as the 'gold standard' ?
As they avoid/minimise bias
What are the advantages and disadvantages of a systematic review?
- comprehensive analysis of all best primary evidence using explicit and reproducible methodology
- results can be combined and statistically analysed as if were one study
- considered an evidence-based resource and the best guide to practice
- less costly to review studies rather than initiate a new study
- results often disagree
- publication bias
- very time consuming
What is a meta-analysis?
Combines qualitative and quantitative study data from several selected studies to develop a single conclusion from a greater statistical power
1. Establish statistical significance with studies that have conflicting results
2. Develop more accurate estimate of effect magnitude
3. Provide more complex analysis of harms, safety data, and benefits
4. Examine subgroups with individual numbers that are not statistically significant
What are the advantages and disadvantages of a meta-analysis?
- greater statistical power
- greater ability to extrapolate to the general pop
- considered an evidence-based resource
- results often disagree
- heterogeneity of study pops
- v. time consuming
- requires advanced statistical techniques
What is the definition of an allergy?
Disease following a response by the immune system to an otherwise innocuous antigen
- allergies reside within hypersensitivities (harmful immune responses that produce tissue damage)
For a type I hypersensitivity reaction, what is the (i) immune reactant (ii) antigen (iii) effector mechanism (iv) example?
(iii) mast cell activation
(iv) allergy, asthma
Describe the type of exposure to occur for an allergy to arise?
Allergies always occur on secondary exposure to an allergen, so an initial exposure event has always taken place
What are serum IgE levels normally? (roughly not an exact value)
What produces IgE? Where is it located?
Produced by plasma B cells in lymph nodes or locally at site of inflammation
Located mostly in tissue, bound to mast cell surface through high affinity IgE receptor (FcεRI)
Certain antigens & routes of delivery appear to favour IgE production, describe these routes.
Transmucosal at low doses
CD4+ T cells of Th2 phenotype which produce IL4 cytokines favour IgE responses
Th2 T cells also force B cells to secrete IgE instead of IgM
What are the 4 common sources of allergens?
What is the major allergen in the faeces of house dust mite? Describe said allergen/
Der p 1
- it can cleave tight junctions between epithelial cells in airways => enhancing access
Der p 1 is then taken up by dendritic cells, presented to T cells ( which become Th2), causing B cells to secrete IgE
What is the most important factor in what symptoms occur during an allergic reaction?
The location and distribution of antigen
- inhaled antigens affect nasal epithelium
- allergen induced degranulation further down airway results in allergic asthma
What is allergic asthma?
Bronchial constriction resulting in increased secretion of fluid and mucus, trapping inhaled air
Chronic inflammation can occur with continued presence of Th2 T cells, eosinophils, neutrophils
Describe what a skin allergy is and the response that is induced.
Wheal and flare, first appearing within a few mins of allergen entering as a result of vasodilation after mast cell degranulation (localised redness)
Around 8 hours later more diffuse oedema at site due to influx of lymphocytes & other leukocytes (attracted by chemokines)
What are the 2 main symptoms associated with an ingested allergen? What are other problems which can occur?
Activation of GI Mast cells results in transepithelial fluid loss and smooth muscle contraction
=> DIARRHEA and VOMITING
If allergen enters the blood stream then urticaria (hives, a generalised disseminated rash)
In severe cases of food allergy (nuts) life threatening anaphylaxis and CV collapse may occur
Mast cells granules contain a wide range of inflammatory mediators, what are these? Describe them. (HINT: there;s 4)
- prostaglandins which increase vascular permeability, body temperature
- PAF which increases adhesion between endothelium and neutrophils
- leukotrienes attract and activate neutrophils (increasing vasc permeability)
2. TOXIC MEDIATORS
- histamine which increases vasc permeability and promotes fluid movement from vasculature by constricting vasc smooth muscle
- heparin inhibits coagulation
- IL-4, IL-13 amplify Th2 response
- IL-3, IL-5, GM-CSF promote eosinophil activation and production
- TNF alpha is a pro inflam that activates epithelium
- chemokine MIP-1alpha attracts macrophages and neutrophils
- tryptase, chymase etc.
