1
Q
What is inflammation?
A
A reaction to injury or infection involving cells such as neutrophils and macrophages
2
Q
Give 5 cardinal signs of inflammation.
A
- Redness (rubor).
- Swelling (tumor).
- Pain (dolor).
- Heat (calor).
- Loss of function.
3
Q
Give a disadvantage of inflammation.
A
Inflammation can produce disease and can lead to distorted tissues with permanently altered function.
4
Q
When is inflammation bad?
A
- Autoimmunity
- When it’s an overreaction to the stimulus
5
Q
What is the expected outcome of acute inflammation?
A
The complete elimination of a pathogen followed by resolution of damage, disappearance of leukocytes and regeneration of tissue.
6
Q
Acute inflammation features
A
- Sudden onset
- Short duration
- Usually resolves
7
Q
Give 6 causes of acute inflammation.
A
- Microbial infections (bacteria and viruses).
- Chemicals (corrosives, acids/alkalis).
- Physical agents (trauma, burns, frost bite).
- Hypersensitivity reactions (TB).
- Bacterial toxins.
- Tissue necrosis.
8
Q
Chronic inflammation features
A
- Slow onset or sequel to acute
- Long duration
- May never resolve
9
Q
What is chronic inflammation?
A
Persistent, unresolved inflammation.
10
Q
Give 4 causes of chronic inflammation.
A
Primary chronic inflammation.
Transplant rejection.
Recurrent acute inflammation.
Progression from acute inflammation.
11
Q
Give examples of primary chronic inflammation.
A
- Infective substances having resistance to phagocytosis e.g. TB, leprosy.
- Endogenous materials e.g. uric acid crystals.
- Exogenous materials e.g. asbestos.
- Autoimmune diseases e.g. chronic gastritis, rheumatoid arthritis etc.
- Other chronic inflammatory diseases e.g. chronic inflammatory bowel disease.
12
Q
Which one of the following is a chronic inflammatory process from its start?
A. Appendicitis
B. Cholecystitis
C. Infectious mononucleosis
D. Lobar pneumonia
A
C. Infectious mononucleosis
13
Q
What cells are involved in acute inflammation?
A
- Neutrophil polymorphs
14
Q
Give 3 endogenous chemical mediators of acute inflammation.
A
Bradykinin.
Histamine.
Nitric Oxide.
15
Q
Features of neutrophil polymorphs
A
- Short lived cells
- First on the scene of acute inflammation
- Cytoplasmic granules full of enzymes that kill bacteria
- Usually die at the scene of inflammation
- Release chemicals that attract other
inflammatory cells such as macrophages
16
Q
What are 4 systemic effects of acute inflammation?
A
Fever.
Feeling unwell.
Weight loss.
Reactive hyperplasia of the reticuloendothelial system.
17
Q
What cells are involved in chronic inflammation?
A
Macrophages and plasma cells (B and T lymphocytes).
18
Q
Features of macrophages
A
- Long lived cells (weeks to months)
- Phagocytic properties
- Ingest bacteria and debris
- May carry debris away
- May present antigen to lymphocytes
19
Q
What cell can form when several macrophages try to ingest the same particle?
A
Multinucleate giant cell.
20
Q
What are some macroscopic features of chronic inflammation?
A
Chronic ulcer.
Chronic abscess cavity.
Granulomatous inflammation.
Fibrosis.
21
Q
Features of lymphocytes
A
- Long lived cells (years)
- Produce chemicals which attract in other inflammatory cells
- Immunological memory for past infections and antigens
22
Q
Plasma cell function and features.
A
- B cell antibody production
- Lots of endoplasmic reticulum to make protein.
23
Q
Endothelial cells features
A
- Line capillary blood vessels in areas of inflammation
- Become sticky in areas of inflammation so inflammatory cells adhere to them
- Become porous to allow inflammatory cells to pass into tissues
- Grow into areas of damage to form new capillary vessels
24
Q
What happens to the arterioles and capillary beds during inflammation?
A
In acute inflammation, the precapillary sphincters open, causing blood to flow through all capillaries. This is good in localised areas.
25
Define exudate.
A protein rich fluid that leaks out of vessel walls due to increased vascular permeability.
26
Why does inflammation lead to oedema
- Normally, fluid leaves the arteriole end and enters through the venous end.
- In acute inflammation, the sphincter is open and there is a higher pressure in the arteriole end and capillaries are more porous.
- There is a net loss of fluid together with plasma protein into the extracellular space.
- This leads to oedema
27
Fibroblasts features
- Long lived cells
- Produce collagenous connective tissue in scarring following some types of inflammation
28
What occurs during acute appendicitis? (eg of acute inflammation)
– Unknown precipitating factor
– Neutrophils appear
– Blood vessels dilate
– Inflammation of serosal surface occurs
– Pain felt
– Appendix either surgically removed or inflammation resolves or appendix bursts with generalised peritonitis and possible death
29
What are the 4 outcomes of inflammation?
1. Resolution.
2. Suppuration.
3. Organisation (scar tissue formation).
4. Progression onto chronic inflammation.
30
What occurs during tuberculosis? (eg of chronic inflammation)
– No initial acute inflammation
– Mycobacteria ingested by macrophages
– Macrophages often fail to kill the mycobacteria because of the cell wall
– Lymphocytes appear
– Macrophages appear
– Fibrosis occurs
31
What are granulomas?
A aggregation of epithelioid histocytes surrounded by lymphocytes
32
What is granulation tissue?
Granulation tissue is composed of small blood vessels in a connective tissue matrix with myofibroblasts. It is important in healing and repair.
33
What is a chronic granulomatous disease (CGD)?
Give 4 examples of granulomatous disease.
An inherited disorder that occurs when the white blood cells (phagocytes) do not work properly. Therefore, the phagocytes cannot protect the body from bacterial or fungal infections.
TB, leprosy, Crohn’s disease and sarcoidosis.
34
The activity of what enzyme in the blood can act as a marker for granulomatous disease?
Angiotensin converting enzyme.
35
How would you treat inflammation?
| List 5 things
- Ice
- Antihistamine for insect bites: histamine drives inflammation
- Aspirin, ibuprofen: inhibits prostaglandin synthetase, prostaglandins are chemical mediators of inflammation
- Corticosteroids: inhibitors of inflammation down regulate chemical mediators of inflammation
36
What leads to thrombus formation in arteries ?
Endothelial cell injury -> exposing collagen -> platelets aggregate -> Turbulent flow -> fibrinogen polymerises to fibrin -> blood clot
37
What are the 3 factors that can lead to thrombosis formation?
1. Change in vessel wall.
2. Change in blood constituents.
3. Change in blood flow.
38
Define thrombosis.
Formation of a solid mass from blood constituents in an intact vessel in the living.
39
Give 2 reasons why thrombosis formation is uncommon.
1. Laminar flow.
2. Non sticky endothelial cells.
40
What drug can be used to prevent Thrombosis?
Aspirin. Inhibits platelet aggregation
41
How is COVID-19 related to thrombosis
- COVID virus causes massive inflammation boosting cytokines
- Increases the liver's production of clotting factors
- Leads to thrombosis.
42
Define embolus
Mass of material in the vascular system able to become lodged within vessel and block it.
| Most commonly, thrombus
43
What are the consequences of an arterial embolus?
An arterial embolus can go anywhere! The consequences could be stroke, MI, gangrene etc.
44
What are the consequences of a venous embolus?
An embolus in the venous system will go onto the vena cava and then through the pulmonary arteries and become lodged in the lungs causing a pulmonary embolism. This means there is decreased perfusion to the lungs.
45
Through which blood system would an embolus have travelled if it resulted in a pulmonary embolism?
Venous system.
46
What are the effects of thrombosis and embolism
Can lead to ischaemia and infarction.
47
Define ischaemia.
Decreased blood flow.
48
What complication may happen if ischaemia is rectified?
Re-perfusion injury can occur due to the release of waste products.
49
Define infarction.
Decreased blood flow with subsequent cell death.
50
What are most organs in the body supplied by. What issue does this cause?
Most organs are supplied by the end arterial supply. If it blocks, can lead to infarction.
51
What organs have more than one supply?
The lungs (bronchial arteries and pulmonary veins), liver (hepatic arteries and portal veins), and some parts of the brain (circle of Willis).
52
What is the difference between resolution and repair?
Resolution
–initiating factor removed
–tissue undamaged or able to regenerate
Repair
–initiating factor still present
–tissue damaged and unable to regenerate
53
What prevents the liver from regenerating in patients with alcoholic liver disease?
Initiating factor not taken away (patient still drinking), leads to cirrhosis where the liver repairs instead of regenerates.
54
What damages occur in lobar pneumonia and severe COVID lung damage?
- Pneumocytes can regenerate, but alveolar cannot.
In lobar pneumonia the lungs can regenerate and can completely recover. In severe cases of Covid, the alveolar cannot regenerate, lungs can only repair.
55
What are abrasion skin wounds?
Superficial skin wounds that have only damaged the top layer of the epidermis, will heal up normally.
56
What happens when healing by 1st intention?
Edges by skin are closely re-approximated.
57
What happens when healing by 2nd intention?
Occurs in traumatic wounds when skin lost and cannot heal through edges. Blood vessels have to grow in from either side. Takes longer to heal.
58
Define repair.
* replacement of damaged tissue by fibrous tissue
* collagen produced by fibroblasts
59
List 3 examples of repair in the human body.
–heart after myocardial infarction
–brain after cerebral infarction
–spinal cord after trauma
60
Name 6 types of cells capable of regeneration.
* hepatocytes
* pneumocytes
* all blood cells
* gut epithelium
* skin epithelium
* osteocytes
61
Name 2 type of cells that don't regenerate?
* myocardial cells
* neurones
62
Man aged 30 takes a large overdose paracetamol overdose and doesn’t come to hospital for 2 days. He spends a few days on ITU with liver failure but then recovers.
What will be happening in his liver - resolution or repair?
Resolution!
Only 1 overdose, and hepatocytes are capable of regeneration.
63
A child aged 3 falls off a climbing frame onto his hand, he fractures his clavicle. He has his arm in a sling for 4 weeks and is very good about keeping it in the sling
What will be happening in his clavicle - resolution or repair?
Resolution!
The patient is keeping the sling in and osteocytes are capable of regeneration.
64
A child aged 3 falls off a climbing frame onto his hand, he fractureshis clavicle. He has his arm in a sling for 4 weeks but won’t keep the sling on and moves his arm a lot
What will be happening in his clavicle - resolution or repair?
Repair!
The patient won't keep the sling on and keeps moving his arms about. Body unable to regenerate because it becomes fibrous and only repair can occur.
65
Give a benefit of inflammation.
Inflammation can destroy invading micro-organisms in injuries and can prevent the spread of infection.
66
What do viral infections result in?
Cell death due to intracellular multiplication.
67
What does bacterial infection result in?
The release of exotoxins (involved in the initiation of inflammation) or endotoxins.
68
Define abscess.
Acute inflammation with a fibrotic wall.
69
Define atherosclerosis.
Inflammatory process characterised by accumulation of fibrolipid plaques in the intima of a vessel wall. It causes a huge amount of illness by reducing the blood flow in important areas.
70
What is the time course of atherosclerosis?
- Birth - no atherosclerosis
- Late teenage/early 20s - fatty streaks in aorta, may not progress to established atherosclerosis
- 30s/40s/50s - development of established atherosclerotic
plaques
- 40s-80s - complications of atherosclerotic plaques e.g. thrombosis, intraplaque haemorrhage
71
What is the distribution of atherosclerosis plaques?
It is common in high pressure systems such as aorta and systemic arteries, never in pulmonary circulation.
72
What is in an atherosclerosis plaque?
1. Lipid core.
2. Necrotic debris.
3. Connective tissue.
4. Fibrous cap.
5. Lymphocytes.
73
List 5 risk factors of atherosclerosis.
- Cigarette smoking
- Hypertension
- Poorly-controlled diabetes mellitus
- Hyperlipidaemia
- Lower social economic status
74
What secondary preventative measure can a GP introduce to a patient post myocardial infarction, known ischaemic disease or known peripheral arterial disease? List 5 examples.
- Statins 80mg (primary prevention would be 20mg)
- Aspirin 75mg
- ACE inhibitors
- Beta blockers
- Control BP with anti-hypertensives
75
What is the endothelial damage theory
- Endothelial cells are delicate, they require oxygen to produce lots of nitric oxide.
- If they are in any way impaired will not produce nitric oxide and die.
76
Describe the main stages involved in the formation of an atherosclerotic plaque
- Macrophages form foam cells from lipids in arterial wall - fatty streak formation (platelets) > intermediate lesion
- Plaque protrudes into artery lumen and disrupts laminar flow - medial thinning and platelet aggregation
- Secondary platelet plug forms fibrin mesh over itself and traps red blood cells
- Fibroblasts form smooth muscle 'fibrous cap' over this
- Continuous formation of secondary platelet plug, this is a stable atheroma - plaque stabilisation/( fibrous cap formation)
77
How does cigarette smoke cause damage to the endothelial cells
Free radicals, nicotine and carbon monoxide can damage endothelial cells.
78
How does hypertension damage the endothelial cells?
High blood pressure has shearing forces exerted on endothelial cells and this can lead to damage
79
How does poorly-controlled diabetes mellitus damage endothelial cells.
Super oxide anions present and glycosylation products both
cause oxidative stress and endothelial injury.
80
What does cumulative damage to the endothelium lead to?
Endothelial ulceration -> microthrombi -> eventual development of established atherosclerotic plaques
Complete block to an artery will mean no blood flow to the organ and infarction can occur.
81
Give 6 examples of complications of atherosclerosis?
- Cerebral infarction
- Carotid atheroma
- Myocardial infarction
- Aortic aneurysms
- Peripheral artery disease with intermittent claudication
- Gangrene
82
What is the anatomy of a normal artery and which part of it is important with regards to atherosclerosis?
- Intima, media and adventitia
- Intima is the most important with regards to ACS. It is formed of only a single layer of endothelium – this is involved in the immune response, releases antithrombotic molecules
to prevent clots, releases vasodilators and constrictors
83
Where does the left and right coronary arteries arise from?
The aortic sinuses
84
How can occlusion of coronary arteries be detected and treated?
Occlusion of any of the coronary arteries can be seen on ECG and via coronary angiogram. It is diagnostic and relieving treatment. Immediate treatment can be done = coronary angioplasty = balloon & stent.
85
Define apoptosis
Programmed cell death of a single cell.
86
What is the role of p53 protein?
Cells can detect DNA damage using p53 protein which can then trigger apoptosis.
87
What protein can switch on apoptosis if DNA damage is present?
p53 protein.
88
How does a cell apoptose?
The cell triggers a series of proteins which lead to the release of caspases within the cell which can turn on apoptosis.
89
Activation of what receptor can activate caspase and therefore apoptosis?
FAS receptor.
90
Give an example of a disease where there is a lack of apoptosis.
Cancer; mutations in p53 mean cell damage isn’t detected.
91
Give an example of a disease where there is too much apoptosis.
HIV
92
Define necrosis.
Unprogrammed death of a large number of cells due to an adverse event.
93
Give 5 examples of events that can lead to necrosis.
* Infarction due to loss of blood supply e.g. myocardial infarction, cerebral infarction
* Frostbite
* Toxic venom from reptiles and insects
* Avascular necrosis of bone
* Pancreatitis
94
Give 3 differences between apoptosis and necrosis.
1. Apoptosis is programmed cell death whereas necrosis is unprogrammed.
2. Apoptosis tends to effect only a single cell whereas necrosis effects a large number of cells.
3. Apoptosis is often in response to DNA damage. Necrosis is triggered by an adverse event e.g. frost bite.
95
Which one of the following is not an example of apoptosis?
A. Loss of cells from tips of duodenal villi
B. Loss of cells during embryogenesis
C. Renal infarction
D. Graft versus host disease
C. Renal infarction.
Necrosis not apoptosis
96
How does the spinal cord form?
- Initial epithelium
- Columnar base
- Invagination
- Tube formation and closure
97
What are the types of spina bifida?
| a congenital defect of the spine
- Spina bifida occulta
- Meningocele
- Myelomeningocele
98
What genes control how cells migrate and differentiate?
Homeobox genes
99
Define congenital.
Present at birth.
100
Give an example of a disease which is congenital but not genetic.
Club foot.
101
Why do people with Down syndrome tend to have earlier dementia?
This is because they have trisomy 21, this leads to excessive beta amyloid being produced which can clump together to form plaques between neurons.
102
Define polygenic inheritance.
Polygenic inheritance refers to inheritance in which the trait is produced from the cumulative effects of many genes.
103
Give an example of a congenital acquired disease.
Foetal alcohol syndrome.
104
Is dwarfism inherited?
Yes, caused by genetic inheritance leading to growth hormone deficiency.
105
Is gigantism inherited?
No, it's caused by growth hormone excess from pituitary adenoma.
106
Define hypertrophy.
Increase in the size of a tissue due to an increase in the size of constituent cells.
107
Why are cows able to grow muscle despite a grass-fed diet?
Mutation in the myostatin gene
108
Define hyperplasia.
Increase in the size of a tissue due to an increase in the number of constituent cells.
109
Define atrophy.
Decrease in the size of a tissue due to a decrease in the size of the constituent cells OR due to a decrease in the number of constituent cells.
110
Define metaplasia.
A change in the differentiation of a cell from one fully differentiated cell type to another fully differentiated cell type.
111
Give an example of a disease that demonstrates metaplasia.
Barrett’s oesophagus - the cells at the lower end of the oesophagus change from stratified squamous cells to columnar.
112
Define dysplasia.
Morphological changes seen in cells in the progression to becoming cancer.
113
Dysplasia is sometimes used to refer to developmental abnormalities. Give an example of this.
Focal cortical dysplasia.
114
What happens to a cell when the telomere gets too short?
It can no longer divide.
115
What is the limit to how many times a human cell can divide called?
The Hayflick limit.
