Introductory Clinical Sciences Flashcards
1
Q
Define inflammation.
A
A local physiological response to tissue injury.
2
Q
Give a benefit of inflammation.
A
Inflammation can destroy invading micro-organisms and can prevent the spread of infection.
3
Q
Give a disadvantage of inflammation.
A
Inflammation can produce disease and can lead to distorted tissues with permanently altered function.
4
Q
Define exudate.
A
A protein rich fluid that leaks out of vessel walls due to increased vascular permeability.
5
Q
What are the 4 outcomes of inflammation?
A
- Resolution.
- Suppuration.
- Organisation (scar tissue formation).
- Progression onto chronic inflammation.
6
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.
7
Q
What does viral infection result in?
A
Cell death due to intracellular multiplication.
8
Q
What does bacterial infection result in?
A
The release of exotoxins (involved in the initiation of inflammation) or endotoxins.
9
Q
Give 5 cardinal signs of inflammation.
A
- Redness (rubor).
- Swelling (tumor).
- Pain (dolor).
- Heat (calor).
- Loss of function.
10
Q
How can acute inflammation be diagnosed histologically?
A
By looking for the presence of neutrophil polymorphs.
11
Q
Give 3 endogenous chemical mediators of acute inflammation.
A
- Bradykinin.
- Histamine.
- Nitric Oxide.
12
Q
What are 4 systemic effects of acute inflammation?
A
- Fever.
- Feeling unwell.
- Weight loss.
- Reactive hyperplasia of the reticuloendothelial system.
13
Q
What cells are involved in chronic inflammation?
A
Macrophages and plasma cells (B and T lymphocytes).
14
Q
What cell can form when several macrophages try to ingest the same particle?
A
Multinucleate giant cell.
15
Q
Give 4 causes of chronic inflammation.
A
- Primary chronic inflammation.
- Transplant rejection.
- Recurrent acute inflammation.
- Progression from acute inflammation.
16
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.
17
Q
In which type of inflammation would you see neutrophil polymorphs?
A
Acute inflammation.
18
Q
What are some macroscopic features of chronic inflammation?
A
- Chronic ulcer.
- Chronic abscess cavity.
- Granulomatous inflammation.
- Fibrosis.
19
Q
What is granulation tissue?
A
Granulation tissue is composed of small blood vessels in a connective tissue matrix with myofibroblasts. It is important in healing and repair.
20
Q
Define granuloma.
A
An aggregate of epithelioid histocytes.
21
Q
Give an example of a granulomatous disease.
A
TB, leprosy, Crohn’s disease and sarcoidosis.
22
Q
The activity of what enzyme in the blood can act as a marker for granulomatous disease?
A
Angiotensin converting enzyme.
23
Q
What kind of disease is TB?
A
A granulomatous disease.
24
Q
What is the difference between resolution and repair?
A
Resolution is when the initiating factor is removed and the tissue is able to regenerate. In repair, the initiating factor is still present and the tissue is unable to regenerate.
25
Name 5 types of cells capable of regeneration.
1. Hepatocytes.
2. Osteocytes.
3. Pneumocytes.
4. Blood cells.
5. Gut and skin epithelial cells.
26
Name 2 types of cells that are incapable of regeneration.
1. Myocardial cells.
| 2. Neuronal cells.
27
Define abscess.
Acute inflammation with a fibrotic wall.
28
Define thrombosis.
Formation of a solid mass from blood constituents in an intact vessel in the living.
29
Give 2 reasons why thrombosis formation is uncommon.
1. Laminar flow.
| 2. Non sticky endothelial cells.
30
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.
31
Define embolus.
A mass of material (often a thrombus) in the vascular system that is able to become lodged in a vessel and block it.
32
Define ischaemia.
Decreased blood flow.
33
Define infarction.
Decreased blood flow with subsequent cell death.
34
Why are tissues with an end arterial supply more susceptible to infarction?
They only have a single arterial supply and so if this vessel is interrupted infarction is likely.
35
Give 3 examples of organs with a dual arterial supply.
1. Lungs (bronchial arteries and pulmonary veins).
2. Liver (hepatic arteries and portal veins).
3. Some areas of the brain around the circle of willis.
36
What can happen if ischaemia is rectified?
Re-perfusion injury can occur due to the release of waste products.
37
What are the consequences of an arterial embolus?
An arterial embolus can go anywhere! The consequences could be stroke, MI, gangrene etc.