What are the 2 main treatments currently for allergies? Describe them.
Desensitisation and blockade of effector pathways
- aims to shift response from IgE to IgG dominated
- pts are injected with escalating doses of allergen, gradual shift from Th2 to Th1 T cells
Potentially life threatening reactions are treated with epinephrine (adrenaline) injection, what is the dosage for adults and children? Where is it to be administered and how many times?
0.15 mg for child and 0.30 mg for adult
- delivered in thigh
- second dose possible if no signs of improvement in 10-15 mins
Where are mast cells strategically placed?
At mucosal surfaces
What does engagement of IgE on Mast cells result in?
- also basophil and eosinophi involvement
What can the late phase of the allergic response involve?
How is intermediate resistance treated?
With an increase from the standard dose
What is the therapeutic index?
the difference between the dose necessary for treatment and that causing harm
What is the (i) MIC (ii) MBC?
(i) minimum inhibitory conc
- the lowest concentration of an antibiotic that COMPLETELY inhibits the growth of a bacterium
(ii) minimum bactericidal conc
- the lowest dose that completely kills a bacterium
What 3 things define the 'breakpoint'?
1. The distribution of MICs of target bacteria
2. Achievable therapeutic conc in tissue
3. max. achievable conc
What are 4 types of intrinsic resistance?
1. Streptococci are naturally resistant to aminoglycosides
2. Pseudomonas spp., are normally resistant to beta lactams
3. Mycoplasma spp., are all resistant to beta- lactam antibiotics
4. Enterobacteriaciae are all resistant to metronidazole
When does acquired resistance occur?
When a previously susceptible strain/species develops an increase in the MIC that takes it beyond the therapeutic range
What are the 6 types of resistance mechanisms?
1. Enzyme inactivation
e.g. beta-lactamases, cephalosporins
2. Enzymatic addition
e.g. tetracyclines, quinolones, macrolides
5. Alternative pathway
e.g. MRSA mecA
6. Altered target
e.g. rifampicin, fluoroquinolones, suphonamides
How has resistance evolved?
Development of resistance through mutation in critical chromosomal genes
- critical genes involved that are the target of the antibiotic
e.g. rifampicin, DNA gyrases
Describe the evolution of quinolone resistance.
There're 2 genes involved - gyrA and parC
Point mutations in the genes change the affinity of the proteins for DNA
Mutations in one gene encodes low level resistance
Mutations in both genes encodes high level resistance
What are the 3 ways that resistance is transmitted? Give detailed examples.
e.g. penicillin in s.pneumoniae
e.g. beta-lactamases, enterobacteria
- many bacteria have plasmids (accessory circular DNA), transmitted with the cell. They can encode virulence, metabolic functions and resistance determinants. It allows characteristic to be shared rapidly by bacteria
e.g. erythromycin in S.pyogenes
- small segments of DNA which encode their own transmission. Many bacteria have these mobile genetic elements. They allow genome plasticity and may collect resistance determinants
What is a superbug? What are 4 examples of superbugs?
- an organism that has gained resistance to a critical antibiotic
- an organism that has gained resistance to multiple antibiotics
2. Glycopeptide resistant staph aureus (GISA)
3. Vancomycin resistance enterococcus (VRE)
4. Extended spectrum beta-lactamases (ESBLs)
What are the 3 different types of carbapenemases?
1. Klebsiella pneumoniae carbapenemase (KPC)
2. New Delhi metallo-betalactamase (NDM)
2. Oxa-48 group
Why do we worry about some things and not others? (HINT: there's 3 reasons)
1. When the consequences of infection are severe and the organism is common (e.g. MRSA and ESBL Gram -ves)
2. When the organism is naturally resistant to many organisms (E. faecium and Ps. aeruginosa)
3. When the infection is in a site where it's difficult to get high concentrations of antibiotic (pneumococcal meningitis)
What are the 4 ways to address the problem of bacterial resistance?
1. Optimise the treatment of bacterial disease
2. Better diagnosis
3. Focussed treatment
4. Appropriate length of courses
What are the main type of yeast fungi that infect humans? Name 4 species and their disease entity.