116
What are the effects of ageing on skin? What is the cause of it?
Dermal elastosis is caused by UV-B light causing cross-linking of the proteins, especially collagen, in the dermis.
117
How can osteoporosis be prevented?
Can be prevented by hormone replacement therapy at menopause and calcium/vitamin D supplements.
118
Give 6 examples of ageing in different body parts?
- Wrinkling of skin (dermal elastosis)
- Eyes - cataracts
- Osteoporosis
- Dementia
- Loss of muscle (sarcopaenia)
- Deafness
119
Why does ageing cause osteoporosis?
Lack of oestrogen post menopause leading to increased bone resorption and decreased bone formation
120
What are the effects of ageing on the eyes? What is the cause of it?
Cataracts - caused by UV-B cross-linking of proteins in the lens causing opacity.
121
How can cataracts in old age be prevented and treated?
Can be prevented by wearing sunglasses that cut out UV light.
Can be treated by replacement of the lens with a plastic implant.
122
Cause of sarcopenia in old age?
Reduced levels of growth hormone and testosterone, increased catabolic cytokines in later life.
123
How can sarcopenia be prevented?
Regular exercise including resistance/weight training
124
What causes deafness in old age?
The hair cells in the cochlear do not divide so if they are damaged by high volumes they will die and not be replaced eventually producing deafness.
125
Which one of the following is an example of atrophy?
A. Biceps of a body builder
B. Uterus in pregnancy
C. Brain in dementia
D. Prostate in older age
C. Brain in dementia
126
Give an example of:
a) a dividing tissue.
b) a non dividing tissue.
a) Gut or skin tissue can divide.
b) Brain tissue is non dividing.
127
Why can excision be used as a cure for basal cell carcinoma?
Because BCC only invades locally and doesn’t metastasise.
128
Define carcinoma.
Malignant epithelial neoplasm
129
Why can't excision be used as a cure for leukemia?
Leukemia is systemic, it circulates and always spreads all around the body, therefore excision can’t be used.
130
Suggest a treatment that could be used for leukemia?
Chemotherapy
131
Where can the majority of breast carcinomas spread to?
Breast cancers can spread to the lymph nodes that drain the site of the carcinoma.
132
Which 5 carcinomas commonly spread to bone?
1. Breast
2. Kidney
3. Lung
4. Prostate
5. Thyroid
| PORTABLE
PO=prostate, R=renal, TA=thyroid, B=breast, LE=lung
133
How would you plan for treatment of breast cancer?
- Confirm diagnosis of breast cancer. (eg core biopsy needle)
- Confirm whether it has spread to the axilla to decide whether axillary node clearance is needed. (eg ultrasound of the axilla)
- Confirm whether its has spread to the rest of the body. (eg bone scan)
- If cancer has spread to rest of body, systemic therapy needed. If not, then surgery with, or without axillary lymph node clearance can take place.
134
Even if a tumour is completely excised, what complications may there be? What can be used to treat these patients?
Micro metastases could be present.
Adjuvant therapy (extra treatment given after surgical excision) can be used to suppress secondary tumour formation.
135
What common treatment is given to patients who have undergone lumpectomy?
Radiotherapy to the breast.
136
What secondary treatment is given to breast cancer patients who test oestrogen receptor positive?
adjuvant anti-oestrogen therapy
137
What secondary treatment is given to breast cancer patients who test positive for amplified HER2 gene?
Herceptin (Trastuzumab)
138
Define carcinogenesis.
The transformation of normal cells to neoplastic cells through permanent genetic alterations or mutations.
139
What does oncogenesis cause?
Cause the development of benign and malignant tumours
140
What is the difference between carcinogenic and oncogenic?
carcinogenic = cancer causing
oncogenic = tumour causing
141
What percentage of cancer risk is due to environmental factors? What problems does this have?
85% of cancer risk is environmental
Rest are chance, genetics, micro-organisms
Problems:
- latent interval may last decades
- complexity of environment
- ethical constraints
142
Chemical carcinogens: what types of cancer do polycyclic aromatic hydrocarbons cause?
Skin cancer and lung cancer.
143
Chemical carcinogens: what types of cancer does Beta-Naphthylamine cause?
Bladder cancer.
144
Chemical carcinogens: what can expose people to polycyclic aromatic hydrocarbons?
Smoking cigarettes and mineral oils.
145
Chemical carcinogens: what types of cancer do aromatic amines cause?
Bladder cancer
146
Chemical carcinogens: what types of people are more susceptible to bladder cancer caused by aromatic amine exposure?
People who work in the rubber/dye industry.
147
Chemical carcinogens: what types of cancer do nitrosamines cause?
Gut cancer
148
Chemical carcinogens: what types of cancer do alkylating agents cause?
Leukaemia; the risk is small in humans.
149
Chemical carcinogens: what types of cancer does radioactive iodine cause?
Thyroid cancer (seen during Chernobyl)
150
Name the 5 different classes of carcinogens.
1. Viral.
2. Chemical.
3. Ionising and non-ionising radiation.
4. Hormones, parasites and mycotoxins.
5. Miscellaneous e.g. asbestos and metals.
151
List 4 features of chemical carcinogens.
- No common structural features
- Some act directly
- Most requires metabolic conversion from procarcinogens to ultimate carcinogens
- Enzyme required may be ubiquitous or confined to certain organs
152
What percentage of all cancers are made up by viruses?
10-15% of all cancers are caused by viruses. Most oncogenic viral infections don't results in cancer.
153
Name 5 viral DNA carcinogens and the cancer they cause.
1. Human Herpes Virus 8 (HHV8) - Kaposi sarcoma
2. Epstein Barr Virus (EBV) - Burkitt lymphoma, Nasopharyngeal carcinoma
3. Hepatitis B Virus (HBV) - Hepatocellular carcinoma
4. Human papillomavirus (HPV) - Squamous cell carcinomas of the cervix, penis, anus, head and neck
5. Merkle cell polyomavirus (MCV) - Merkle cell carcinoma
154
Name 2 viral RNA carcinogens and the cancer they cause
1. Human T-lymphotrophic virus (HTLV-1) - Adult T-cell leukemia
2. Hepatitis C Virus (HCV) - Hepatocellular carcinoma
155
Features of radiant energy carcinogens.
- Ionising radiation
- Long term effect
- Skin cancer in radiographers
- Lung cancer in uranium miners (radon gas)
-Thyroid cancer in Ukrainian children
156
What biological agents cause cancer?
- Hormones such as oestrogen (mammary/endometrial cancer) and anabolic steroids (hepatocellular carcinoma)
- Mycotoxins such as aflatoxin B1 (hepatocellular carcinoma)
- Parasites such as Chlonorchis sinensis (cholangiocarcinoma) and Shistosoma (bladder cancer)
157
Give 5 host factors that can affect cancer risk.
1. Ethnicity.
2. Diet.
3. Constitutional factors (gender, age).
4. Premalignant conditions.
5. Transplacental exposure.
158
Host factors - premalignant conditions. Name 3 identifiable local abnormalities which are associated with increased risk of malignancy at that site
- Colonic polyps
- Ulcerative colitis
- Cervical Dysplasia (CIN)
159
Give an example of a situation when transplacental exposure lead to an increase in cancer risk.
The daughters of mothers who had taken diethylstilboestrol for morning sickness had an increased risk of vaginal cancer.
160
A 72 year old man from Singapore has smoked for all his adult life, placing the lit end of his cigarettes in his mouth. 'Reverse smoking' increases the risk of developing which cancer?
Oral cancer
161
A 42 year old woman has recently returned from Uganda. She continued her hobby of fresh water swimming during her trip. She now complains of an itchy rash and a fever. Her doctor suspects she may have schistosomiasis. Left untreated, this parasitic infection increases the risk of which cancer?
Bladder cancer
162
A 51 year old woman with HIV presents to her doctor with multiple purple bruise-like lesions on the skin of her face, torso and limbs. A biopsy confirms the diagnosis of Kaposi sarcoma. Which virus causes Kaposi sarcoma?
Human Herpes Virus 8 (HHV8)
163
A 27 year old man is worried about his alcohol consumption and seeks advice about the effect it might have on his health. Which cancer can be caused by excess alcohol consumption?
Colon cancer
164
A 32 year old man is admitted to hospital with abdominal pain. The pain is in his right iliac fossa. A scan is performed and his appendix is removed by laparoscopic surgery. The appendix is sent for histopathology examination. What is the predominant cell that the pathologist sees on microscopic examination?
Neutrophil polymorphs
165
Pathologist finds a white area of scarring in the myocardium and takes a sample for histology. What is the predominant cell the pathologist will see in the white area?
Fibroblasts
166
What is carcinoma in situ?
When the carcinoma hasn't reached the basement membrane, thus it can't enter the lymphatic system or blood vessels and cannot spread.
167
What do you call carcinoma that has reached the basement membrane?
Invasive carcinoma
168
What is micro-invasive carcinoma?
Carcinoma that has invaded through the basement membrane, but only by a little. Potentially, it could spread through the body, but the risk of it spreading is extremely low.
169
What properties help the carcinoma invade the basement membrane? (intravasation)
- proteases - matrix metalloproteases
- cell motility
170
How does the invasive carcinoma metastasise?
- Tumour invades basement membrane and stroma
- Tumour has to enter system (ie lymphatic vessels, venules, transcoeleomic, arteries though unlikely)
- Tumour cells have to resist immune response in the lymphatic fluid or venous blood as the lymphocytes and macrophages would act against it
- Tumour cells have to exit and invade the extracellular matrix and start growing
171
What is required for a tumour to exit the blood stream (extravasation)?
- Adhesion receptors.
- Collagenases.
- Cell motility.
172
Give 2 promoters of tumour angiogenesis.
1. Vascular endothelial growth factors.
2. Fibroblast growth factors.
173
Give 3 inhibitors of tumour angiogenesis.
1. Angiostatin.
2. Endostatin.
3. Vasculostatin.
174
What 3 mechanisms do tumour cells use to evade host immune defence?
- Aggregation with platelets
- Shedding of surface antigens
- Adhesion to other tumour cells
175
What kind of drugs can be used in targeted chemotherapy?
Monoclonal antibodies (MAB) and small molecular inhibitors (SMI).
MAB can be used to treat constitutive activation of receptors.
SMI can be used to treat overexpression of receptors.
176
Give an example of a malignant tumour that often spreads to the lung.
Sarcoma (via venae cava -> heart -> pulmonary arteries).
177
Give an example of carcinomas that can spread to the liver.
Colon, stomach, pancreas, carcinoid tumours of intestine can spread to the liver via the portal vein.
178
What are the common cancers to metastasise to the bone?
PORTABLE
Po – Prostate
R – Renal
Ta – Thyroid
B – Breast
Le – Lung
179
Conventional chemotherapy: how does vinblastine work?
In order for cells to divide cells have to replicate. Binds to the microtubules and prevents them working.
180
Conventional chemotherapy: how does etoposide work?
In order for cells to divide cells have to replicate. Etoposide inhibits topoisomerase II
181
Conventional chemotherapy: how does ifosamide work?
Ifosamide binds directly to DNA
inhibits DNA synthesis by cross linking
182
Conventional chemotherapy: how does cisplatin work?
Cisplatin binds directly to DNA and inhibits DNA synthesis by cross linking
183
Give an advantage and a disadvantage of conventional chemotherapy.
Advantage: works well for treatment against fast dividing tumours e.g. lymphomas.
Disadvantage: it is non selective for tumour cells, normal cells are hit too; this results in bad side effects such as diarrhoea and hair loss.
184
What type of tumours are conventional chemotherapy good for? List 5 examples
Fast dividing tumours
- germ cell tumours of testis
– acute leukaemias
– lymphomas
– embryonal paediatric tumours
– choriocarcinoma
185
What type of tumour is conventional chemotherapy not good for?
Slow dividing tumours - some tumour cells increase by mitigating apoptosis.
186
What is the histogenetic classification of neoplasms?
Histopathological tests specify tumour type by determining the cell of origin of a tumour.
187
Name two genetic drivers of carcinogenesis?
- Proto-oncogenes: genes that promote cell growth and survival
- Tumour suppressor genes: genes which inhibit cell growth and proliferation
188
How would you diagnose bronchial carcinoma (small and non small)?
- Sputum
- Radiology-guided biopsy
- Bronchoscopy
189
What is tumour grading and staging?
Tumour grading:
How much the tumour cells resemble their normal counterparts
Tumour staging:
How much the tumour has spread. Involves assessment of lymph nodes, extent of spread to other organs and tissues.
190
What is the name of a malignant tumour of straited muscle?
rhabdomyosarcoma
191
What term describes a cancer that has not invaded through the basement membrane?
Carcinoma in situ
192
What is the name of a benign tumour of glandular epithelium?
Adenoma
193
What is the name of a benign tumour of fat cells?
lipoma
194
What is the name of a malignant tumour of glandular epithelium?
adenocarcinoma
195
True or False: Ovarian cancer commonly spreads in the peritoneum.
True
196
A 27 year old woman presents to the Accident and Emergency Department with abdominal pain. She says that it started the day before when she felt non-specifically unwell and felt pain in the middle of her abdomen. She slept rather fitfully and woke up this morning with a more severe pain that had moved to her right groin region. A diagnosis of acute appendicitis is made and her appendix is removed during a laparoscopic operation. The appendix is sent to the Department of Histopathology where it is sampled and microscopic slides are produced. The Consultant Histopathologist looks at the lumen of the appendix on a high power lens on her microscope.
What is the predominant type of inflammatory cell that she sees?
- Eosinophil
- Lymphocyte
- Macrophage
- Mast cell
- Neutrophil polymorph
Neutrophil polymorph - acute inflammation
197
Define neoplasm
An autonomous, abnormal, persistent new growth.
198
What are the 3 commonest causes of cancer death in males?
1. Lung cancer
2. Prostate cancer
3. Bowel cancer
199
What are the 3 commonest causes of cancer death in women?
1. Lung cancer
2. Breast cancer
3. Bowel cancer
200
What is the structure of a neoplasm?
1. Neoplastic cells.
2. Stroma.
201
Describe neoplastic cells.
- Derived from nucleated cells.
- Usually monoclonal
- Growth pattern and synthetic activity is related to the parent cell.
202
Describe the stroma of a neoplasm.
- Connective tissue composed of fibroblasts and collagen; it is very dense.
- There is a lot of mechanical support and blood vessels provide nutrition
203
What is essential for neoplasm growth?
Angiogenesis.
204
Why does central necrosis occur in neoplasm?
The neoplasm grows quickly and outgrows its vascular supply.
205
What are the two ways in which neoplasms can be classified?
1. Behavioural classification.
2. Histogenetic classification.
206
What are the 5 features of a benign neoplasms.
- non invasive, localised
- slow growth rate
- well-circumscribed or encapsulated
- low mitotic activity
- close resemblance to normal tissue
207
What is the behavioural classification of neoplasms?
Neoplasms can be classified as benign, malignant or borderline. Borderline tumours (e.g. some ovarian lesions) defy precise classification.
208
List 4 histological features of benign neoplasms.
- Nuclear morphometry often normal
- Necrosis rare
- Ulceration rare
- Growth on mucosal surfaces usually exophytic
209
What are the 5 complications of benign neoplasms?
- Pressure on adjacent structures
- Obstruct flow
- Produce hormones
- Transform to malignant neoplasm
- Anxiety
210
What are the 5 features of malignant neoplasms?
- Invasive
- Metastases
- Rapid growth rate
- Variable resemblance to normal tissue
- Poorly defined or irregular border
211
List 5 histological features of malignant neoplasms.
- Hyperchromatic nuclei
- Pleomorphic nuclei
- Increased mitotic activity
- Necrosis and ulceration common
- Growth on mucosal surfaces and skin often endophytic
212
List 7 complications of malignant neoplasms?
- Destruction of adjacent tissue
- Metastases
- Blood loss from ulcers
- Obstruct flow
- Produce hormones
- Paraneoplastic effects
- Anxiety and pain
213
What is a papilloma?
A benign neoplasm of non-glandular non-secretory epithelium
214
What is an adenoma?
Benign tumour of glandular or secretory epithelium.
215
What are carcinomas of glandular epithelium called?
adenocarcinomas
216
What is a leiomyoma?
A benign smooth muscle neoplasm.
217
What is a neuroma?
A benign neoplasm of nerves.
218
What is a chondrosarcoma?
A malignant neoplasm of cartilage.
219
What is a liposarcoma?
A malignant neoplasm of adipose tissue.
220
What is a melanoma?
A malignant neoplasm of melanocytes.
221
What is a lymphoma?
A malignant neoplasm of lymphoid cells.
222
What is a mesothelioma?
A malignant neoplasm of mesothelial cells.
223
Carcinomas and sarcomas are further classified according to the degree of differentiation. Is a carcinoma/sarcoma with a close resemblance to normal tissue classified as well differentiated or poorly differentiated?
A carcinoma/sarcoma with a close resemblance to normal tissue is classified as well differentiated. These types of neoplasms are low grade and have a better prognosis.
224
What is the neoplasm called if its cell of origin is unknown?
Anaplastic
225
What are teratomas?
A teratoma is a rare type of neoplasm that may contain immature or fully formed tissue, including teeth, hair, bone and muscle.
226
A 43 year old woman is referred to a gynaecologist with a history of pain during sexual intercourse and vaginal bleeding after intercourse and in between her periods. The gynaecologist takes a biopsy of the ectocervix which reveals a primary malignant neoplasm. What is the likely diagnosis?
Squamous cell carcinoma
- As the ectocervix is lined by stratified squamous epithelium. Malignancy of stratified squamous epithelium is squamous cell carcinoma.
227
A 46 year old woman undergoes an elective hysterectomy to treat severe menorrhagia (heavy period). The pathologist examining the specimen reports the presence of multiple benign smooth muscle neoplasms within the myometrium. What are these neoplasms called?
Leiomyomas
228
A 72 year old man undergoes a biopsy of his colon. The biopsy reveals a disease process that is not neoplastic or due to an infection. What is the likely abnormality?