38
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.
39
Through which blood system would an embolus have travelled if it resulted in a pulmonary embolism?
Venous system.
40
What drug can be used to prevent Thrombosis?
Aspirin.
41
Define atherosclerosis.
Inflammatory process characterised by hardened plaques in the intima of a vessel wall.
42
Is atherosclerosis more common in the systemic or pulmonary circulation?
It is more common in the systemic circulation because this is a higher pressure system.
43
What are the 3 main constituents of an atheromatous plaque?
1. Lipids.
2. Fibrous tissue.
3. Lymphocytes.
44
Give 5 risk factors for atherosclerosis.
1. Cigarette smoking.
2. Hypertension.
3. Hyperlipidaemia.
4. Uncontrolled diabetes mellitus.
5. Lower socioeconomic status.
45
What can be done to prevent atherosclerosis?
Reduce risk factors and taking low dose aspirin regularly.
46
What is the primary cause of atherosclerosis?
Endothelial cell damage.
47
Why can cigarette smoking lead to atherosclerosis?
Cigarette smoking releases free radicals, nicotine and CO into the body. These all damage endothelial cells.
48
Why can hypertension lead to atherosclerosis?
A higher blood pressure means there is a greater force exerted onto the endothelial cells and this can lead to damage.
49
Define apoptosis.
Programmed cell death of a single cell.
50
What is the role of p53 protein?
p53 protein looks for DNA damage, if damage is present p53 switches on apoptosis.
51
What protein can switch on apoptosis if DNA damage is present?
p53 protein.
52
Activation of which family of protease enzymes can turn on apoptosis?
Caspases.
53
Activation of what receptor can activate caspase and therefore apoptosis?
FAS receptor.
54
Give an example of a disease where there is a lack of apoptosis.
Cancer; mutations in p53 mean cell damage isn't detected.
55
Give an example of a disease where there is too much apoptosis.
HIV.
56
Define necrosis.
Unprogrammed death of a large number of cells due to an adverse event.
57
Give 3 examples of events that can lead to necrosis.
1. Frost bite.
2. Avascular necrosis.
3. Infarction.
58
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.
59
Define hypertrophy.
Increase in the size of a tissue due to an increase in the size of constituent cells.
60
Define hyperplasia.
Increase in the size of a tissue due to an increase in the number of constituent cells.
61
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.
62
Define metaplasia.
A change in the differentiation of a cell from one fully differentiated cell type to another fully differentiated cell type.
63
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.
64
Define dysplasia.
Morphological changes seen in cells in the progression to becoming cancer. The cells become more 'jumbled up'.
65
Define acute inflammation.
Initial and short lived tissue reactions to injury.
66
Define chronic inflammation.
Subsequent and prolonged tissue reactions to injury.
67
What happens to a cell when the telomere gets too short?
It can no longer divide.
68
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.
69
Why can excision be used as a cure for basal cell carcinoma?
Because BCC doesn't metastasise.
70
Suggest a treatment that could be used for leukemia?
Chemotherapy. Leukemia is systemic, it circulates all around the body, therefore excision can't be used.
71
Define carcinoma.
Malignant tumour of epithelial tissue.
72
Give an example of 5 carcinoma's that can spread to bone.
1. Breast.
2. Kidney.
3. Lung.
4. Prostate.
5. Thyroid.
73
Give an example of a carcinoma that can spread to the axillary lymph nodes.
Breast carcinomas.
74
Why is adjuvant therapy often used in the treatment of carcinomas?
Micrometastes are possible even if a tumour is excised and so adjuvant therapy is given to suppress secondary tumour formation.
75
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.
76
What kind of carcinomas would targeted chemotherapy be most effective against?
Slower dividing tumours e.g. lung, colon and breast.
77
What is the theory behind targeted chemotherapy?
It exploits the differences between cancer cells and normal cells; this means it is more effective and has less side effects.
78
What kind of drugs can be used in targeted chemotherapy?
Monoclonal antibodies (MAB) and small molecular inhibitors (SMI).
79
What is required for a tumour to invade through a basement membrane?
1. Proteases.
| 2. Cell motility.
80
What is required for a tumour to enter the blood stream (intravasation)?
1. Collagenases.
| 2. Cell motility.
81
What is required for a tumour to exit the blood stream (extravasation)?
1. Adhesion receptors.
2. Collagenases.
3. Cell motility.
82
Give 2 promoters of tumour angiogenesis.