1. CANDIDA spp.
- thrush, fungaemia (immunocompromised pts)
2. CRYPTOCOCCUS NEOFORMANS
- meningitis, pneumonia, fungaemia
3. PITYRIASIS VERSOCIKIR
- chronic skin infection
4. SYSTEMIC YEASTS e.g. histoplasma capsulatum
- pulmonary or disseminated infections
What are the main types of filamentous fungi that infect humans? Name 2 species subtypes and their disease entity.
1. Aspergillus spp., mucor, rhizopius, absidia
- pulmonary, ocular infection, "farmer's lung", bronchopulmonary aspergillosis, fungaemia
2. Dermatophytes: epidermophyton, microsporum, trichophyton
- chronic infection of skin and nails, kerion
What are the 4 types of tri-azole drugs? Describe them.
- well absorbed orally, good penetration into CSF => treat fungal meningitis. Excreted largely unchanged in urine, used to treat candiduria
- requires acid environment in stomach for optimal absorption. Associated with liver damage so avoid/use with caution in liver diseased pts
- treat invasive fungal infections unresponsive to conventional treatment
- broad spec, used in life-threatening infections
For fluconazole, what are the (i) cautions (ii) contra-indications (iii) hepatic impairment (iv) renal impairement (v) pregnancy (vi) breast feeding?
(i) concomitant use with hepatotoxic drugs, monitor liver function with high doses or extended courses— discontinue if signs or symptoms of hepatic disease (risk of hepatic necrosis); susceptibility to QT interval prolongation
(ii) acute porphyria
(iii) less hepatotoxic than related drugs
(iv) usual loading dose then halve subsequent doses if eGFR less than 50 mL/minute/1.73 m2
(v) avoid unless advantages outweigh risks
(vi) present in milk but amount too small to be harmful
For Flucytosin, what are the (i) indications (ii) cautions (iii) renal impairment (iv) pregnancy (v) breast feeding?
(i) Systemic yeast and fungal infections; adjunct to amphotericin in cryptococcal or severe systemic candidiasis
(ii) elderly; blood disorders; liver- and kidney-function tests and blood counts required
(iii) Reduce dose in the case of renal impairment and measure drug concentrations
(iv) only if potential benefits outweigh risks
What are 2 examples of polyenes?
Amphtericin and Nystatin
NYSTATIN - oral, oropharyngeal and peioral infections
AMPHOTERICIN - by IV for systemic fungal infections. When given parentally it's toxic - the liquid formulations are less toxic2
What are 3 types of echinocandins? What is their MoA? What do they act against?
Anidulafungin, caspofungin and micafungin
- act by inhibiting beta-(1,3)-D-glucan synthase
- active against Aspergillus spp. (caspofungin only) and candida spp.
NOT effective against fungal infections of CNS
For Terbinafine, what are the (i) indications (ii) cautions (iii) hepatic impairment (iv) renal impairment (v) pregnancy (vi) breast feeding?
(i) dermatophyte infections of the nails, ringworm infections (including tinea pedis, cruris, and corporis) where oral therapy appropriate
(due to site, severity or extent)
(ii) psoriasis (risk of exacerbation); autoimmune disease (risk of lupus-erythematosus-like effect);
(iii) maufacturer advises avoid as elimination is reduced
(iv) use half normal dose if eGFR less than 50 mL/minute/1.73 m2 and no suitable alternative available
(v) if benefit>risk
(vi) avoid - present in milk
For Griseofulvin, what are the (i) indications (ii) driving (iii) contra-indications (iv) hepatic impairment (v) pregnancy (vi) breast feeding?
(i) dermatophyte infections of the skin, scalp, hair and nails where topical therapy has failed or is inappropriate
(ii) may impair performance of skilled tasks, effects of alcohol enhanced
(iii) severe liver disease, systemic lupus erythematosus, acute porphyria
(iv) avoid in severe liver disease
How is invasive candidiasis treated?