Granuloma (chronic inflammation)
229
What are the 7 hallmarks of cancer?
- Growth self-sufficiency
- Evade apoptosis
- Ignore anti-proliferative signals
- Limitless replication potential
- Sustained angiogenesis
- Invade tissues
- Escape immune surveillance
230
What is cancer immunosurveillance?
When the immune system recognises and destroys transformed cells, this is an important host protection process.
231
What is cancer immunoediting?
Immune responses can change tumours to be hidden from recognition by the immune system and tumours can promote immune suppression
232
What are the two types of tumour antigens and where are they found?
1. Tumour specific antigens
- Only found on tumour cells.
- As a result of point mutations or gene rearrangement
- Derive from viral antigens
2. Tumour associated antigens
- Found on both normal and tumour cells, but are overexpressed on cancer cells
- Developmental antigens which become derepressed. (CEA)
- Differentiation antigens are tissue specific
- Altered modification of a protein could be an antigen
233
List 5 evidence for human tumour immunity
- Spontaneous regression
- Regression of metastases after removal of primary tumour
- Infiltration of tumours by lymphocytes and macrophages
- Lymphocyte proliferation in draining lymph nodes
- Higher incidence of cancer after immunosuppression, immunodeficiency (AIDS, neonates), aging, etc.
234
What is tumour escape?
Immune responses change tumours such that tumours will no longer be seen by the immune system.
235
What is immune evasion?
Tumours change the immune responses by promoting immune suppressor cells
236
How can we kill tumours without killing normal cells?
To induce an immune response against the tumour that would discriminate between the tumour and normal cells: Adaptive immunity
237
What are the two types of immunotherapy?
- Active immunotherapy
- Passive immunotherapy -
238
List 6 examples of active immunotherapy.
Vaccines!
- Killed tumour vaccine
- Purified tumour antigens
- Professional APC-based vaccines
- Cytokine- and costimulator-enhanced vaccines
- DNA vaccines
- Viral vectors
239
List 2 examples of passive cancer immunotherapy.
- Adoptive Cellular Therapy (T cells)
- Anti-tumour Antibodies (Her-2/Neu, CD20, CD10, CEA, CA-125, GD3 ganglioside)
240
Features of cell-based therapy.
- Cellular therapies can be used to activate a patient's immune system to attack cancer.
- They can also be used as delivery vehicle to target therapeutic genes to attack the tumour
- They do not act directly on cancer cells. Instead, they work systemically to activate the body's immune system.
241
What 2 cell types are commonly used for cell-based therapy?
- Dendritic cells
- T cells
242
Features of dendritic cells.
- Antigen presenting cells
- Found throughout the body (0.1-0.5%)
- Interstitial cells (Liver, heart, liver), Langerhans cells of the epidermis.
- Detect and chew up foreign "invader" proteins and then "present" piece of the invaders on their surface.
243
How would you create a dendritic cell cancer vaccine?
To make a DC vaccine, the blood of the cancer patient is collected and enriched to increase the population of DC.
244
How would you create a T cell cancer vaccine?
| eg for melanoma
- Tumour biopsy
- Isolation: tumour fragments and tumor infiltrated lymphocytes (TILs) are isolated
- Cultivation: TILs propagated on tumour fragments and cultivated
- Expansion: expansion of melanoma reactive TILs
- T cell infusion
245
What is tumour hypoxia?
Hypoxia is a prominent feature of malignant tumours. The inability of the blood supply to keep up with growing tumour cells can lead to hypoxic tumour cells that have adapted to low oxygen
246
What are the problems with tumour hypoxia?
Tumour hypoxia usually means poor patient prognosis.
- Stimulates new vessel growth
- Suppresses immune system
- Resistant to radio- and chemotherapy (repopulate the tumour)
- Increased tumour hypoxia after therapy
247
Why is hypoxia a prominent feature of a lot of malignant tumours?
Malignant tumours grow rapidly and so outgrow their blood supply
248
What are the 3 types of vaccines traditionally used?
- whole-killed
- toxoid
- live attenuated
249
Define passive immunisation.
The administration of pre-formed “immunity” from one person or animal to another person
250
Limitation of passive immunisation.
Only humoral (antibody) mediated
(will not work if cell mediated!)
251
What are the advantages and disadvantages of passive immunity
Advantages
- Gives immediate protection
- Effective in immunocompromised patients
Disadvantages
- Short-lived
- Possible transfer of pathogens
- “Serum sickness” on transfer of animal sera
252
Give 4 examples of passive immunisation
Specific Immunoglobulin (Ig)
- Human Tetanus Ig (HTIG) Rapid protection of exposed individuals
- Human Rabies Specific Ig - Used after exposure to rabies to give protection until vaccine becomes effective
- Human Hepatitis B Ig (HBIG)
- Varicella Zoster Ig (VZIG)
253
What are the 3 main approaches to making a vaccine for active immunisation?
- Using a whole virus or bacterium
- Using parts that trigger the immune system
- Using just the genetic material
254
List 3 features of the whole microbe vaccine
- Bacteria or viruses grown in vitro and inactivated using agents such as formaldehyde or Β-propionolactone.
- Non-living vaccines do not cause infection, but the antigens contained in it induce an immune response that protects against infection – by non-self antigen recognition.
- Non-living vaccines can also be cell-free toxoids - inactivated toxins
255
List 4 problems and limitations of whole killed vaccines.
1. The organisms must be grown to high titre in vitro (viruses and some bacteria difficult/expensive to grow in the lab)
2. Whole pathogens can cause excessive reactogenicity (i.e., adverse reactions, excessive immunological responses)
3. Immune responses are not always close to the normal response to infection, e.g., no mucosal immunity, no CD8 Tc responses
4. Usually need at least 2 shots
256
Gives examples of bacteria that have been used in active vaccine.
- Diphtheria - formaldehyde treated toxin - rendered a non-toxic “toxoid”
- Tetanus - toxoid, causes muscle contractions/spasms - treat purified toxoid in the lab with formalin leading to loss of toxicity but NOT epitopes
- Pertussis (whooping cough) - killed whole bacteria (Bordetella pertussis) given with the two above as DTP. 3-doses. UK has now moved to acellular pertussis (aP)
- Cholera - heat-killed bacteria (Vibrio cholerae)
257
Give examples of viruses that have been used in active vaccine.
Polio vaccine (Salk) - inactivated virus-IPV
Influenza vaccine - inactivated virus
Hepatitis A vaccine - inactivated virus
Rabies vaccine - inactivated virus
SARS-Co-V2 (Valneva) - inactivated virus
258
How do Live Attenuated Vaccines work?
The organisms replicate within the host and induce an immune response which is protective against the wild-type organism but does not cause disease.
259
Define attenuation.
Where an organism is cultured in such a way that it does not cause disease when inoculated into humans.
It has lost its pathogenicity but retains its antigenicity – (i.e., shape).
260
List 4 advantages of Live Attenuated Vaccines.
1. Immune response more closely mimics that following real infection because its not fixed – no shape change.
2. Better immune response so lower doses are required, so the scale of in vitro growth needed is lower.
3. Route of administration may be more favourable (oral).
4. Fewer doses may be required to provide protection.
261
Problems and limitations of live attenuated vaccines.
1. Often impossible to balance attenuation and immunogenicity
2. Reversion to virulence
3. Transmissibility
4. Live vaccines may not be so attenuated in immunocompromised hosts
262
Give 2 examples of live attenuated bacterial vaccines.
Bacille Calmette-Guérin (BCG) Mycobacterium bovis grown over many passages in vitro. Gives some protection against TB (tuberculosis)
Salmonella typhi - temperature sensitive strain given orally.
263
Give 3 examples of viral live attenuated vaccines.
Poliomyelitis (Sabin) - widely used to bring polio to the brink of eradication
Vaccinia virus - used in billions of doses to eradicate smallpox due to cross-reactivity between itself and the variola virus
Measles, Mumps and Rubella - 3 given together as MMR
264
In this day and age, why do so many pathogens still do not have a vaccine? List 4 possible reasons.
- Pathogen too difficult to grow
- Killed pathogen not protective (shape change)
- Impossible to obtain attenuated and suitably immunogenic strain
- Too many strains causing disease etc.
265
Recombinant proteins are a novel approach in creating vaccines. How are they created?
Genetically engineered and produced from bacteria, yeast, insect or mammalian cells
266
What are the advantages and disadvantages of recombinant protein vaccines
Advantages:
Avoid the problem of having to grow pathogen in vitro
Disadvantages:
Major difficulties are finding a protein or proteins that are protective and generate a strong enough immune response
267
Give examples of recombinant proteins
Hepatitis B Surface Antigen
HPV vaccines Cervarix and Gardasil (HPV16 and 18)
SARS-Co-V2 – Novavax (recombinant spike protein produced by moth cells in culture, these are purified, assembled into a synthetic nanoparticle for injection – 14 spike proteins per particle)
268
What are synthetic peptides
Peptides synthesized directly using a machine - avoids the need for pathogen growth
269
Problems with synthetic peptides.
Difficulties
* Identifying protective epitopes
* Inducing a strong response
* Inducing a broad response
270
What are live attenuated vectors – viral vector
Composed of a safe living attenuated viruses that have inserted genes encoding foreign antigens, which are displayed to the immune system.
271
How do viral vectors work?
When injected the virus is taken up by an APC, the viral DNA is released and enters the nucleus. The viral DNA is transcribed to mRNA and translated to a protein – some of this spike protein is presented with MHC II on the cell surface as a foreign antigen. This is recognised by T-cells and initiates an immune response to the spike protein.
The virus is replication deficient and can not replicate in human cells limiting its spread.
272
What are DNA vaccines?
A mammalian plasmid containing DNA that encodes for the foreign protein of interest is injected directly.
This requires a lipid nanocarrier to get the DNA into a human cell. The DNA goes to the nucleus, gets transcribed and the foreign protein expressed with MHC to stimulate the immune response.
273
Advantages and disadvantages of DNA vaccines.
* Avoid the need to grow the pathogen, viral vector
* No live organism involved
* DNA is cheap to produce
* Problem is often poor immunogenicity
274
What are mRNA vaccines
mRNA of the target foreign protein is synthesized in vitro. It is complexed with lipid nanoparticles that stabalise and protect the mRNA from degradation and allow the mRNA to cross the plasma membrane.
The mRNA is translated in the cytoplasm and the protein presented on the surface of the cell with MHC
Stimulating the immune response.
275
Advantages of mRNA vaccines
* Avoid the need to grow the pathogen, viral vector
* No live organism involved
* mRNA is relatively cheap to produce
* Quick to make new variations of vaccine
276
Features of T-Independent Antigens
Bacterial capsular polysaccharides cannot be processed and presented on MHC class II
No T cell help
Antibody response of low magnitude
Low affinity
Predominantly IgM
Little or no boosting on secondary exposure
Infants respond especially poorly and are major target group for these vaccines
Haemophilus influenzae
Neisseria meningitidis
Streptococcus pneumoniae
277
Examples of conjugate vaccines.
Neisseria meningitidis type C
polysaccharide-protein conjugate vaccine
Streptococcus pneumoniae
23-valent polysaccharide vaccine or 7-valent conjugate
Haemophilus influenzae type B (HiB)-Polysaccharide protein conjugate vaccine
278
What are recent changes to the vaccination programme in children?
The addition of a pneumococcal conjugate vaccine (PCV) at 2, 4 and 13 months of age;
A dose of MenC vaccine at 3 and 4 months;
A booster dose of Hib and MenC vaccine (given as a combined Hib/MenC vaccine) at 12 months of age.
HPV vaccine for teenage girls and boys soon
BCG no longer routinely given to teenagers. Targeted on at risk infants.
279
Why do people not trust vaccines?
Misinformation and hearsay on the internet/social media that are not based on any science
Religion – its un-natural
Studies linking immunisation with contraction of other diseases/conditions
Japan – HPV vaccine with neurological disorders
UK – MMR and autism
280
Describe innate immunity
- 1st line of defence
- Instinctive
- Non-specific does not depend on lymphocytes
- Present from birth
- Slow response
- No memory
- Provides barrier to antigen
281
Describe adaptive immunity.
Specific ‘Acquired/learned’ immunity, requires lymphocytes, antibodies.
Response specific to antigen
Learnt behaviour
Memory to specific antigen
Quicker response
282
What are both innate and adaptive immunity made up of?
Cells and soluble factors (humoral)
283
What is haematopoiesis?
The commitment and differentiation processes that leads to the formation of all blood cells from pluripotent haematopoietic stem cells.
284
Where does haematopoiesis take place?
Bone marrow (10^11 new cells each day)
285
How do the pluripotent haematopoietic stem cells decide what to differentiate into?
Stem cells in the bone marrow are stimulated by colony stimulating factors (soluble proteins) that bind to receptors on the stem cell.
286
What 2 are the two pathways the pluripotent haematopoietic stem cells can split into?
1. Myeloid pathway
2. Lymphoid pathway
287
Which 3 types of cells are polymorphonuclear leukocytes?
- Neutrophils (70% of wbcs in body)
- Eosinophils
- Basophils
288
Which 3 types of cells are mononuclear leukocytes?
- Monocytes: differentiates into macrophages when entering tissue.
- T-cells
- B-cells: differentiates into plasma cells which produce antibodies.
289
What process are mast cells important in?
Allergic reactions - have histamines
290
What are natural killer cells important for? (Type of T cell)
Anti tumour responses
291
What are dendritic cells important for?
Immune surveillance
292
Which 3 soluble factors make up the immune system?
- Complement
- Antibodies
- Cytokines and chemokines
293
Define complement.
Group of ~20 serum proteins secreted by the liver that need to be activated to be functional.
294
What are the 3 modes of actions of complement?
1. Direct lysis
2. Attract more leukocytes to site of infection
3. Coat invading organisms
295
What are antibodies?
Antibodies (also called immunoglobulins) are soluble glycoproteins that recognize and bind antigens, specifically.
296
Antibodies (Ab) can also be called immunoglobulins (Ig) What are the 3 features of immunoglobulins?
- soluble
- secreted
- bound to B cells as part of B-cell antigen receptor
297
What are the 5 distinctive classes of Ig?
IgG (IgG1-4)
IgA (IgA1 & 2)
IgM
IgD
IgE
298
Describe the basic structure of an antibody (IgG).
Antibodies have a basic structure of four polypeptide chains – two identical light chains and two identical heavy chains. Each chain contains a variable region (fab region).
The chains are held together by disulphide bonds.
The C-terminal (Fc) regions of the light and heavy chains form the constant regions which determine the effector functions of an antibody.
299
In an antibody what does the Fc region and Fab region bind to?
Fc region binds to receptors on the surface of wbcs.
Fab region bind to non-self elements, they are very specific.
300
Which is the most predominant Ig in the human serum?
IgG: accounts for 70 - 75% of Igs in human serum
301
List 5 features of IgM.
- Accounts for 10% of Igs in serum.
- Pentamer, formation requires J chain.
- Mainly found in blood – too big to cross endothelium.
- Mainly primary immune response, initial contact with Ag.
(First responder during immune response)
- The monomeric form (mIgM) is present as an antigen-specific receptor on B cells - which is important for the adaptive immune response.
302
List 3 features of IgA
- Accounts for 15% of Igs in serum
- In humans 80% of serum IgA is as a monomer (in most animals serum IgA is a dimer)
- The predominant Ig in mucous secretions such as saliva, colostrum, milk, bronchiolar & genitourinary secretions
Called Secretory IgA (sIgA)
sIgA is held together with a J chain and a secretory component
303
List 2 features of IgD.
Accounts for 1% of Ig in serum
A transmembrane monomeric form (mIgD) is present on mature B cells
304
List 5 features of IgE
Accounts for only ~0.05% of Ig in serum
Basophils and Mast Cells express an IgE-specific receptor that has high affinity for IgE
Basophils and Mast Cells are continually saturated with IgE
Binding Ag triggers release of histamine by these cells
Associated with hypersensitivity allergic response and defence against parasitic infections
305
What is an epitope?
Each antibody binds to a restricted part of the antigen called an epitope.
306
What are the functions of an antibody?
Antibodies acts as an adaptor that links a microbe to a phagocyte.
1. Neutralise toxins.
2. Opsonisation.
3. Activate classical complement system.
307
What are cytokines?
Proteins secreted by immune and non-immune cells.
308
Name 4 types of cytokines.
1. Interferons.
2. Interleukins.
3. Colony stimulating factors.
4. Tumour necrosis factors.
309
Cytokines: Function of interferons (IFN)
Induce a state of antiviral resistance in uninfected cells & limit the spread of viral infection
310
Cytokines: Function of interleukins (IL)
- Can be pro-inflammatory (IL1) or anti-inflammatory (IL-10)
- Can cause cells to divide, to differentiate and to secrete factors
- Produced by many cells, over 30 types
311
Cytokines: Function of Colony Stimulating Factors (CSF)
- Involved in directing the division and differentiation on bone marrow stem cells – precursors of leukocytes.
312
Cytokines: Function of Tumour Necrosis Factors (TNFa & b)
Proinflammatory molecules. Mediate inflammation and cytotoxic reactions.
313
What are chemokines?
Chemotactic cytokines
Group of approx 40 proteins that attract leukocytes to sites of infection from the bloodstream into the tissues or lymph organs by binding to specific receptors on cells
314
What are the 4 subclasses of chemokines?
CXCL – mainly bind to neutrophils
CCL – monocytes, lymphocytes, eosinophils, basophils
CX3CL – mainly T lymphocytes & NK Cells
XCL – mainly T lymphocytes
315
What is innate immunity composed of?
- Physical and chemical barriers
- Phagocytic cells (neutrophils and macrophages)
- Blood proteins (complement, acute phase)
316
Give examples of physical and chemical barriers used in innate immunity?