- fluconazole is an alternative for candida albicans for pts who haven't received an antifungal recently
- amphotericin when either of the above can't be used OR in the initial treatment of CNS candidiasis
- voriconazole - for infections caused by fluconazole-resistant candida spp. or in pts intolerant of amphotericin or an echinocandin
How is superficial candidiasis treated?
treated locally (e.g. miconazole)
- widespread requires antifungal treatment (fluconazole)
- vaginal treated with locally acting antifungals or fluconazole orally
What is aspergillosis? What is the various medication used for treatment?
Most commonly affects RT, but in severely immunocompromised pts, invasive forms can affect the heart, brain and skin
VORICONAZOLE = treatment of choice
- liposomal amphotericin when voriconazole can't be used
- caspofungin, itraconazole or posaconazole for pts who can't tolerate either of the above
- itraconazole for chronic pulmonary aspergillosis or as an adjunct in the treatment of allergic bronchopulmonary aspergillosis
How is cryptococcal meningitis treated?
Treatment of choice = amphotericin by IV and flucytosine by IV for 2 weeks
- then fluconazole orally for 8 weeks or until cultures are negative
- fluconazole is given alone in HIV-positive pts with milk localised infections (or those that can't tolerate amphotericin)
- fluconazole is used as prophylaxis until immunity recovers
Name 2 other systemic mycoses.
How are systemic fungal infections treated (e.g. Histoplasmosis)?
Parental itraconazole may be used for the treatment of immunocompetent pts with indolent non-meningeal infection (incl. chronic pulmonary histoplasmosis)
Parental amphotericin is preferred in pts with fulminant/severe infections
- itraconazole can then be used for prophylaxis against relapse till immunity recovers
Describe type II hypersensitivity. Ensure to give examples of type II reactions.
Usually as a result of antibodies (IgG) binding to components of cell membranes of ECM
Can be self components, or exogenous components
SELF Ex = GOODPASTURE'S SYNDROME
- antibodies bind to BM collagen type IV, glomerulonephritis in kidney, pulmonary haemorrhage in lung
Antibodies to substances bound to host cell surface Ex = haemolytic anaemia caused by penicillin
Describe type III hypersensitivity.
Caused by antibody (usually IgG but also sometimes IgM)
- antibodies directed to soluble antigens
What are the 5 sites of immune complex deposition?
1. GLOMERULI: filtration process makes the glomeruli a v.common site in IC deposition, damage is driven by complement activation
2. BLOOD VESSEL WALLS: IC accumulate on veins and arteries, causing vasculitis
3. SYNOVIAL MEMBRANES: RA, the IgG of immune complexes becomes an antigen itself and IgM rheumatoid factor antibodies develop
4. SKIN: causes rashes
5. SYSTEMIC SITES: In systemic lupus erythematosus IC deposits in kidney, joints, skin, vasculature, muscle and other organs
Describe type IV hypersensitivity.
Entirely cell mediated and complement does NOT play a role
- most caused by CD4+ delayed type hypersensitivity reactions (2-4 days after exposure)
- macrophages which cause damage are non specific and harm both infected and non-infected tissue
Describe what errors can happen with regards to DTH reactions? What are contact sensitivities?
They can be prolonged and damaging (Listeria, M. tb)
- can lead to walling off infectious sites => granulomas.
Special category of DTH in which antigen is not an infectious agent but a chemical which binds to cell surface (heavy metal, poisin ivy)
Name 5 syndromes that arise as a result of type II hypersensitivity reactions.
1. Autoimmune haemolytic anaemia
2. Autoimmune thrombocytopenic purpura
3. Goodpasture's syndrome
4. Pemphigus vulgaris
5. Acute Rheumatic fever
Name 3 syndromes that arise as a result of type III hypersensitivity reactions.
1. Mixed essential cryoglobulinemia
Name 3 syndromes that arise as a result of type IV hypersensitivity reactions.
1. Type 1 diabetes mellitus
3. Multiple sclerosis
What are the 3 main approaches to dealing with cancer?
1. Surgical excision
What is the MoA of alkylating agents? What are the 6 major groups
They form covalent bonds with suitable nucleophilic substances in the cell under physiological conditions causing intrastrand cross-linking of DNA
1. Nitrogen mustards - cyclophosphamide
2. Ethylenimines - thiotepa
3. Alkylsulphonates - busulphan
4. Hydrazines & triazines - temozolomide
5. Nitrosureas - lomustine, carmustine
6. Platinum based compounds - cisplatin
What are the 3 major groups of antimetabolites? Give examples.