- Lysozymes in tears
- Skin
- Low pH and commensals of vagina
- Mucociliary escalator
- Gastric acid
317
Sometimes physical barriers are breached leading to tissue damage (trauma) or infection. This will induce an inflammatory response. What response is the body aiming for during inflammation?
- Coagulation: stop bleeding.
- Acute inflammation (leukocyte recruitment).
- Kill pathogens, neutralise toxins, limit pathogen spread.
- Phagocytosis: clear pathogens/dead cells.
- Proliferation of cells to repair damage.
- Remove blood clot – remodel extracellular matrix to maintain homeostasis.
318
What are the 3 hallmarks of inflammation?
1. Increased blood supply
2. Increased vascular permeability
3. Increased leukocyte transendothelial migration ‘extravasation’
319
Name 3 pattern recognition receptors (PRR) that can sense microbes?
1. Toll-like receptors (TLR).
2. Lectin receptors.
3. Scavenger receptors.
320
What kind of immunity are PRR’s and PAMP’s associated with?
Innate immunity.
321
What are PRR’s a receptor for?
PAMP's (on microbes)
322
What happens when a PAMP binds to a PRR?
The innate immune response and inflammatory response is triggered.
323
What are C-Type lectin receptors?
Expressed by Macrophages and DC, can recognise foreign carbohydrates.
324
What are scavenger receptors?
They are a very large family of receptors - They mainly recognise foreign lipids on bacteria. (ie LPS in Gram -ve bacteria)
325
What are toll-like receptors?
TLRs recognise Pathogen-Associated Molecular Patterns expressed by microbes. Different TLRs activate different signalling cascades depending on the pathogen being detected.
326
TLRs and their targets
TLR2: Gram positive bacteria and mycobacteria (inc fungi)
TLR4: Gram negative bacteria and lipopolysaccharides
TLR5: Bacteria and flagellin
TLR7: Single-strand RNA
TLR9: Non-methylated DNA
327
What are the 3 different activation pathways that make up the complement system? How are they activated?
1. Classical: Antibody bound to microbe.
2. Lectin: Mannose binding lectin bound to microbe.
3. Alternative: Complement bound to microbe.
328
Which complement plasma proteins are chemoattractants that recruit leukocytes to the site of infection.
C3a and C5a.
329
Which complement plasma proteins have opsonic properties (insert itself into the membrane of bacterium "coating it" to increase its susceptibility to ingestion by phagocytosis) when bound to a pathogen?
C3b, C4b.
330
Which complement plasma proteins make up the membrane attack complex (MAC) and are responsible for the cytolytic function?
C5b-9
331
What is extravasation?
Leukocyte (WBC) migration across the endothelium.
332
What do macrophages at the tissues secrete to initiate extravasation?
TNF alpha.
333
Describe the process of extravasation.
1. Macrophages at tissues release TNF alpha.
2. The endothelium is stimulated to express adhesion molecules and to stimulate chemokines.
3. Neutrophils bind to adhesion molecules; they roll, slow down and become stuck to the endothelium.
4. Neutrophils are activated by chemokines.
5. Neutrophils transmigrate through the endothelium to the tissue to help fight infection.
334
Describe the process of phagocytosis?
1. Pathogen binds to neutrophil/macrophage.
2. Engulfment of pathogen.
3. Phagosome formation.
4. Lysosome fusion - phagolysosome.
Pathogen is destroyed.
335
What are the two killing pathways present in neutrophils and macrophages?
- O2 dependent
- O2 independent
336
What is the role of NO in killing pathogens in O2 dependent killing?
NO leads to vasodilation and increased extravasation. This means more neutrophils etc pass into the tissues to destroy pathogens.
337
Why can superoxides be used to destroy pathogens in O2 dependent killing?
Superoxides can be converted to H2O2 and then to hydroxyl free radicals. Hydroxyl free radicals are highly reactive and can destroy pathogens.
338
What mechanisms or cells are involved in O2 independent killing?
Enzymes: Lysozymes
Proteins: Defensins, TNF
pH
339
What are the advantages adaptive immunity have over innate immunity?
- Microbes can evade innate immunity
- Intracellular viruses and bacteria ‘hide’ from innate immunity
- Adaptive immunity have memory to specific antigen – ‘seen it before so faster response’
340
What are the two types of adaptive immunity?
- Cell Mediated - T cells - intracellular microbes
- Humoral (Ab) - B cells - extracellular microbes
341
In which primary lymphoid tissue do T cells mature?
Thymus
342
In which primary lymphoid tissue do B cells mature?
Bone marrow.
343
Give examples of secondary lymphoid tissue.
Spleen, lymph nodes, mucosa associated lymphoid tissue - MALT.
344
In which primary lymphoid tissue do antigen present cells mature?
Bone marrow
345
Which cells are involved in cell-mediated immunity?
1. Antigen Presenting Cells (APC)
- Macrophages
- Dendritic Cell
- B cells
2. T cells
346
What do T lymphocytes respond to?
T lymphocytes only respond to intracellular presented antigens, they do NOT respond to soluble antigens.
347
What is T cell selection?
T cell selection refers to how T cells that recognise self are killed in the foetal thymus as they mature
348
T cell receptors only recognise foreign antigens under what conditions?
T Cell Receptor (TCR) recognises foreign antigens in association with Major Histocompatibility Complex (MHC)
349
What do Major Histocompatibility Complexes MHCs do?
Major Histocompatibility Complex (MHC) display peptides from self OR non-self proteins
350
Whare the 2 types of MHC?
MHC I and MHC II
351
Which cells express MHC1?
All nucleated cells express MHC1. e.g. a virus infected or cancer cell would express MHC1.
352
Which cells express MHC2?
Antigen presenting cells ONLY e.g. macrophages, B cells, dendritic cells.
353
Which MHC would an intracellular antigen (endogenous) lead to the expression of?
MHC1.
354
Which MHC would an extracellular antigen (exogenous) lead to the expression of?
MHC2.
355
What type of T cell binds to MHC1?
Cytotoxic T cells (CD8).
356
What type of T cells binds to MHC2?
Helper T cells (CD4).
357
Intracellular signalling happens when a helper T cell is bound to a T cell receptor. Which interleukin is secreted?
IL-2. This then binds to an IL-2 receptor on the T cell and produces a positive feedback mechanism (clonal expansion) leading to division, differentiation, effector functions, and memory.
358
What happens when naive T cells become activated?
Naive cell -> CD4 and CD 8
Any infected cell presents Ag with MHC I to a CD8 T cell
CD 8: Kills intracellular pathogens directly (cytotoxic T cells)
APC presents Ag with MHC II to a naïve CD4 T cell.
If microenvironment has a lot of IL-12, it forms TH1 -> secretes IFNγ and IL-2 -> helps kill intracellular pathogens
If no IL-12, it forms TH2 -> secretes IL-4,5,10, Antibody production
359
What is the function of T helper 1 (CD4)?
It helps the immune response against intracellular pathogens. Secretes cytokines.
360
What is the function of T helper 2 (CD4)?
It helps produce antibodies against extracellular pathogens. Secretes cytokines.
361
What is the function of Cytotoxic T cell (CD8)?
It can kill cells directly by binding to antigens; they can form proteolytic granules & releases perforins and granulysin they also induce apoptosis.
362
How many antibodies can each B cell make?
Each B cell can only make 1 antibody. This 1 antibody can only bind to 1 epitope.
363
What do B cells express?
B cells express membrane bound Ig (IgM or IgD monomer)
364
What happens to B cells that recognise ‘self’?
They are killed in bone marrow.
365
B cells can function as an APC. Describe the process of a T helper cell binding to a B cell.
A B-cell antibody binds an antigen -> phagocytosis -> epitope is displayed on the surface of the B-cell bound to an MHC2 -> TH2 binds to B-cells -> cytokine secretion induces B-cell clonal expansion -> differentiation into plasma cells and memory B cells.
366
Give examples of PAMPs in bacteria, virus, and parasites.
Bacteria:
- Peptidoglycan (PGN)
- Lipoproteins
- DNA
- Flagellin
- Lipopolysaccharide (LPS)
Virus:
- Coat protein
- Nucleic acid
Parasite:
- GPI anchor
367
What are Damage associated molecular patterns (DAMPs)
Endogenous molecules created to alert the host to tissue injury and initiate repair.
368
Why do we not recognise our own DNA and RNA and mount an innate response?
Our DNA and RNA is normally located where our pattern recognition receptors (PRRs) cannot access it
369
TLRs and their targets
TLR2: Gram positive bacteria and mycobacteria (inc fungi)
TLR4: Gram negative bacteria and lipopolysaccharides
TLR5: Bacteria and flagellin
TLR7: Single-strand RNA
TLR9: Non-methylated DNA
370
What is the main function of TLR’s?
TLR’s send signals to the nucleus to secrete cytokines and interferons. These signals initiate tissue repair. Enhanced TLR signalling = improved immune response.
371
Membrane bound PRR: Where could mannose receptors be found?
on macrophages (fungi)
372
What is the main function of RLR’s?
RLR’s detect intracellular double stranded RNA. This triggers interferon production and so an antiviral response.
373
Name 3 receptors that make up the PRR family.
Toll-like receptors (TLR).
Nod-like receptors (NLR).
Rig-like receptors (RLR).
374
What is the main function of NLR’s?
NLR’s detect intracellular microbial pathogens. They release cytokines and can cause apoptosis if the cell is infected.
375
What is the damage chain reaction?
Harmful stimulus leads to tissue damage, this causes the release of DAMPs and release TLRs and proinflammatory cytokine production. Inflammation will lead to tissue damage and lead to chain reaction of DAMP release.
376
What high levels of DAMPs associated with?
Many inflammatory and autoimmune diseases as well as atherosclerosis and cancer.
377
What is the cytokine storm?
- Profound increase in cytokines, chemokines & interferons
- Causes severe inflammation and tissue damage
- Role in sepsis, influenza, severe COVID-19 pathogenesis, etc.
- Induction due to:
1. genetic makeup of the host
2. persistence of the pathogen (evasion mechanisms)
378
What are the 2 main strategies of immunomodulation?
1. Agonists (enhance TLR signalling):
- adjuvant effect (used with a primary treatment) promoting protective responses e.g. vaccines
- immune stimulators
- Modify adaptive immune response: bias Th and Treg responses
- side-effects: potentially enhance inflammation
2. Antagonists (inhibit TLR signalling):
- block binding of ligands or protein-ligand complexes to receptors / interfere with intracellular adaptor molecules of common signalling pathways
- sepsis syndromes, inflammation, arthritis, etc
- side-effects: potentially allow pathogen outgrowth, mutation, etc
379
What is type I hypersensitivity?
Type I hypersensitivity is an immediate reaction to environmental antigens mediated via IgE
380
What is atopy?
Atopy is an inherited trait for Type 1 hypersensitivity
381
What are allergens?
Allergens are antigens that trigger allergic reactions
382
What are the main steps in a Type I hypersensitivity reaction?
1. Sensitisation
2. Mast cell degranulation
3. Early phase response
4. Late phase response
383
Define sensitisation
Sensitisation is the term to describe the initial event that lead to the specific IgE being developed for that allergen.
384
What occurs during sensitisation?
1. Body is exposed to allergens.
2. Allergens are taken up by APCs, processed and expressed by MHC II where they are presented to naive T cells.
3. Naive T cells differentiate into Th2
4. Th2 cells produce IL-4 and IL-13 which activate B cells and induce them to class switch to produce IgE.
5. IgE can circulate in blood and bind to mast cells and basophils in various tissues in our body.
385
What are the differences in structure between IgG and IgE?
IgE has 4 constant domains, while IgG only has 3 constant domains.
IgG has a hinge region.
IgE is more heavily glycosylated.
386
What are the 3 main body surfaces that come into contact with allergens?
- Skin
- GI tract
- Lung
387
What happens during mast cell degranulation?
1. Upon subsequent re-exposure to the allergen, the antigens can bind to the IgE on the surface of the mast cells.
2. Cross linkage of the receptors can occur through the IgEs that are bound to them.
3. This leads to mast cell degranulation and stimulates the synthesis of new cytokines.
388
What happens during early phase response?
1. Early phase mediators such as histamine are released.
2. Histamine causes vasodilation, increased vascular permeability and broncho-constriction, causing symptoms of allergy (itch, flushing, rash, angioedema and wheeze).
389
Which receptor of histamine is mainly responsible for mediating allergic reactions?
H1 receptor
390
Clinical use of tryptase during type 1 hypersensitivity?
Diagnostic purposes, tryptase levels spike following allergic reaction.
391
List the clinical manifestations of allergy?
- Itchiness
- Runny nose
- Hives
- Sneezing
- Red/watery eyes
- Trouble breathing
392
Systemic type 1 hypersensitivity reaction would lead to what clinical syndrome?
Anaphylaxis
393
Type 1 hypersensitivity reaction to airways would lead to what clinical syndrome?
- Asthma (lower airways)
- Rhinitis (upper airways)
394
Type 1 hypersensitivity reaction to eyes would lead to what clinical syndrome?
Allergic conjunctivitis
395
Type 1 hypersensitivity reaction to skin would lead to what clinical syndrome?
- Urticaria
- Angioedema
- Atopic eczema
396
What happens during late phase response?
Recruitment of other cells would lead to a second response, prolonging the inflammatory response.
397
What are the three conditions that elicit a type I hypersensitivity reaction?
1. Allergen characteristics
2. Host factors
3. Environmental influences
398
What makes certain proteins allergenic (induce a strong IgE response)?
- Protease activity: Der p 1 (found in dust mites)
- Surface features of protein: Ves v 5 (found in wasps)
- Glycosylation pattern of protein: Ara h1 (found in peanuts)
- Host factors: polymorphisms of various receptors that make them gene targets
- Environmental influences
399
Define pharmacokinetics.
The fate of a chemical substance administered to a living organism
- What the body does to the drug
400
When describing pharmacokinetics, ADME is used, what does it stand for?
Absorption route
Distribution (how well distributed)
Metabolism (i.e IV skips 1st pass metabolism)
Excretion (hepatic or renal)
401
Pharmacokinetics: What is absorption?
Transfer of a drug molecule from site of administration to systemic circulation
402
Which routes of administration have 100% of the dose reach systemic circulation?
IV and IA administration. For any other route, drugs must cross at least one membrane to reach systemic circulation.
403
What are the three mechanisms for drugs to permeate membranes
Passive diffusion through hydrophobic membrane
Lipid soluble molecules
Passive diffusion aqueous pores
Very small water soluble drugs (eg lithium)
Most drug molecules are too big
Carrier mediated transport
Proteins which transport sugars, amino acids, neurotransmitters and trace metals (and some drugs)
404
What 2 factors affecting drug absorption?
Lipid solubility
Drug ionisation
405
What factors affect oral drug absorption?
- Drug ionisation.
- Stomach
- Intestine
-First pass metabolism
406
In terms of ionisation, what happens to Aspirin in the stomach?
Aspirin is a weak acid and so becomes less ionised in the stomach due to the low gastric pH.
407
What is the advantage of aspirin becoming less ionised in the stomach?
This allows rapid non-ionic diffusion across the gut membrane into the plasma. Once in the plasma aspirin becomes more ionised again.
408
Where are weak acid drugs and weak base drugs best absorbed?
Weak acids - best absorbed in stomach. Weak bases - best absorbed in intestine
409
How could the stomach affect oral drug absorption?
- Gastric enzymes - drug molecule may be digested (peptides, proteins)
Eg. insulin and biologicals
- Low pH - molecule may be degraded (benzylpenicillin)
- Food (full stomach will generally slow absorption)
- Gastric motility (altered by drugs and disease state)
- Previous surgery (eg gastrectomy)
410
How could the intestine affect oral drug absorption?
1. Drug structure
- Lipid soluble/unionised molecules diffuse down concentration gradient
- Large or hydrophilic molecules are poorly absorbed
2. Medicine formulation
- Capsule/tablet coating can control time between administration and drug release
- Modified release controls (slows) the rate of absorption (less frequent dosing)
3. P-glycoprotein
- Substrates are removed from intestinal endothelial cells back into lumen
411
What is first pass metabolism?
Metabolism of drugs preventing them reaching systemic circulation.
412
List examples of first pass metabolism.
Degradation by enzymes in intestinal wall
Absorption from intestine into hepatic portal vein and metabolism via liver enzymes
413
How can first pass metabolism be avoided?
By giving via routes that avoid sphlanchnic circulation (eg rectal)
414
What is bioavailability (F)?
Proportion of administered dose which reaches the systemic circulation
415
Features of bioavailability (F).
- Dependent on extent of drug absorption and extent of first pass metabolism
- Not affected by rate of absorption
- Varies with route of administration
- Variation between individuals (genetic, disease states)
Expressed as % or fraction (e.g 70% or 0.7)
416
Pros and cons of rectal administration (PR).
Pros:
Local administration
Avoids first pass metabolism
Nausea and vomiting
Cons:
Absorption can be variable
Patient preference
417
Pros and cons of inhaled administration (Inh)
Pros:
Well perfused large surface area
Local administration
Cons:
Inhaler technique can limit effectiveness
418
Pros and cons of Sub- cutaneous administration (S/C)
Pros:
Faster onset than PO
Formulation can be changed to control rate of absorption
Cons:
Not as rapid as IV
419
Pros and cons of Trans- dermal administration (TD)
Pros:
Provides continuous drug release
Avoids first pass metabolism
Cons:
Only suitable for lipid soluble drugs
Slow onset of action
420
Pharmacokinetics: What is distribution?
Drug properties will influence ability to move between compartments.
421
What factors can affect distribution of drugs?
- Molecule size
- Lipid solubility
- Protein binding
422
What is the volume of distribution (Vd)?
Theoretical volume a drug will be distributed in the body (apparent volume of distribution)
423
Features of Vd.
Volume of plasma required to contain the total administered dose
Drugs that are well distributed will have high Vd
Drugs that are poorly distributed will have low Vd
424
Digoxin is a small molecule, highly lipophyllic, would it be likely to have a small Vd or large Vd?
- Small molecule size and lipophilic so would have a large Vd
Vd = 5-8L/kg
425
What is the blood brain barrier (BBB)?
Membrane that separates foreign substances in the blood from the CNS
426
What features of the BBB poses a challenge for treating CNS conditions?
- Continuous layer of endothelial cells with tight junctions
- Efflux pumps remove water soluble molecules
This allows BBB to maintain a stable environment and protects the brain, but poses a challenge for treating CNS conditions
427
Ways for drugs to reach the CNS despite the presence of the BBB.
- High lipid solubility. e.g. Ѱ drugs usually very lipid soluble (therefore large Vd)
- Intrathecal administration (e.g. baclofen in MS and spinal cord injury, chemotherapy)
- Inflammation (causes barrier to become leaky)
428
Pharmacokinetics: What is drug elimination?
the process by which the drug becomes no longer available to exert its effect on the bod
429
What are the two routes of drug elimination in pharmacokinetics?
Metabolism: modification of chemical structure to form new chemical entity (metabolite)
Excretion of unchanged drug (hydrophillic, polar molecules)
430
What are the 2 phases of metabolism in drug elimination? Describe them briefly
Phase 1: Oxidation/reduction/hydrolysis to introduce reactive group to chemical structure. Cytochrome P450 enzymes are responsible for majority of phase 1.
Phase 2: Conjugation of functional group to produce hydrophilic, inert molecule which can then be excreted
431
What are the three processes for renal excretion of drugs?
1. Glomerular filtration
- 20% of plasma filtered
- Free/unbound drug molecules
- Very large molecules excluded
2. Active tubular secretion
- 80% of renal blood flow passes on to peritubular capillaries
- Can clear protein bound drugs
- Most effective renal clearance mechanism
3. Passive reabsorption
- Diffusion down the concentration gradient from tubule into peritubular capillaries
- Hydrophobic drugs will diffuse easily
- Highly polar drugs will be excreted
432
A 66 year old woman is admitted to the medical ward after a fall. She is a heavy drinker and is showing signs of alcohol withdrawal. She is prescribed lorazepam to control her withdrawal symptoms. What property allows it to cross the blood brain barrier?
A) substrate for CYP3A4
B) Avoids first pass metabolism
C) Highly protein bound
D) Large molecule
E) Highly lipid soluble
E) Highly lipid soluble
433
List 6 examples of how ageing impacts the immune response in the molecular level.
- Genomic instability
- Telomere shortening
- Epigenetic alteration
- Loss of proteostasis
- Compromised autophagy ( body's cellular recycling system)
- Mitochondrial dysfunction
434
List 3 examples of how ageing impacts the immune response in the cellular level.
- Cellular senescence
- Stem cell exhaustion
- Altered intercellular communication
435
List an example of how ageing impacts the immune response in the systemic level.
Nutritional dysregulation
436
What is immunosenescence?
The state of dysregulated immune function that contributes to the increased susceptibility of the elderly to infection and possibly to autoimmune disease and cancer.
437
Interventions to reduce immunosenescence in the elderly.
Modifications to lifestyle:
- Physical activity
- Caloric restriction
- Maintaining optimal nutrition
Pharmacological interventions:
- Statins
438
What is meant by ‘first order kinetics’?
First order: Rate of elimination is proportional to the plasma drug concentration (processes involved in elimination do not become saturated)
A constant % of the plasma drug is eliminated over a unit of time.
439
What is meant by ‘zero order kinetics’?
Zero order: Rate of elimination is NOT proportional to the plasma drug concentration (metabolism processes become saturated)
A constant amount of the plasma drug is eliminated over a unit of time
440
What is clearance (CL)?
Efficiency of irreversible elimination of a drug from the systemic circulation
441
Single modified release oral dose vs single oral dose.
Modified release formulations usually require less frequent dosing.
442
Features of Half life (t1/2)
- Dependent on clearance (CL) of drug from body by all eliminating organs (hepatic, renal, faeces, breath)
- Dependent of volume of distribution (Vd) - A drug with large Vd will be cleared more slowly than a drug with a small Vd
- Not dependent on drug dose or drug formulation
- A drug will be 97% cleared from the body after 5 x half lives (considered ‘cleared’ in clinical practice)
443
What are single or STAT doses useful to treat?
Acute conditions, effects will usually wear off after a few minutes - hours
444
When is continuous IV infusions used?
Critical care patients
Antibiotics
Unfractionated heparin
General anaesthetics
445
Pharmacokinetics: What is the steady state?
When the rate of drug input is equal to rate of drug elimination
446
Why is the steady state important?
Aim for Css which lies between the Maximum safe concentration (MSC) and minimum effective concentration (MEC)
447
Waiting to reach the steady state may be detrimental. What can we do to speed up the time to steady state?
Using a loading dose.
448
Give 2 examples of zero order drugs
Ethanol, phenytoin
449
Pharmacokinetics: What is tmax and cmax
Cmax= maximum plasma concentration
tmax= time taken to reach Cmax
450
A 66 year old woman is admitted to ED with SOB and haemoptysis. CTPA confirms bilateral PEs. She is prescribed an IV loading dose of unfractionated heparin 5000 units followed by an IV continuous infusion.
What effect will the loading dose have on the heparin pharmacokinetics?
Reduce time to steady state plasma concentration (Css)
451
Define pharmacogenetics
The use of genetic and genomic information to tailor pharmaceutical treatment to an individual.
452
Benefits of medicine use through genomics.
improved patient outcomes, cost efficiency
453
Most drug targets are proteins. List 4 drug targets.
- Enzymes
- Receptors
- Transporters
- Ion channels
454
What is a receptor?
A component of a cell that interacts with a specific ligand* and initiates a change of biochemical events leading to the ligands observed effects.
455
Receptors are the principal means by which chemicals communicate. List three chemicals receptors can communicate with.
- Neurotransmitters: acetylcholine, serotonin
- Autacoids (local) Greek "autos" (self) and "acos" (relief): cytokines, histamine
- Hormones: testosterone, hydrocortisone
456
List 4 examples of receptors involved in drug reactions.
Ligand-gated ion channels
nicotinic ACh receptor
G protein coupled receptors
beta-adrenoceptors
Kinase-linked receptors
receptors for growth factors
Cytosolic/nuclear receptors
steroid receptors
457
Features of G protein coupled receptors
GPCRs are the largest and most diverse group of membrane receptors in eukaryotes.
Ligands include light energy, peptides, lipids, sugars, and proteins.
458
How is G coupled protein receptor activity regulated?
Their activity is regulated by factors that control their ability to bind to and hydrolyse guanosine triphosphate (GTP) to guanosine diphosphate (GDP)
459
Give an example of a GPCR.
Muscarinic and β2 adrenoceptor.
460
What do the majority of GPCRs interact with?
GPCR's usually interact with adenylate cyclase or phospholipase C
461
How do kinase-linked receptors work?
Kinases are enzyme that catalyze the transfer of phosphate groups between proteins - process is known as phosphorylation.
The substrate gains a phosphate group ”donated” by ATP
Transmembrane receptors activated when the binding of an extracellular ligand causes enzymatic activity on the intracellular side.
462
How do steroid hormones/nuclear receptor work?
Work by modifying gene transcription
463
Give an example of a drug which targets nuclear receptors.
Tamoxifen (Breast Cancer) acts as a selective oestrogen receptor modulator (SERM), or as a partial agonist of the oestrogen receptors
- Used in ER+ cancers.
464
Give examples of how imbalance of chemicals and receptors can lead to pathology.
Imbalance of chemicals
allergy; increased histamine
Parkinson’s; reduced dopamine
Imbalance of receptors
myasthenia gravis; loss of ACh receptors
Mastocytosis (Mast cells); increased c-kit receptor
465
What is an agonist and antagonist?
Agonist
a compound that binds to a receptor and activates it
Antagonist
a compound that reduces the effect of an agonist
466
What is the two state model of receptor activation?
Describes how drugs activate receptors by inducing or supporting a conformational change in the receptor from “off” to “on”.
467
Describe the shape of a log concentration response curve.
Sigmoidal
468
What does EC50 tell us about a drug?
Its potency!
469
Would a drug with a lower EC50 have a lower or greater potency?
Greater potency.
470
Define affinity, efficacy/intrinsic activity (IA) and potency
Affinity:
-How well a ligand binds to receptor
Efficacy/IA:
-How well a ligand ACTIVATES a receptor
Potency:
-Relative strength of the drug
(potency is solely comparative, i.e drug A vs B. Efficacy, is what % of bound drugs activate the receptor)
471
Role of antagonist
Antagonists reverse the effects of agonists.
472
Difference between competitive and non-competitive antagonism.
Competitive antagonists bind to the same site as the agonists, while in non-competitive antagonism, the antagonist binds to an allosteric (non-agonist) site on the receptor to prevent activation of the receptor
473
What are factors governing drug action?
Receptor-related
affinity
efficacy
Tissue-related
receptor number
signal amplification
474
Do agonists and antagonists display efficacy and affinity?
Agonists
Have affinity and efficacy
Antagonists
Have affinity but zero efficacy
475
What is the effect of fewer receptors on receptor response?
Some agonists needs to activate only a small fraction of the existing receptors to produce the maximal system response. (Partial agonists don't have receptor reserve).
476
What is inverse agonism?
When a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist.
(negative activity)
477
What is tolerance?
Tolerance (slow)
- reduction in agonist effect over time
- continuously, repeatedly, high concentrations
478
What is desensitization?
Desensitization (rapid)
- uncoupled
- internalized
- degraded
479
Use of the terms specificity and selectivity in drug interactions.
Selective is a better term to describe activity as no compound is ever truly specific.
480
What are the two types of enzyme inhibitors.
Irreversible inhibitors - usually react with the enzyme and change it chemically (e.g. via covalent bond formation).
Reversible inhibitors - bind non-covalently and different types of inhibition are produced depending on whether these inhibitors bind to the enzyme, the enzyme-substrate complex, or both.
481
Give an example of an enzyme that acts as drug products
- Streptokinase
- tPA
482
How do statins work?
HMG-CoA reductase inhibitors
Block the rate limiting step in the Cholesterol pathway
483
What is the renin-angiotensin-aldosterone system?
Renin-angiotensin-aldosterone system is a major blood pressure regulating mechanism. The system increases blood pressure by increasing the amount of salt and water the body retains
484
How does inhibition of angiotensin converting enzyme help lower blood pressure?
Inhibiting ACE reduces ATII production and therefore causes a reduction in blood pressure
485
Angiotensin converting enzyme can be hijacked. Give an example of when this could happen.
SARS-CoV-2 uses ACE2 as an entry receptor
486
Enzymes can target multiple steps in biosynthetic pathways such as in Parkinson's disease.
Treatment is through multiple enzymatic inhibitor drugs. This includes: L-DOPA, Peripheral DDC Inhibitor, Peripheral COMT Inhibitor, Central COMT Inhibitors, Mono Amine Oxidase B Inhibitors.
How much each of these drugs help the management of Parkinson's,
L-DOPA is a precursor for neurotransmitter biosynthesis.
Peripheral DDC Inhibitor blocks DDC in the periphery generating more for the CNS pathway
Peripheral COMT Inhibitor prevents breakdown of L-DOPA generating more for the CNS pathway
Central COMT Inhibitors function within the CNS to keep Dopamine levels up
Mono Amine Oxidase B Inhibitors prevents Dopamine breakdown and increases availability
487
What non enzymatic inhibitor drug can be used to help management Parkinson's disease?
Central Dopamine Receptor Agonists
Antagonise dopamine receptors
488
How and where do loop diuretics work?
They act on the ascending loop of henle and inhibit NKCC2 channels, this stops Na, K and Cl reabsorption.
489
Name a loop diuretic.
Furosemide - acts on Na+/K+/2Cl- transporter (NKCC2).
490
Name 3 TNF blockers.
1. Etanercept (TNF alpha specific).2. Infliximab.3. Adalimumab.
491
List 2 naturally occurring opioids.
- Morphine
- Codeine
492
List 3 simple chemically modified opioids
diamorphine (heroin), oxycodone, dihydrocodeine
493
List 4 synthetic opioids.
- Pethidine
- Fentanyl
- Alfentanil
- Remifentanil
494
10 mg of morphine orally is equal to how many mg in s/c, IM, IV?
5mg! 50% of oral morphine is metabolised by first pass metabolism.
495
Which route of administration is the quickest between sub-cutaneous, IM and IV?
IV>IM>Sub-cutaneous
496
What are the 4 opioid receptors?
MOP KOP DOP and NOP
497
What are the relative potencies of diamorphine morphine and pethidine?
(5mg of diamorphine)
Diamorphine 5 mg
Morphine 10 mg
Pethidine 100 mg
498
What do opioids act on?
- CNS + GI tract receptors
- Resp centres of the brain (pontine)
499
Side effects of opioids
- Addiction
- Constipation
- Nausea and vomiting
- Respiratory distress/depression
500
How long does opioid withdrawal last?
- Starts within 24 hours
- Lasts about 72 hours
501
What to do for opioid induced respiratory depression?
- Call for help
- ABC (check airway, breathing, circulation)
- Naloxone
- IV is fastest route
- Titrate to effect - don’t have to give it all at once - once you’ve injected a drug you
can’t get it back!
- Short half-life of naloxone - beware drug addict overdoses in A&E
502
Codeine is a pro-drug what does this mean?
Needs to be metabolised by cytochrome CYP2D6 to morphine to work.
- 10% of people don’t have cytochrome CYP2D6 that converts it, codeine will have no effect in these people.
- 5% of people have too much of the enzyme, these individuals may be at increased risk of respiratory depression with codeine
503
What is morphine metabolised to?
Morphine 6 glucuronide.
504
In renal failure, what may morphine 6 glucuronide lead to?
Morphine 6 glucuronide is renally excreted. In renal failure it will build up and may cause respiratory depression
505
What should patients with renal failure use instead of morphine?
Oxycodone
506
Parasympathetic (Ach) responses
- Rest + digest
- Pupil constricts
- Lower heart rate
- Bronchoconstritction
- Increased GI motility and secretion
- Detrusor muscle contracts
- Penis points (erect)
507
Sympathetic (NAd) response
- Fight or flight
- Pupil dilates
- Increased heart rate
- Bronchodilation
- Decreased GI motility and secretion
- Detrusor muscle relaxes
- Penis shoots (ejaculation)
508
Sympathetic nervous system receptors
alpha 1 (postsynaptic) - vasoconstriction
alpha 2 (presynaptic) - negative feedback suppresses norad release
beta 1 - increased heart rate and contractility
beta 2 - bronchodilation
509
When does a pharmacodynamic interaction occur?
Occurs when drugs have an effect on the same target or physiological system
510
When does a pharmacokinetic interaction occur?
Occurs when a drug affects the pharmacokinetics (absorption, distribution, metabolism or excretion) of another drug
511
Features of a pharmacodynamic interactions.
* Pharmacodynamic interactions are either synergistic or antagonistic
* Due to drugs acting on the same drug receptor(s) or physiological system
* Generally predictable (related to pharmacology of drug)
* Highly selective drugs are less likely to be problematic
512
72 year old female prescribed amitriptyline (for nerve pain) and solifenacin (for bladder spasm)
Solifenacin is a highly selective antagonist for M3 receptors
M3 receptors widespread (bladder, CNS, salivary glands, GIT)
Amitriptyline increases serotonin and NA in synaptic cleft. Poor specificity for target, also antagonist at M3 receptors
This leads to amplified anticholinergic effects (dry mouth, constipation, flushed+dry skin, delirium)
In the above scenario is the pharmacodynamic interaction synergistic or antagonistic?
Synergistic interaction
513
54 year old male prescribed atenolol (ß antagonist) for hypertension and salbutamol (ß2 agonist) for asthma
Experiencing wheeze
This is due to an antagonist reaction between the two drugs. Explain how?
Salbutamol agonist at ß2 receptors (located in bronchial smooth muscle)
Atenolol cardioselective ß blocker (cardioselective antagonist at ß1 receptors but also antagonist at ß2)
Atenolol and salbutamol compete at ß2 receptors
Results in incomplete agonist effect and reduced bronchodilation/increased bronchospasm
514
34 year old male prescribed morphine (pain relief) and lorazepam (anxiety)
Increased sedation
This is due to a synergistic reaction between the two drugs. Explain how?
Morphine agonist at MOP, KOP and DOP opiate receptors
Benzodiazepines potentiate actions of GABA (inhibitory CNS neurotransmitter)
MOP and KOP agonism and GABA transmission cause sedation
Different mechanisms within the CNS
Results in increased risk of sedation
515
48 year old female prescribed methadone (opioid misuse) and ciprofloxacin (antibiotic)
Complaining of dizziness and palpitations
This is due to synergistic reaction between the two drugs. Explain how?
Methadone agonist at MOP, KOP and DOP opiate receptors
Ciprofloxacin quinolone antibiotic
Methadone and ciprofloxacin block voltage gated K channels
Results in increased risk of QT prolongation and Torsades de Pointes
516
51 year old female prescribed amlodipine (hypertension) and ramipril (hypertension)
This will result in a synergistic reaction between the two drugs. Explain how, and whether this is beneficial or not?
Amlodipine: dihydropyridine calcium channel blocker reduces Ca2+ influx into vascular smooth muscle
Ramipril: ACE inhibitor inhibits conversion of angiotensin I to angiotensin II
Both lead to reduced vasoconstriction
Results in increased risk of hypotension (may be beneficial)
In practice: CCBs and ACEIs are used in combination in management of hypertension
517
Pharmacokinetic drug interactions: What mechanisms of a drug could affect the absorption of another drug?
1. Drugs which alter pH of GI tact
2. Formation of insoluble drug complexes
3. P-glycoprotein induction/inhibition
518
How can a drug which causes changes in GI Tract pH
affect absorption of another drug?
Changes in pH will alter the proportion of ionised and unionised drug
519
Famotidine (H2 antagonist) increases stomach pH and reduces absorption of ketoconazole (antifungal). In practice what can be done to prevent this?