1. Antifolates - methotrexate
2. Antipyrimidines - 5 FU, gemcitabine
3. Antipurines - mercaptopurine, thioguanine
What is the MoA of cytotoxic antibiotics? Give 4 examples.
By direct action on DNA
- anthracyclines e.g. doxorubicin
Wha are the 5 types of plant derivatives?
1. Spindle poisons
- affect microtubule function and prevent mitotic spindle formation
2. Vinca alkaloids
- e.g. vincristine, vinblastine
- paclitaxel, docetaxel
What are the 5 main drawbacks of the current chemotherapy of cancer?
1. It targets cell proliferation and not the more lethal properties of invasiveness and metastasis
2. Non-specific cell killers rather than being aimed at the particular changes which make a cell malignant
3. The development of resistance to anticancer drugs
4. Some remaining cells since the total elimination of malignant cells is not possible using therapeutic doses, and the host's immune response is often not adequate to deal with the remainder
5. Pt compliance due to side-effects i.e. not completing the therapy regimen
What is the function of (i) rituximab (ii) herceptin (iii) Gleevec?
(i) targets B cell surface protein, used for B cell lymphomas
(ii) targets epidermal growth factor receptor, used for breast cancer
(iii) inhibits bcr-abl gene signalling pathways, used for chronic myeloid leukaemia
What does personalised medicine take into account?
Individual genetic differences
What is the new paradigm used for efficient medical care?
What are the 4 current priorities for the NHS?
1. Improved prevention based on underlying predisposition
2. Earlier diagnosis of disease as a result of identifying abnormality earlier
3. More precise diagnosis based on cause
4. Targeted interventions through the use of companion diagnostics to identify and stratify patients for effective treatments
What are the various types of personalised medicine used for lung cancer(NSCLC)?
1. EGFR mutation analysis
- activating mutation
2. KRAS mutation analysis
- activating mutations
- no drug available
3. ALK rearrangement analysis
- 4% of pts
What are the various types of personalised medicine used for colorectal cancer?
Cetuximab = anti-EGFR monoclonal antibody therapy
KRAS/NRAS mutation analysis: no mutations
- cetuximab PLUS chemo
What are the various types of personalised medicine used for treating melanomas?
Approx 40-60% of cutaneous melanomas carry mutations that activate a gene called BRAF (leads to further growth).
Vermurafenib = mutated B-raf inhibitor
BRAF activating mutations - vermurafenib
NRAS mutations use MEK inhibs
KIT mutations use imatinib
What are the various types of personalised medicine used for treating brain tumours?
Temozolomide = alkylating agent
MGMT promoter gene methylation: if high use temozolomide
- promoter methylation of MGMT decreases the xpression of the MGMT protein => longer pt survival
What are the various types of personalised medicine used for treating gastric tumours?
Trastuzamab = anti-Her2 drug (given alongside cisplatin plus 5-FU or capecitabine)
- treats metastatic adenocarcinoma if not received prior treatment and tumour expresses high HER2 levels
Imatinib in C-KIT positive metastatic GIST
What is the type of analysis used for treating bone and soft tissue in order to maintain a more accurate diagnosis?
FISH analysis for Ewing's sarcomas, alveolar rhabdomyosarcomas, leiomyosarcomas, fibromyxoid sarcomas
What are the various types of personalised medicine used for treating anti-PD-1/PD-L1?
NIVOLUMAB - targets PD-L1 and restores antitumour immunity. Is an anti-PD-1 antibody
- used in melanoma and squamous NSCLC
IPILIMUMAB - anti-CTLA-4 antibody
- used in metastatic melanoma
What is the structure of the respiratory tract?
nose & nasal sinuses
eustachian tube & middle ear
trachea & bronchi
What are the 7 respiratory defence mechanisms?
1. nasal mucus
2. ciliated cells
3. mucociliary clearance elevator
5. alveolar macrophages
6. polymorphonuclear leucocytes
7. complement and circulating factors
What are beta defensins? What is their function? Where are they found?