In practice: If taking famotidine, oral ketoconazole should be taken with an acidic drink
520
How can complex formation affect absorption?
Insoluble drug complexes will not be absorbed and will be retained in the GIT
521
doxycycline and iron can form complexes which will not be absorbed. In practice what can be done about this?
In practice: separate administration of doxycycline and oral iron by 2-3 hours
522
How can a drug causing P-glycoprotein induction/inhibition affect the absorption of another drug?
P-glycoproteins (P-gp) are drug transporter proteins widely distributed in body
Excretory function to remove toxic substances (incl drugs) out of cells
Amongst other locations - situated in intestinal lumen to reduce absorption
523
Pgp inhibitors and inducers lead to increased or decreased level of Pgp substrates
Carbamazepine = Pgp inducer
Upregulates P-gp and therefore reduces the absorption of P-gp substrates
Carbamazepine significantly reduces rivaroxaban levels (note interaction also occurs due to CYP3A4 induction)
In practice what can be done about this?
NOTHING. In practice: combination can lead to anticoagulant treatment failure, therefore concurrent use is contraindicated
524
Pharmacokinetic drug interactions: What issues could occur during distribution of a drug?
Give an example.
Only unbound drug will be distributed from plasma volume. Interactions can occur when drugs compete for protein binding
Warfarin is highly protein bound (~99%)
1% unbound and pharmaceutically active
Amiodarone displaces warfarin from albumin to create unbound warfarin molecules
Change of 99% bound to 98% bound = free drug doubles from 1% to 2%
525
What enzymes are responsible for majority of phase 1 metabolic reaction
Cytochrome P450 (CYP450) enzymes
526
What are inducer drugs?
- Increase Cytochrome P450 activity and speed up metabolism of other drugs
527
List examples of inducer drugs
PCARBS
Phenytoin
Carbamazepine
Alcohol (chronic use)
Rifampicin
Barbiturates (St John's Wort)
Sulfonylureas and smoking
528
What are drugs which decrease CYP450 activity and decrease metabolism of other drugs called?
Give an example.
Inhibitor drugs
Macrolides (clarithromycin, erythromycin)
Azoles (fluconazole)
Grapefruit juice
529
Pharmacokinetic drug interactions: What issues could occur during elimination of a drug?
Give an example.
Competition for renal tubular secretion. Drugs are transported by OAT (organic anion transporters) and OCT (organic cation transporters.
Methotrexate (MTX) is 80-90% excreted unchanged by the kidneys
Secreted into renal tubule by OAT
NSAIDs compete with MTX for secretion by OAT leading to reduced MTX elimination
MTX toxicity: cirrhosis, fatal blood dyscrasias, renal damage (acute renal failure)
530
How does grapefruit juice affect CYP450? And what drugs might this impact on?
Grapefruit juice is a CYP450 inhibitor, it affects CYP3A4 specifically and increases the bioavailability of some drugs e.g. warfarin, statins
531
Eating foods high in which vitamin can affect the action of warfarin?
High in vitamin K - opposes warfarin
532
Why should cranberry juice be avoided by patients taking warfarin?
Cranberry juice is a CYP2C9 inhibitor
533
Milk can affect absorption of some drugs such as doxycycline, levothyroxine, ciprofloxacin, how?
Milk can affect absorption of some drugs due to insoluble complex formed with Ca
534
It is important to identify and avoid drug interactions.
What types of drugs are considered high risk?
Obtain complete drug history (DHx)
Enzyme inducers, inhibitors and substrates
Drugs with a narrow therapeutic index
High risk/critical medicines
New drugs (e.g. biologics) - little data
535
It is important to identify and avoid drug interactions.
What indicators are there for patients considered high risk?
Polypharmacy
Kidney or liver impairment
Extremes of age
536
Mr K (86 year old male) is brought to A&E by his daughter after falling at home and hurting his wrist. He has recently started taking codeine for pain relief.
Which of his regular medicines would interact with codeine to increase his risk of falls?
1. Aspirin
2. Metformin
3. Morphine
4. Omeprazole
5. Ramipril
3. Morphine - duplicated agonism at opioid receptors.
537
Define adverse drug reaction (ADR)
A response to a medicinal product, or combination of medicinal products, which is noxious and unintended
538
List some examples of the impact of ADR on patients.
* Reduced Quality of life
* Poor compliance
* Reduced confidence in clinicians and the healthcare system
* Unnecessary investigations or treatments
539
List some examples of the impact of ADR on the NHS
* Increased hospital admissions
* Longer hospital stays
* GP appointments
* Inefficient use of medication
540
How can ADRs be classified using the ABCDE system?
A = Augmented
B = Bizarre
C = Chronic/continuing
D = Delayed
E = End of use/withdrawal
F = Failure of treatment
G = Genetic
541
Type A ADR features
Most common type of ADR (80%)
Exaggerated effect of drugs pharmacology at a therapeutic dose
Often not life threatening
Dose dependent and reversible upon withdrawing the drug
542
Give an example of a Type A ADR
* AKI with ACE inhibitors
* Bradycardia with betablockers
* Hypoglycaemia with gliclazide, insulin
* Respiratory depression with opiates
* Bleeding with anticoagulants
543
Type B ADR features
* Not related to pharmacology of drug
* Not dose related
* Can cause serious illness or mortality
* Symptoms do not always resolve upon stopping drug
544
Give an example of a Type B ADR.
* Anaphylaxis with penicillins
* Tendon rupture with quinolone antibiotics
* Steven Johnson Syndrome with IV vancomycin
545
Type C ADR features
ADRs that continue after the drug has been stopped
546
Give an example of a Type C ADR
* Osteonecrosis of the jaw with bisphosphonates
* Heart failure with pioglitazone
547
Type D ADR features
ADRs that become apparent some time after stopping the drug.
548
Give an example of a Type D ADR
Leucopenia with chemotherapy
549
Type E ADR features
ADR develops after the drug has been stopped.
550
Give an example of a Type E ADR
* Insomnia after stopping benzodiazepine
* Rebound tachycardia after stopping beta-blocker
* Nasal congestion after stopping xylometolazine nasal spray
551
Type F ADR features
* Unexpected treatment failure
* Could be due to drug-drug interaction or drug-food interaction
* Poor compliance with administration instructions
552
Give an example of a Type F ADR
* Failure of oral contraceptive pill due to St John’s Wort
* Failure of DOAC due to enzyme inducer (eg carbamazepine)
* Failure of bisphosphonate due to taking with food
553
What is the DoTS method of classifying ADR
Do = Dose-relatedness
T = Timing: ADRs which can develop during any time during treatment (often due to clinical changes in the patient).
S = Susceptibility
More complex than ABCDE, but provides more detail.
Useful for those working in pharmacovigilance, undertaking research or developing medicines
554
DoTS: What are the three ADRs that could occur at different stages of doses.
Hypersusceptibility: ADRs at subtherapeutic doses (eg anaphylaxis with penicillins)
Collateral effects (side effects): ADRs at therapeutic doses (eg hypokalaemia with loop diuretic)
Toxic effects: ADRs at subpratherapeutic doses (eg liver damage with paracetamol)
555
DoTS: Certain patient groups/populations may have a specific susceptibility to ADRs from a drug. Give factors which may make people more susceptible.
Age (anticholinergics in elderly patients)
Gender (metoclopramide in females)
Disease states (eg diclofenac in CVD)
Physiological states (eg phenytoin in pregnancy)
556
What systems are in place to allow identification of ADRs?
Pre-clinical testing (computer models, cells and toxicity testing in animals)
Clinical trial data (pre-marketing evaluation)
Post marketing surveillance
Pharmacovigilance
557
ADRs can be reported to the MHRA using the Yellow Card system. Which of the following ADRs is an augmented type ADR?
* Treatment failure of warfarin due to dietary consumption of vitamin K
* Neurodevelopmental disorder in child of patient taking sodium valproate
* Constipation in patient taking morphine sulphate
* Rebound tachycardia in patient after stopping atenolol
* Angioedema in patient taking amoxicillin
* Constipation in patient taking morphine sulphate
558
Outline the steps taken if it is suspected that a patient has an ADR to a certain drug?
1. Assess if ADR requires treatment (reversal, symptom management)
2. Take a history
3. Review medication history
4. Review ADR profile of suspected drug (BNF, SPC)
5. Modify dose, stop or swap
6. Document allergy/ADR in patient record (including nature of reaction)
7. If criteria met…report
559
What are the different types of hypersensitivities mediated by?
Type 1 – IgE mediated drug hypersensitivity
Type 2 – IgG mediated cytotoxicity
Type 3 – Immune complex deposition
Type 4 – T cell mediated
560
Features of Type 2 hypersensitivity
Type 2 reactions – Antibody-antigen complex formation
- Antibody-antigen complex formation
Drug or metabolite combines with a protein
Body treats it as foreign protein and forms antibodies (IgG, IgM)
Antibodies combine with the antigen and complement activation damages the cells e.g. methyl-dopa-induced haemolytic anaemia, pemphigus
561
Features of Type 3 hypersensitivity
Type 3 reactions – Antibody-antigen complex deposition
Antigen and antibody form large complexes and activate complement
Small blood vessels are damaged or blocked
Leucocytes attracted to the site of reaction release pharmacologically active substances leading to an inflammatory process
Includes glomerulonephritis, vasculitis,
562
Features of Type 4 hypersensitivity
Type 4 reaction – Lymphocyte mediated
Antigen specific receptors develop on T-lymphocytes
Subsequent admin, adminstration leads to local or tissue allergic reaction
E.g. contact dermatitis
E.g. Stevens Johnson syndrome (TEN)
563
Main features of anaphylaxis
Exposure to drug, immediate rapid onset
Rash (absent in 10-20%)
Swelling of lips, face, oedema, central cyanosis
Wheeze / SOB
Hypotension (Anaphylactic shock)
Cardiac Arrest
564
Features of non immune anaphylaxis
Due to direct mast cell degranulation.
Some drugs recognised to cause this
No prior exposure
Clinically identical
565
Management of anaphylaxis
1. Commence basic life support. ABC (airway, breathing, circulation)
2. Remove the trigger if possible
- Stop the drug if infusion
3. Adrenaline IM 500 micrograms (300mcg epi-pen)
4. High flow oxygen
5. IV fluids – aggressive fluid resuscitation
If anaphylactic shock may need IV adrenaline with close monitoring
Antihistamines not first line treatment but can be used for skin symptoms
Corticosteroids no longer recommended
566
How does adrenaline work?
Adrenaline acts on alpha 1, alpha 2, beta 1 and beta 2 receptors.
Vasoconstriction - increase in peripheral vascular resistance, increased BP and coronary perfusion via alpha1-adrenoceptors
Stimulation of Beta1-adrenoceptors positive ionotropic and chronotropic effects on the heart
Reduces oedema and bronchodilates via beta2-adrenoceptors
Attenuates further release of mediators from mast cells and basophils by increasing intracellular c-AMP and so reducing the release of inflammatory mediators
567
Risk factors for hypersensitivity
Medicine factors:
Protein or polysaccharide based macro molecules
Host factors:
Females > Males – we don’t know why
EBV, HIV
Prev drug reactions
Uncontrolled asthma
Genetic factors:
Certain HLA groups
Acetylator status
568
For a patient to have allergy for a drug, what criteria do they have to fulfil?
Does not correlate with pharmacological properties of the drug
No linear relation with dose (tiny dose can cause severe effects)
Reaction similar to those produced by other allergens
Induction period of primary exposure
Disappearance on cessation
Re-appears on re-exposure
Occurs in a minority of patients on the drug
569
Define refractory anaphylaxis.
No improvement in respiratory or cardiovascular symptoms despite 2 appropriate doses of intramuscular adrenaline.
570
Define commensal.
Organism which colonises the host but causes no disease in normal circumstances
571
Morphological term for round shaped bacteria?
Cocci
572
Morphological term for rod shaped bacteria?
Bacilli
573
Features of typical bacteria structure
- Cell wall
- Chromosome of circular double stranded DNA
- Outer membrane
- Inner membrane
- Pili
- Capsule
574
What are Gram positive bacteria bacterial cell envelope's made up of?
Capsule
Peptidoglycan
Lipoteichoic acid
Cytoplasmic membrane
575
How do Gram negative bacteria's cell envelope differ from Gram positive?
Gram negative bacteria have a Lipopolysaccharide (ENDOTOXIN) cell wall, an outer membrane, lipoprotein, periplasmic space, and an inner membrane
576
What colour does Gram positive bacteria stain?
Violet
577
What colour does Gram negative bacteria stain?
Red
578
Under what environments can bacteria survive in?
1. Temperature
<-800C to + 80C (1200C for spores)
2. pH
<4-9
3. Water/dessication
2 hours – 3 months (>50 years for spores)
4. Light
UV
579
What are the four phases used to describe bacterial growth?
- LAG phase
- Exponential LOG phase
- Stationary phase
- Death phase
580
What are the two bacterial toxins that bacteria can produce?
ENDOTOXIN
Component of the outer membrane of bacteria, eg lipopolysaccharide in Gram negative bacteria
EXOTOXIN
Secreted proteins of Gram positive and Gram negative bacteria
581
Differences between endotoxins and exotoxins.
Exotoxin:
* Composed of proteins
* Action is specific
* Heat labile
* Strong antigenicity
* Produced by both Gram +ve and -ve
* Can convert to toxoids
Endotoxins:
* Composed of lipopolysaccharide
* Action is non specific
* Heat stable
* Weak antigenicity
* LPS Gram -ve
* Cannot convert to toxoids
582
What can lead to genetic variation in bacteria (antibiotic resistance)?
Mutations:
- deletion
- insertion
- base substitution
Gene transfer:
- Transformation eg via plasmid
- Transduction eg via phage
- Conjugation eg via sex pilus
583
What is meant by obligate intracellular bacteria?
Bacteria that cannot be cultured in media, requires a host cell to replicate.
584
Give examples of obligate intracellular bacteria.
- Chlamydia
- Coxiella
- Rickettsia
585
Give an example of a slow growing bacteria.
TB
586
Give an example of a fast growing bacteria.
E.coli and S.aureus.
587
Give 2 functions of pili.
1. Help adhere to cell surfaces
2. Plasmid exchange.
588
Give an example of a gram negative aerobic diplococci?
Neisseria e.g. N.meningitidis and N.gonorrhoeae.
589
Give two examples of gram positive cocci?
Staphylococcus and streptococcus.
590
What type of organism would you stain with Ziehl Neelsen?
Mycobacteria e.g. TB.
591
What test can be done to distinguish between staphylococcus and streptococcus?
The catalase test; detects the presence of catalase enzyme using hydrogen peroxide. Staph = catalase + ve. Strep = catalase - ve.
592
How would you describe the arrangement of staphylococci?
Clusters of cocci.
593
How would you describe the arrangement of streptococci?
Chains of cocci.
594
Pain in shoulder, elevated temperature
MRI scan, disc infection and osteomyelitis C6 &C7,
Blood cultures grow Gram positive cocci in clusters. What is the likely bacterial infection? How is it treated?
Staphylococcus aureus; flucloxacillin 3 months
595
What test could be done to further distinguish between staphylococci bacteria.
Coagulase test; looks at whether a fibrin clot is produced.
Staphylococci aureus = coagulase +ve
All other staph bacteria = coagulase -ve
596
What is the normal habitat of Staphylococci?
Nose and skin
597
How is Staph. aureus spread?
Spread by aerosol and touch - carriers and shedders
598
Virulence of factors of Staph. aureus
Pore-forming toxins (some strains)
a - haemolysin & Panton-Valentine Leucocidin
Proteases
Exfoliatin
Toxic Shock Syndrome toxin (stimulates cytokine release)
Protein A (surface protein which binds Ig’s in wrong orientation)
599
S.epidermidis is coagulase -ve. How may they cause infections?
They are opportunistic
Infections in debilitated, prostheses (opportunistic)
Main virulence factor - ability to form persistent biofilms
600
How might S.saprophyticus
cause infections?
Acute cystitis
haemagglutinin for adhesion
urease
601
Wound received to shoulder
3 days later spreading inflammation
Fever, malaise
Swab culture showed Gram positive cocci in chains. What is the bacteria involved likely to be? How could it be treated?
Streptococcus pyogenes
Penicillin sensitive
602
What test could be done to distinguish between different streptococci?
Blood agar haemolysis.
Beta- complete lysis
e.g. S.pyogenes
Haemolysins O & S
Alpha- partial, greening
e.g. S.intermedius
non (or Gamma) - no lysis
e.g. some S.mutans
603
What further test can be done for those streptococci in the β haemolysis group?
Serogrouping; detecting carbohydrate cell surface antigens. e.g. lancefield grouping.
604
In Lancefield grouping, what are the members of Group A and Group B?
Group A - S.pyogenes; important pathogen
Group B - S.agalactiae neonatal infections
605
S.pyogenes virulence factors
Exported factors
Enzymes
Hyaluronidase - spreading
Streptokinase - breaks down clots
C5a peptidase - reduces chemotaxis
Toxins
Streptolysins O&S - binds cholesterol
Erythrogenic toxin - SPeA – exaggerated response
Surface factors
Capsule - hyaluronic acid
M protein – surface protein
(encourages complement degradation)
606
Infections caused by S.pyogenes
Wound infections >> cellulitis, puerperal fever
Tonsillitis & pharyngitis
Otitis media
Impetigo
Scarlet fever
Complications
rheumatic fever
glomerulonephritis
607
Chains of purple cocci are seen on a gram film. They show alpha haemolysis when grown on blood agar. They don’t grow near the optochin disc. What bacteria is likely to have caused this?
Streptococcus pneumonia.
608
How can you differentiate streptococci pneumoniae from other streptococci?
The optochin test can differentiate streptococci pneumoniae from other streptococci. Pneumococci are sensitive and so a clear area would be seen.
609
What illnesses can S.pneumoniae cause?
pneumonia, otitis media, sinusitis, meningitis
610
Predisposing factors for S.pneumoniae infections
impaired mucus trapping (e.g. viral infection)
hypogammaglobulinaemia
asplenia
611
S.pneumoniae virulence factors
1. Capsule
polysaccharide (84 types), antiphagocytic
polyvalent vaccine
2. Inflammatory wall constituents
teichoic acid (choline)
peptidoglycan
3. Cytotoxin
pneumolysin
612
What can Viridans group streptococci cause?
Some cause dental caries & abscesses
Important in infective endocarditits
S. sanguinis, S. oralis
Cause deep organ abscesses (e.g. brain, liver)
613
Haemolysis of Viridans group streptococci
alpha- haemolytic (or non-haemolytic)
614
Features of bacillus anthracis
Gram positive bacilli
Spore forming - pneumoniae, skin infection
615
Corynebacterium diphtheriae clinical feature?
Thick greyish pseudo membrane on tonsils
616
Virulence factors of Clostridia
Spore forming
Survive in environment
Produce toxins
617
What does C. tetani cause?
Tetanus
618
What does C. botulinum cause?
Botulism
619
What does C. difficile cause?
antibiotic associated diarrhea
pseudomembranous colitis
620
LPS (‘endotoxin’) forms the outer leaflet of the outer membrane of Gram -ves, what is the LPS comprised of?
- Lipid A, the toxic portion of LPS that is anchored in the outer leaflet of the outer membrane.
- Core (C) antigen (core oligosaccharide), short chain of sugars, some are unique to LPS.
- Somatic (O) antigen (O-polysaccharide), a highly antigenic repeating chain of oligosaccharides.
621
Which three main aerobic Gram negative bacteria rod groups are there?
1. Coliforms
2. Vibrio
3. Pseudomonads
622
Coliform features
Enterobacteriaceae or Enterobacteria
Rod-shaped
Motile (most)
Peritrichous flagella
Facultatively anaerobic
Colonise the intestinal tract
623
What kind of bacteria is MacConkey agar used with?
Gram negative bacilli.
624
What is MacConkey agar?
MacConkey agar contains bile salts, lactose and pH indicator. If an organism ferments lactose, lactic acid will be produced and the agar will appear a red/pink colour.
625
Name 2 gram negative bacilli that will give a positive result with MacConkey agar.
1. E.Coli.
2. Klebsiella pneumoniae.
626
What category of bacteria does shigella fall under?
Gram negative bacilli.
627
Does shigella give a positive result with MacConkey agar?
No. Shigella does not ferment lactose and so gives a negative result.
628
Does e.coli give a positive result with MacConkey agar?
Yes. E.coli does ferment lactose and so you would see a red/pink colour indicating a positive result.
629
How can you distinguish between gram negative bacilli (salmonella, shigella and e.coli)?
Xylose Lysine Deoxycholate (XLD):
- e. coli +ve results turn phenol red in media yellow
- shigella cannot ferment lactose remains red
- salmonella cannot ferment lactose, but reduce thiosulphate to produce hydrogen sulphide (black)
630
Which type of e.coli would you associate with causing travellers diarrhoea?
Enterotoxigenic e.coli (ETEC).
631
Principal infections caused by pathogenic E. coli
Wound infections (surgical)
UTIs
Gastroenteritis
Travellers’ diarrhoea
Bacteraemia
Meningitis (infants) – rare in UK
632
Why are there pathogenic strains of e.coli?
Due to the acquisition of genes from other bacteria.
633
What are the symptoms of shigella infection?
Severe bloody diarrhoea (bacillary dysentery) and frequent passage.
634
How is shigella passed on?
Via contaminated food/water or from person to person.
635
What bacteria is responsible for salmonellosis?
S.enterica.
636
Name the 3 forms of salmonellosis.
1. Gastroenteritis.2. Enteric fever.3. Bacteraemia.
637
What causes gastroenteritis?
Frequent cause of food poisoning, 6-36 hour incubation period.
638
What causes enteric fever?
Frequent cause of poor quality drinking water/poor sanitation
Systemic disease
639
Describe the pathogenesis of enteric fever.
1. Endocytosis.2. Migration to the basolateral membrane. 3. Survival in macrophage -> systemic spread.
640
What infections are caused by p. auruginosa?
Acute infections (due to multiple toxins):
1. Localised
- Burn/surgical wounds
- UTI
- Keratitis
2. Systemic (bacteraemic -> sepsis)
- neutropenic patients (leukaemia, chemotherapy, AIDS)
3. ICU patients (ventilator acquired pneumonia)
- leading cause of nosocomial pneumonia
Chronic infections:
1. Cystic fibrosis (CF) patients
641
What are the symptoms of v.cholerae?
Most severe diarrhoeal disease. Huge volumes of watery stools (no blood or pus).
642
Why is v.cholerae so dangerous?
Release of cholera toxin causes huge amounts of water loss which can result in hypovolemic shock and severe dehydration, this can lead to death.
643
Why would you need to be infected with a large amount of v.cholerae to show symptoms of the disease?
The optimum pH for v.cholerae growth is 8; alkaline. It is therefore very sensitive to the pH of the stomach.
644
Why bacteria is the most common cause of food poisoning in the US and UK?
Campylobacter
- causes mild to severe diarrhoea, often with blood
645
How would you grow haemophilus influenzae?
On chocolate agar as it requires haem and NAD.
646
What diseases can haemophilus influenzae cause?
Mostly opportunistic infections:
Meningitis and pneumonia.
647
Virulence determinants of H. influenzae
Capsule, LPS
648
What diseases can Helicobacter pylori cause?
Major role in gastritis and peptic ulcer disease (80-90% of ulcers)
649
What disease can Bordetella pertussis cause?
Pertussis (whooping cough)
- Highly contagious
Non-specific flu-like symptoms (~7 d), followed by paroxysmal coughing
650
Name the bacteria that can cause legionnaires disease?
Legionella pneumophila
651
Who might be susceptible to infection by legionella?
Immunocompromised individuals.
652
What problems are there with treating the anaerobic bacteroides?
Opportunistic - tissue injury
Often present in polymicrobial infections with enterobacteria, thus require specific anti-anaerobe antibiotics
653
What are the main Gram negative cocci groups?
Veillonella
Neisseria
654
What are the two medically important species of neisseria?
N.meningitidis and N.gonorrhoeae.
655
Describe the pathogenesis of N.meningitidis.
Crosses nasopharyngeal epithelium and enters blood stream. Can cause asymptomatic bacteraemia or septicaemia. If the bacteria crosses the BBB it can cause meningitis.
656
What are the consequences of N.gonorrhoeae infection?
STI - rectal, vaginal or oral inflammation.
657
What are the three main groups of Gram negative spirochaetes?
Borrelia
Treponema
Leptospira
658
Describe the flagellum of a spirochaete.
Spirochaete's have an endoflagellum, it propels bacterium in a corkscrew motion
659
Name the spirochaete that is responsible for causing lyme disease.
B.burgdorferi.
660
Name the spirochaete that is responsible for causing syphilis.
T.pallidum.
661
Describe the three stages of syphilis.
1. Primary stage: localised infection.
2. Secondary stage: systemic - skin, lymph nodes etc.
3. Tertiary stage: CV syphilis and neuro syphilis.
662
Can you grow chlamydia on agar?
No, chlamydia is an obligate intracellular parasite.
663
How can you detect chlamydia?
Cannot culture in bacteriological media, thus can only be detected by serum antibodies or PCR.
664
What are the 2 developmental stages of chlamydia's unique growth cycle?
1. Elementary bodies (infective).
2. Reticulate bodies (intracellular multiplication).- Reticulate bodies are converted back into elementary bodies and are released. The cycle continues.
665
Which bacteria is responsible for chlamydia?
c.trachomatis
666
Name 2 bacteria in the chlamydophila genre.
1. C.pneumoniae - respiratory tract infection
2. C.psittaci - associated with birds.
667
Give an example of mycobacteria.
M.tuberculosis (TB).
M.leprae (leprosy).
668
Why are Mycobacteria resistant to Gram stain?
High lipid content with mycolic acids in cell wall makes Mycobacteria resistant to Gram stain
669
What staining is used for Mycobacteria?
Ziehl-Neelsen stain
670
Challenges of treating and diagnosing TB?
1. Thick lipid rich cell wall making immune cell killing and penetration of drugs challenging
2. SLOW growth
- Gradual onset of disease
- Takes much longer to diagnose
- Takes longer to treat
671
What is pulmonary tuberculosis?
Granulomas forms around bacilli that have settled in apex
672
How does TB infect us?
- Aerosol transmission
- Primary TB in lung
- Latent TB can remain for decades
Can spread beyond lungs
673
What does our body do to protect us from TB?
- Primarily controlled by macrophages
- Requires a CD4 T cell response to be controlled
- Involves many cells of immunity- formation of granulomas
- Granuloma stability controls reactivation of TB
674
How are Mycobacteria adapted to evade the immune system?
Mycobacteria can withstand phagolysosome killing and escape to the cytosol.
Mycobacteria can form granulomas - when they become unstable can result in the break out of systemic disease
675
What is a rapid diagnosis method for detecting M. tb?
Nucleic acid detection
676
How can you use the immune response as a diagnosis test?
Tuberculin skin test (mantoux)
677
Standard treatment for TB?
- Isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA), ethambutol (ETA) for two months
- Isoniazid and rifampicin for four more months
678
List the resistance mechanisms of TB
Drug inactivation:
Mtb produces beta-lactamase
Drug titration:
Target overproduction
Alteration of drug target:
Missense mutations
Altered cell envelope:
Increased permeability and drug efflux
679
XDR-TB: resistant to four commonly used TB drugs. How would you treat these strains?
BPaL regimen for 6 months
However this could fail as well
680
Define what a virus is.
An infectious, obligate intracellular parasite
Comprising genetic material
(DNA or RNA) surrounded by a protein coat and/or a membrane
681
List an example of a non-enveloped virus
Adenovirus
Parvovirus
682
List an example of an enveloped virus
HIV
Influenza
683
How do viruses replicate?
1. Attachment to specific receptor
2. Cell entry
3. Host cell interaction + replication
4. Assembly of virion
5. Release of new virus particles
684
How do viruses cause disease?
a) Direct destruction of host cells
b) Modification of host cell
c) “Over-reactivity” of immune system
d) Damage through cell proliferation
e) Evasion of host
685
Give an example of a virus that causes damage by direct destruction of host cells.
Poliovirus
-> host cell lysis and death after a viral replication period of 4 hours
686
Give an example of a virus that causes damage by modification of host cell.
Rotavirus
-> atrophies villi and flattens epithelial cells, this leads to decrease of small intestine s.a, nutrients not absorbed, hyperosmotic state, profuse diarrhoea
687
Give an example of a virus that causes damage by 'over-reactivity' of immune system.
Hepatitis B
SARS-CoV-2
688
Give an example of a virus that causes damage by cell proliferation.
human papillomavirus -> cervical cancer
689
How can a virus evade of host defences on a cellular level?
Cellular level:
- Herpesviridae - latency
- Measles, HIV - cell-cell spread
690
How can a virus evade of host defences on a molecular level
Molecular level:
- Influenza, HIV, rhinovirus - antigenic variability
- Herpesviridae - prevention of host cell apoptosis
- Downregulation of interferon and other intracellular host defence proteins
- Herpesviridae, measles, HIV - Interference with host cell antigen processing pathways
691
Why do viruses vary wildly in the range of clinical syndromes they can cause?
- Different host cells and tissues that they can infect
- Different methods of interaction with the host cell
692
What is meningitis?
Inflammation of the meninges (membranes) which cover the brain and spinal cord
693
Give an example of meningitis caused by bacteria
meningococcus, pneumococcus
694
Given an example of meningitis caused by virus
coxsackievirus, echovirus, herpes virus, mumps virus, influenza, HIV etc
695
List some non infectious causes of meningitis
- Medications such as antibiotics, NSAIDs
- Cancers such as melanoma, lung cancer
- Autoimmune diseases such as SLE, Behcet's disease
696
What are the two main manifestations of Neisseria meningitidis?
Meningitis: a localised infection of the meninges, with “local” symptoms
Septicaemia : a systemic infection with widespread signs, and generalised organ damage
697
What kind of bacteria is Neisseria meningitidis?
Gram negative diplococci
698
Symptoms of meningococcal meningitis
- Fever
- Stiff neck
- Headache
- Confusion
- Increased sensitivity to light
- Nausea and vomitting
699
What is Brudzinski's neck sign?
When neck flexion causes the individual to flex their hips and knees automatically, typical sign in patients with meningitis
700
Meningococcal septicaemia symptoms
Fever and chills
Fatigue
Vomiting
Cold hands and feet
Severe aches or pain in the muscles, joints, chest, or abdomen
Rapid breathing
Diarrhoea
Non blanching rash (petechiae)
In the later stages, a dark purple rash (purpura)
701
Meningococcal septicaemia can cause Disseminated Intravascular Coagulation (DIC). What is this?
Activation of coagulation pathways that results in formation of intravascular thrombi (clots) and depletion of platelets and coagulation factors.
These clots can cause arterial occlusions leading to gangrene of extremities & auto-amputations (spontaneous detachment of an appendage from the body)
702
What are some long term consequences of Meningococcal meningitis ?
Deafness or partial hearing loss (34%), seizures (13%), motor deficits (12%), cognitive impairment (9%), blindness (6%), Amputations (8% of children, 3% of adults)
703
How would you make a diagnosis for Meningococcal meningitis?
- Blood sample for blood culture & PCR
- CSF for microscopy, culture and PCR
- Throat swab for culture
704
Features of yeast
Single celled organisms that divide by budding
705
Features of mould
Form multicellular hyphae and spores
706
What are dimorphic fungi?
Fungi which can exist as both yeasts and moulds, switching between the two when conditions suit
707
Why are most fungi unable to cause human infection?
Inability to grow at 37 degrees
Innate and adaptive immune response
708
Why are there limited options for antifungal drugs? Which part of the fungi do these drugs target?
Fungi are eukaryotic which limits options for selective toxicity.
DNA/RNA synthesis is similar to mammalian.
Antifungal drugs usually target - cell wall and ergosterol containing plasma membrane. Some drugs may target protein synthesis.
709
Risk factors for mucosal candidiasis
immunosuppression, diabetes antibacterial therapy and mucosal disruption
710
Treatment of mucosal candidiasis
Treatment with topical or oral azoles
711
How are dermatophyte infections transmitted?
Human-human or animal-human transmission
712
How would you treat dermatophyte infections?
Treatment is usually with topical or oral azoles or terbinafine
713
Give an example of a dermatophyte
Trichophyton spp.,
Microsporum spp.
Epidermophyton floccosum
714
Which fungi can cause severe infections in healthy hosts in endemic areas?
Dimorphic fungi. These are fungi that can exist as both yeast and mould; they are yeast in tissues but mould in vitro
715
Give an example of a dimorphic fungi
Coccidioides immitis
716
Late manifestations of Coccidioides
1. Cavitatory lung disease
may result in pleuritic pain or cough or become colonised by Aspergillus
2. Orthopaedic
Asymetrical chronic arthritis with effusion or vertebral osteomyelitis
3. Cutaneous ulcers and abscesses
4. Cervical lymphadenopathy
5. Intracranial – chronic meningitis- BAD
717
What usually causes invasive candidiasis?
infection of prosthetic devices or intra-abdominal disease
718
What does Cryptococcus cause?
Cryptococcus causes acute or chronic meningitis in patients with reduced cell mediated immunity
719
How would you investigate for Cryptococcus?
CSF microscopy with India ink
720
Who would typically develop invasive aspergillosis?
Invasive aspergillosis is normally associated with profound immunocompromise but is increasingly recognised in patients with severe viral infection
721
How would you treat invasive aspergillosis?
Voriconazole
722
What are Mucoraceous moulds (zygomyctes) ?
Mucoraceous moulds (zygomyctes) are rare but cause devastatingly rapidly progressive infections that cross tissue planes.
Mucoraceous moulds need aggressive antifungal therapy and surgery for optimal outcomes
723
What does pneumocystis jirovecii cause?
Pneumocystis jirovecii causes a pneumonitis with severe hypoxia in the immunocompromised
724
What are protozoa?
Single celled eukaryotic organisms
725
What is African Trypanosomiasis? What is it caused by?
"sleeping sickness"
Caused by Trypanosoma brucei gambiense and rhodesiense - spread by Tsetse fly bite
- Chancre
- Flu like symptoms
- CNS involvement - (sleepy, confusion, personality change)
- Coma and death
726
What is American Trypanosomiasis? What is it caused by?
“Chagas Disease”
Caused by Trypanosoma cruzi - spread by Triatomine bug
Acute:
- Flu like symptoms
Chronic:
- Cardiomyopathy
- Megaoesophagus
- Megacolon
727
What is Leishmaniasis? What is it caused by?
Caused by Leishmania spp
Spread by the bite of the sandfly
>20 species that affect humans
- Cutaneous & Mucocutaneous
* ulceration and destruction
- Visceral
* Fever
* Weight loss
* Massive splenomegaly
* Hepatomegaly
* Anaemia
* High fatality without treatment
728
How is Trichomonas vaginalis transmitted?
Sexually transmitted
- Most common non-viral STI
729
How is Trichomonas vaginalis treated?
Treated with Metronidazole
730
How is Giardiasis spread? What does it cause?
Faeco-oral spread
- Diarrhoea
731
How is Giardiasis treated?
Treated with Metronidazole
732
What is Amoebiasis caused by?
Entaemoeba histolytica
Faeco-oral spread
733
How is Amoebiasis treated?
Metronidazole
734
What is Cryptosporidiosis caused by? How is it spread?
Cryptosporidium spp
Waterborne
735
What is Toxoplasmosis caused by? How is it spread?
Toxoplasma gondii
Ingestion of contaminated food and water/feline faeces
736
What are the 5 classifications of amoeba?