Cysteine rich cationic protein which binds to microbial cell membrane, puncturing it
It is active against a variety of bacteria, fungi and some viruses
Present in inflammatory cells and epithelia
What is the mucociliary clearance elevator? What are the various disruptions which can result in chronic infection?
Particles are trapped in the mucus which covers the RT, the ciliary action drags mucus up and the material is expectorated
- Chronic infections (cystic fibrosis, kartagener's)
- Occupational diseases (silicosis, pneumoniosis)
- Previous infection (pneumonia)
- Bronchial obstruction (foreign body inhaled)
What do respiratory bacteria have to do to cause pneumonia? (HINT: there's 5 things they must do)
1. Colonise the nasopharynx or be inhaled into alveolus
2. Adhere to respiratory cells
3. Evade the immune system
5. Express virulence factors which cause disease
What are the 5 risks associated with respiratory transmission?
1. Bacterial load
2. Host susceptibility
3. Source of infection
4. Mechanism of transmission
5. Susceptibility of host
How does acute inflammation arise in a RTI?
As a result of alveolar damage
Opsonised particle attaches to receptors on neutrophil surface, engulfed and phagosome is formed. Phagolysosomal fusion with degranulation results in respiratory burst and subsequent killing and digestion of particle
What 3 things does acute inflammation trigger? What do they have the greatest impact on within the RT?
1. Vasodilation - nasal passages
2. Exudation - alveoli
3. Oedema - epiglottis
What is myeloperoxidase?
An enzyme located in the neutrophil granules
How does an antibody deficiency arise?
As a result of severe combined immunodeficiency (e.g. HIV, sickle cell, myeloma)
What occurs in a chronic RTI setting?
Granulation tissue formation (alveoli)
Repair/remodelling (trachea/main bronchi, bronchioles)
What can an upper RTI often be confused with?
Type I hypersensitivity reaction
What is primary bronchiolitis?
Uncommon, caused by viruses and common in infants. Symptoms of ARDS with dyspnoea and tachypnoea. A minority may develop secondary pneumonia
What is pneumonia? What are the 2 different types of pneumonia?
Alveolar inflammation with a protein rich exudate that is polymorphs and later lymphocytes and macrophages
LOBAR - uncommon in infants and elderly. Males>females. 90% due to strep. pneumoniae. Cough and fever with purulent or 'rusty' sputum.
BRONCHO - patchy consolidation, several lobes or bilateral. usually in infants and elderly. Normally secondary to pre existing disease. Haemophilus, Klebsiella, Staph. aureus (mixtures)
What is a (i) viral and (ii) fungal RTI?
(i) cytomegalovirus - at risk are immunosuppressed and transplant pts
(ii) aspergillus fumigatus - at risk are immunosuppressed and farmers (mouldy grain)
What can a fungal RTI present as?
i.e. a type I hypersensitivity reaction
What can compromise immune defence?
2. Acquired (leukaemia, HIV, cytotoxic therapy)
3. Opportunistic infection
- organisms = pneumocystis, atypical myobacteria, TB, s.pneumoniae, cryptococcus
What are the risk factors for myobacterium tuberculosis?
2. Socioeconomic (young, malnourished, overcrowding, alcoholism, civil disruption, occupational risks)
What are the 3 different types of TB? Describe them.
1. PRIMARY - small mid-zone lesion with hilar lymph nodes involvement
2. SECONDARY - lesions atypical and bilateral
3. MILIARY - lungs and many other organs contain numerous small granulomas
What is tuberculosis? What type of hypersensitivity reaction is it?
Chronic inflammation with ongoing injury
What was the antibiotic discovery based upon?
On theory that soil organisms may have produced agents to kill myobacterium
- streptomycin discovered
What was the treatment used for TB in (i) 1946 (ii) 1952 (iii) 1960s (iv) 1970s (v) 1980s?