1. Flagellate i.e Trypanosoma, Leishmania, Giardia
2. Amoeba i.e Entaemoeba histolytica
3. Sporozoa i.e Cryptosporidium, Toxoplasma gondii, Plasmodium
4. Microsporidia
5. Cilliates i.e Balantidium coli
737
How is malaria transmitted?
Transmitted by bite of female anopheles mosquito.
5 species:
Plasmodium falciparum
Plasmodium ovale
Plasmodium vivax
Plasmodium malariae
Plasmodium knowlesi
738
What test to diagnose malaria?
Blood film test
Malaria parasites can be identified by examining under the microscope.
Thin (tells you species and parasite count) and thick (low resolution, tells you if you have malaria) blood films.
739
Symptoms of malaria?
Chills
Headache
Myalgia
Fatigue
Diarrhoea
Vomiting
Abdo pain
FEVER
740
What are the 4 signs of malaria?
- Anaemia
- Jaundice
- Hepatosplenomegaly
- 'Black water fever'
741
What does Plasmodium falciparum cause that results in 'complicated malaria'?
OBSTRUCTED MICROCIRCULATION
- Caused by infected RBCs ability to adhere to endothelial cells
742
What are features of Complicated Malaria?
- Cerebral malaria
- ARDS/Pulmonary oedema
- Renal failure
- Sepsis
- Bleeding/Anaemia
743
Treatment for complicated malaria?
- IV artesunate
(IV quinine + doxycycline)
744
Treatments for uncomplicated malaria?
Chloroquine.
745
What 2 species of the plasmodia genus lie dormant, form hypnozoites in the liver and cause late relapse of malaria? How is it treated?
P.ovale and p.vivax.
Primiquine to eliminate
746
What is Aciclovir used for?
Anti-herpesvirus drug
Typically used to treat or prevent HSV1 HSV2 VZV infection.
747
What is Aciclovir's mechanism of action?
748
What is are antibiotics?
Antibiotics are molecules that work by binding a target site on bacteria
749
How do antibiotics work?
750
Beta lactam antibiotics...
don't work as well on Gram negative bacteria and aren't useful for eukaryotic cells.
751
Metronidazole and ciprofloxacin
Inhibit bacteria's nucleic acid synthesis
752
What are we trying to achieve with antibiotics?
Antibiotics give time and support for the immune system to deal with an infection.
753
How are bacteria pathogenic?
1. Attach and enter
2. Local spread
3. Multiply
4. Evade host defences
5. Shed from body
754
Consequences of bacteria being pathogenic on the human body
1. Direct: destroy phagocytes or cells in which bacteria replicate.
2. Indirect: Inflammation - e.g. nectroic cells, immune pathology - e.g. antibody.
3. Exotoxin - protein production. Endotoxin - Gram negative
4. Diarrhoea
755
Bactericidal antibiotics
- The agent kills the bacteria.
- Kills more than 99.9% in 18-24 hrs
- Antibiotics that inhibit cell wall synthesis
- Useful in endocarditis.
- Difficult to treat meningitis.
756
Bacteriostatic antibiotics
- Prevents the growth of bacteria.
- Kills more than 90% in 18-24 hrs
- Antibiotics that inhibit protein synthesis, DNA replication or metabolism.
- Reduce toxin production (i.e. endotoxin)
757
What is mininum inhibitory concentration (MIC)?
Minimum Inhibitory Concentration (MIC) is the lowest concentration (expressed as mg/L or μg/μL) of an antimicrobial agent that inhibits the visible in-vitro growth of microorganisms.
The MIC test determines the antimicrobial activity of a test agent against a specific bacteria.
758
What determines the efficacy of an antibiotic?
Drug must occupy an adequate number of binding sites, which is related to its conc within the microorganism.
Antibiotic should be able to remain at the binding site for sufficient period of time.
759
The two major determinants of anti bacterial effects are...
the conc and time the antibiotic remains on these binding sites.
760
Time dependent killing antibiotics
Key parameter is the time that serum conc remain above the MIC during the dosing interval.
E.g. beta lactams (penicillins, cephalosporins, carbapenems, monobactams), clindamycin, macrolides, oxazolidinones
761
Concentration dependent killing antibiotics
Key parameter is how high the conc is above MIC.
E.g. aminoglycosides, quinolones
762
The antibiotic reaching and staying on the site of bacterial infection depends on...
pharmacokinetics.
763
What is the appropriate or available route of administration of antibiotics?
764
How do antibiotics not work?
1. Bacteria can change the molecular configuration of antibiotic binding site or masks it e.g. flucloxacillin and rifampicin
2. The antibiotic is destroyed or inactivated e.g. Penicillins and cephalosproins hydrolysed by bacterial enzyme "Beta lactamase"
3. Prevent antibiotic stress
4. Remove antibiotic from bacteria
765
Intrinsic resistance of bacteria against antibiotics?
766
Acquired resistance of bacteria against antibiotics?
767
Carbapenems
768
What is the duration of a normal course of antibiotics?
5-7 days
769
Is an antibiotic safe to prescribe? What do we need to consider?
- What pathogen/bacteria are we treating?
- Bioavailability of the drug
- How are we administering the drug?
- Age of the patient
- Side effects
- Intolerance, allergy, anaphylaxis
- Renal and liver function
- Pregnancy and breastfeeding
- Risk of C.difficile
- Drug interactions
770
Beta lactams are
cell wall/peptidoglycan weapons
771
Beta lactams inhibitors
Amoxicillin-clavulanate
Piperacillin-tazobactem
772
What antibiotics work on Gram positive bacteria?
Thick cell wall therefore need beta lactams (simple cell wall weapon).
773
What does MRSA stand for?
Methicillin-resistant Staph. aureus
774
Vancomycin
Does not cross BBB or the eyes so not useful for infections there.
775
Glycopeptides are cell wall weapons
Vancomyosin and Teicoplanin - IV
776
What antibiotics work for Gram negative bacteria?
- Can use beta-lactams but aren't as useful.
- Cefuroxime - IV. Do not cover anaerobic bacteria.
- Co-amoxiclav (Augmentin) oral and IV.
- Piperacillin/tazobactem
- Meropenem - IV restricted at STH
777
Case 1: 23-year old woman attends with dysuria, frequency and cloudy urine for 36 hours
**Likely diagnosis**
Urinary tract infection (lower)
Bacteria: gram negatives (E. coli, proteus, klebsiella)
And gram positives (staph saprophyticus)
**Samples**
Consider urine culture if ? Resistance
✓ Children, pregnancy, men, > 65s, sepsis/pyelonephritis, catheter
**Management**
Self care + back-up antibiotics
Immediate antibiotic treatment
Nitrofurantoin for 3 days
778
Case 2: 66 year old woman
3 day history of fevers and nausea
Leg = hot, red, swollen
**Likely diagnosis**
Cellulitis usually lower limbs - unilateral
Red, hot, painful, tender skin
Spreading
Systemic symptoms
Bacteria: S. aureus and β haemolytic strep (Group A, C & G)
** Samples**
Bacterial swab for culture
Blood cultures
** Management**
Antibiotics
PO or IV flucloxacillin
Penicillin allergy: clarithromycin or clindamycin
Duration ~ 7 days
779
Why is infection prevention and control important?
300,000 healthcare associated infections (HCAI) in England per year
Estimated 9% of in-patients have a HCAI
Cost approx. £1 billion per year
Cause or contribute to estimated 20,000 deaths
Estimated 75% of healthcare workers infected at work
780
Which pathogens do we consider when it comes to infection prevention and control?
**Bacteria**
Methicillin resistant S.aureus
Clostridium difficile
Multi-drug resistant gram negatives
Glycopeptide resistant enterococci
Group A streptococcus
Mycobacterium tuberculosis
**Viruses**
Influenza
Norovirus
SARS-CoV-2
HIV
Hep B
Hep C
Varicella Zoster Virus
Viral haemorrhagic fevers
**Other**
Candida Auris
Creutzfeldt–Jakob disease
781
Infection vs colonisation
Infect: verb affect (a person, organism, etc.) with a disease-causing organism
We are more bacterial cells than human cells – COLONISATION
782
How do we prevent and control infections?
Ensure policies are kept.
Identification of risks:
- Routes and modes of transmission
- Virulence of organisms - ease of spread, likelihood of causing infection, consequences of infection if it occurs
- Some diseases have higher R rate i.e. Measles has R rate of 20 which means it can spread to 20 other people.
Minimise risks
783
How do you identify a risk of an infection?
Risk factors
e.g. recent return from Sierra Leone with fever
Screening
e.g. MRSA admission screening
Clinical diagnosis
e.g. cough and cavity on chest x-ray
Lab diagnosis
Carbapenemase Producing Enterobacteriaceae in urine
784
Routes of transmission
1. Patient A > environment > Patient B
2. Patient A > staff > Patient B
785
What are CPEs?
Carbapenemase-producing Enterobacteriaceae
786
What do CPEs include?
Include E. coli, Klebsiella, Proteus, Serratia, Enterobacter
787
Where do CPEs colonise?
Colonisers of large bowel, skin below waist and moist sites
Most common causes of UTI, intra-abdominal infection
788
What is carbapenemase?
Enzyme which inactivates carbapenem antibiotics
789
MRSA
Methicillin resistant Staph aureus
Staph aureus is a common skin and nasal commensal
Most strains are susceptible to flucloxacillin and other beta-lactem antibiotics.
MRSA was first described in 1971
Huge increase in numbers of cases in 1990s and 2000s
790
Norovirus
High attack rates amongst close contacts
Low infecting dose
Uncontained vomiting and diarrhoea
Short lived immunity only
Staff and patients at risk
Able to persist in the environment
Relatively resistant to conventional cleaning
791
Clostridium difficile
Produce bacterial spores, leads to prolonged hospital stays, toxic megacolon.
Water is the only thing that removes the spores.
Need to wash hands with soap and water.
The antibiotics use to treat it begin with "C"
792
What are endogenous infections?
Infections caused by patients own bacterial flora
Important in hospitalised patients, especially those with invasive devices or surgical patients
793
How can you prevent endogenous infections?
Good nutrition and hydration
Antisepsis/skin prep where indicated
Good theatre practice
Remove lines and catheters as soon as clinically possible
Change from IV to oral treatment whenever appropriate
794
What are some simple things that you can do to protect patients from infections?
Hand Hygiene is the single most effective method of preventing cross infection
(Can be hand washing and/or alcohol gel)
Personal protective equipment e.g. gloves, aprons, masks etc.
Disposal of sharps
795
What are the two blood tests used to monitor HIV infection?
1. CD4 count - measure of immune function
2. HIV viral load test
796
What is the UNAIDS goal by 2020?
90/90/90
*90% diagnosed.
*90% on anti-retroviral treatment.
*90% viral suppression, undetectable viral load.
797
What is the Fast-Track Cities initiative goal by 2030?
*95/95/95
*95% diagnosed, 95% on treatment, 95% virally suppressed.
*200,000 new infections per year
*zero discrimination
798
Did the UK achieve the 90/90/90 target?
YES! :D achieved by 2018
799
HIV transmission routes
*Sexual
*Vertical
800
Prevention of HIV?
*Condoms
*Post exposure prophylaxis (PEP) (72 hrs)
*Oral pre-exposure prophylaxis (PrEP)
*Male circumcision
*Testing STIs
*Treatment as prevention (TasP)
801
What are the steps that should be taken following HIV diagnosis?
- Discuss soon after diagnosis
- length of 'look back' depends on individual circumstances
- Document discussion of safer sex practices, PEPSE, PreP for their partner
802
What is U=U?
Undetectable = untransmittable
803
Why is HIV testing important?
- Access to appropriate treatment and care
- Reduction in morbidity an mortality
- Reduction of vertical transmission
- Reduction of sexual transmission
- Public health/partner notification
- Cost-effective
804
What scenarios would you test for HIV?
*Clinician initiated testing triggered by clinical indicators of immuno-suppression disease/seroconversion
*Routine screening in high prevalence locations
*Routine screening Antenatal screening
*Screening in high risk groups
*Patient initiated requests for testing
805
Why do doctors not test for HIV?
*They don't think of HIV
*Underestimate the risk of HIV in their patients
*Failure to recognise HIV as a modifiable prognostic indicator
*Misconception they need pre-test counselling
*Misunderstanding of the implications for insurance, etc
*Fear of offending the patient
806
What is the most common opportunistic infection seen in HIV patients?
Pneumocystis pneumonia (PCP)
Caused by the Pneumocystis jirovecii fungal infection
Symptoms: fevers, SOB, dry cough, pleuritic chest pain, exertional drop in oxygen saturations
807
Common medical conditions where you should consider the possibility of HIV.
- Flu-like illness, rash
- Blood dyscrasias eg low platelets
- Multi-dermatomal shingles
- Lymphadenopathy
- Weight loss or diarrhoea, night sweats, PUO
808
What method of HIV screening test is preferred?
*Venous blood sample is preferred.
*4th generation HIV tests include p24 antigen and will detect the vast majority of infections at 4 weeks (if negative, repeat at 7 weeks if high index of suspicion)
*High sensitivity and selectivity
809
HIV is a retrovirus what does this mean?
It is an RNA virus which uses reverse transcriptase (RT) to make a DNA copy that becomes integrated into the DNA of the infected cell.
810
Where did HIV come from?
HIV-1 is similar to SIV in chimps from central Africa, and probably arose there
HIV-2 closely resembles SIV isolated from West African sooty mangabey monkeys
811
Why is it hard to create a vaccine for HIV?
HIV-1 mutates rapidly, as it is error-prone and replicates rapidly.
The tried and tested vaccine strategies that we have used for other organisms (live attenuated or killed vaccines) are deemed too risky for HIV
812
HIV genome structure
Small RNA virus ~10KB
Retrovirus family
Lentivirus: long incubation period
813
Briefly describe the mechanism of HIV replication.
1. GP160 binds to CD4 receptors.
2. Viral caspid, enzymes and nucleic acids are uncoated and released into the cell.
3. RNA is converted into DNA using reverse transcriptase.
4. Viral DNA is integrated into cellular DNA by intergrase.
5. Viral DNA is transcribed into viral proteins.
6. Splicing.
7. New HIV cells 'bud' from CD4.
814
What is the CD4+ count when someone is diagnosed with having AIDS?
CD4+ <200.
815
Where in the cell can HIV drugs target?
1. Reverse transcriptase inhibitors.
2. Protease inhibitors.
3. Fusion/entry inhibitors.
4. Integrase inhibitors.
816
How are some people resistant to HIV-1 infection?
Homozygous 32bp deletion in the CCR5 gene.
817
What are the 4 main phases in the natural history of untreated HIV?
1. Acute primary infection. 6-12 weeks
2. Asymptomatic phase. 1-15+ years
3. Early symptomatic HIV.
4. AIDS.
818
Why does the immune response to HIV-1 fail to clear the virus?
*CD4 T helper cells are lost from early in infection as these are the cells HIV infects first.
*Cytotoxic CD8 cell response fails when "immune exhaustion" sets in.
*Antibodies fail to bind to virus due to heavily glycosylated envelope spike.
*Virus can change quickly and evade antibody recognition
819
Which regions are seeing the most rapid rise in new HIV infections?
Eastern European and central Asia
820
List 3 social-economic impact of HIV/AIDS in Africa?
*Significant impact on life expectancy
*Loss of economically-productive adults (including health-care workers)
*Increased spending on healthcare (particularly as ART drug use becomes more widespread)
*Distortion of health-care spending
*Change in social structure: orphans cared for by elderly grandparents
*Stigma of HIV infection persists
821
Who is most at risk of acquiring HIV?
In the modern world
HIV incidence among adolescent girls and young women (aged 15-24) are the highest.
822
What are the three methods of paediatric HIV-1 transmission?
*In utero - transplacental, mostly during third trimester
*Intra partum - exposure to maternal blood and genital secretions during delivery
*Breast milk - ingestion of large amounts of contaminated milk
823
How does male circumcision work to prevent HIV infection?
By removing foreskin, circumcision reduces the ability of HIV to penetrate due to keratinization of the inner aspect of the remaining foreskin.
824
What signs and symptoms might you see when someone is in the acute primary infection phase of HIV?
Symptoms usually start within 2-4 weeks of infection
*Similar to glandular fever/flu
*Abrupt onset of non-specific symptoms e.g. fever, rash, sore throat, Weight loss, myalgia, V+D, headache, lymphadenopathy
825
What signs and symptoms might you see when someone is in the clinical latent phase of HIV?
No symptoms
May notice some enlarged lymph nodes
*persistent generalised lymphadenopathy
826
What signs and symptoms might you see when someone is in the early symptomatic phase of HIV?
Unexpected medical conditions that are recurring with no clear underlying cause.
827
What is the usual treatment for PCP?
High dose co-trimoxazole.
828
What does it mean when a patient has HIV and TB?
Regardless of CD4 count they would be considered to have AIDS.
829
Name 3 CNS diseases associated with HIV.
1. Mass lesions e.g. primary CNS lymphoma, cerebral toxoplasmosis.
2. Meningitis e.g. pneumococcal, cryptococcal.
3. Opthalmic lesions e.g. CMV, toxoplasmosis, choroidal tuberculosis etc.
830
What cancers does HIV increase the risk of?
HIV increases the risk of any cancer that is associated with a virus
Human Herpesvirus 8 -> Kaposi’s sarcoma
Epstein Barr Virus -> Lymphomas
Human Papillomavirus -> Cervical, anal, penile carcinoma
Hepatitis B/C -> Hepatocellulcar carcinoma
831
What symptoms are there in someone with Kaposi's sarcoma?
Single or multiple lesions, usually on the skin
832
What is HAART?
Highly active anti-retroviral therapy where 3 drugs that act on different points in the replication cycle are taken together.
833
What happens when a patient starts HAART?
*Viral load decreases rapidly.
*CD4 count begins to increase.
834
What factors increase the chances of HIV developing drug resistance?
1. Non adherence
2. Drug-drug interactions
2A
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