(ii) strep, PAS and isoniazid (24 months)
(iii) strep, ethambutol, isoniazid (9-12 months)
(iv) strep, ethambutol, isoniazid, rifampicin (9-12 months)
(v) ethambutol, isoniazid, rifampicin, pyrazinamide (6-8 months orally)
What is the (i) initial phase (ii) current phase for the current tuberculosis treatment?
(i) Isoniazid, rifampicin, pyrazinamide and ethambutol for 8 weeks
(ii) Isoniazid and rifampicin for 18 weeks
What is isoniazid? What is its MoA? What is the toxicity associated?
Bactericidal, easy tolerated in single daily dose orally (5mg/kg)
MoA = inhibition of mycolic acid biosynthesis
Toxicity relatively low
- peipheral neuropathy (minimised using pyridoxine i.e. vit B6)
- rheumatologic, rash, nausea
What is rifampicin? What is its MoA? What is the toxicity associated? What drugs can it interact with?
Bactericidal, once daily dose well tolerated
MoA = inhibits bacterial DNA-dependent RNA polymerase
- itch +/- rash
- discolouration of urine, sweat, tears etc
- CYP 450 induction - increased clearance
What is pyrazinamide? What is its MoA? What is its role in combination therapy? What is the toxicity associated?
Bacteriostatic - but bactericidal at acidic pH e.g. inside cells
MoA: exact mechanism unknown
In combo it accelerates the sterilising effect of INH and rifampicin allowing 6 month treatment
- GI intolerance (common)
- hyperuricemia, can exacerbate gout
- rash, blood changes, joint pain
What is ethambutol? What is its MoA? What is the toxicity associated?
Bacteriostatic, single daily dose and is well tolerated
MoA is not well understood but it inhibits arabinsyn transferase
- optic neuritis (uncommon at <15mg/kg)
- eadache, dizziness, confusion
What are the second line drugs mainly used for multi-resistance TB?
What are 4 treatment problems associated with TB?
No. of tablets
Length of therapy
What is a mutation? What is it due to? What does the survival of a mutation depend upon?
Occurs at a steady rate in all organisms and is due to a failure of fidelity in polymerases and proof reading functions
Survival dependent upon the degree of resistance encoded and the effect on the function of the mutated gene
Explain how the resistance to treatment may be prevented when 2 drugs are used.
Resistant rifampicin arises 10^-9/cell division and cavity pus has up to 10^8 cfu/mL => have 1 in 10 chance of a resistant mutant being present at start of treatment
risk of isoniazid resistance = 10^-7/cell division => combined risk = 10^-16/cell division
In what 4 scenarios is the risk of resistance higher?
1. In pts with higher bacterial load and with extensive cavitation
2. When pts take therapy irregularly
3. If pt takes inactive drug (counterfeit)
4. If physician provides wrong prescription
What 4 conditions are associated with MDRTB?
2. Cavitatory disease
4. previous inadequate TB treatment
How is MDRTB controlled?
1. Identify pts @ risk
2. 24 hr Z-N service
3. PCR detection of rpoB mutations
4. Isolate pts @ risk
5. treat effectively
6. Prevent emergence of new cases
What makes a patient more at risk of having/developing MDRTB?
1. Prev anti-TB therapy
2. Travel from country where MDRTB common
3. Contact with known case of MDRTB
4. Continued deterioration despite optimal chemotherapy
Why do patients with MDRTB remain infectious for longer?
As the 2nd and 3rd line agents are very weakly bactericidal
How do you isolate MDRTB?
Negative pressure ventilation
Effective masks for staff
Care consideration of discharge
How is the emergence of new cases prevented? (HINT: there's 7 points)
- better shorter treatment regimens
- open access to diagnostic services
- specialist management of cases
- systems to ensure high cure rates
- molecular epidemiology
- integrated TB diagnostic and clinical service
What 6 factors are associated with a poor outcome in MDRTB?
1. Male gender
2. Smear positivity
3. Alcohol use
4. Low BMI
5. Fluoroquinolone resistance
6. Presence of XDRTB pattern
What is XDRTB?
Extremely drug resistant TB
- resistant to isoniazid, rifampicin, plus any fluoroquinolone and at least one of 3 injectable second-line drugs
- there is limited treatment options available as many of the available drugs are toxic and not very active