1. Vascular endothelial growth factors.
| 2. Fibroblast growth factors.
83
Give 3 inhibitors of tumour angiogenesis.
1. Angiostatin.
2. Endostatin.
3. Vasculostatin.
84
What 3 mechanisms do tumour cells use to evade host immune defence in the blood?
1. Platelet aggregation.
2. Adhesion to other tumour cells.
3. They shed surface antigens so as to 'distract' lymphocytes.
85
Give an example of a malignant tumour that often spreads to the lung.
Sarcoma (via venae cavae -> heart -> pulmonary arteries).
86
Give an example of carcinomas that can spread to the liver.
Colon, stomach and pancreatic carcinomas can spread to the liver via the portal vein.
87
What causes the pain associated with acute inflammation?
1. Stretching and distortion of tissues due to oedema and pus under high pressure in an abscess cavity.
2. Chemical mediators e.g. bradykinin and prostaglandins, are also known to induce pain.
88
Describe the process of neutrophil polymorph migration into tissues as seen in acute inflammation.
1. Margination of neutrophils.
2. Pavementing of neutrophils.
3. Neutrophils pass between endothelial cells.
4. Neutrophils pass through basal lamina and migrate into adventitia.
89
What is the main source of histamine?
Mast cells; histamine is stored in granules in their cytoplasm.
90
What enzymatic cascade systems does plasma contain?
1. The complement system.
2. The kinin system.
3. The coagulation system.
4. The fibrinolytic system.
91
What is the role of tissue macrophages in acute inflammation?
They secrete chemical mediators that attract neutrophil polymorphs.
92
What is the role of the lymphatic system in acute inflammation?
Lymphatic channels dilate and drain away oedematous fluid therefore reducing swelling. Antigens are also carried to lymph nodes for recognition by lymphocytes.
93
What is the major role of neutrophil polymorphs in acute inflammation?
Phagocytosis!
94
Define carcinogenesis.
A multistep process in which normal cells become neoplastic cells due to mutations.
95
What percentage of cancer risk is due to environmental factors?
85% environmental, 15% genetic.
96
Give 5 host factors that can affect cancer risk.
1. Race.
2. Diet.
3. Constitutional factors (gender, age).
4. Premalignant conditions.
5. Transplacental exposure.
97
Give an example of a situation when transplacental exposure lead to an increase in cancer risk.
The daughters of mothers who had taken diethylstiboestrol for morning sickness had an increased risk of vaginal cancer.
98
Name the 5 different categories of carcinogens.
1. Viral.
2. Chemical.
3. Ionising and non-ionising radiation.
4. Hormones, parasites and mycotoxins.
5. Miscellaneous e.g. asbestos and metals.
99
What causes skin cancer?
Exposure to UV light.
100
Chemical carcinogens: what types of cancer do polycyclic aromatic hydrocarbons cause?
Lung cancer and skin cancer.
101
Chemical carcinogens: what can expose people to polycyclic aromatic hydrocarbons?
Smoking cigarettes and mineral oils.
102
Chemical carcinogens: what types of cancer do aromatic amines cause?
Bladder cancer.
103
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.
104
Chemical carcinogens: what type of cancer do nitrosamines cause?
Gut cancer.
105
Chemical carcinogens: what type of cancer do alkylating agents cause?
Leukaemia; the risk is small in humans.
106
Define neoplasm.
An autonomous, abnormal, persistent new growth.
107
What is a neoplasm composed of?
1. Neoplastic cells.
| 2. Stroma.
108
Describe neoplastic cells.
Neoplastic cells are derived from nucleated cells. They're usually monoclonal and their growth is related to the parent cell.
109
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 for the neoplastic cells.
110
What is essential for neoplasm growth?
Angiogenesis.
111
What does a neoplasm release in order to initiate angiogenesis?
Vascular endothelial growth factors.
112
Why does necrosis often occur in the centre of a neoplasm?
The neoplasm grows quickly and outgrows its vascular supply.
113
What are the advantages of classifying neoplasms?
It helps to determine the appropriate treatment and prognosis.
114
What are the two ways in which neoplasms can be classified?
1. Behavioural classification.
| 2. Histogenetic classification.
115
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.
116
What is the histogenetic classification of neoplasms?
Histopathological tests specify tumour type by determining the cell of origin of a tumour. If the origin is unknown the tumour is said to be anaplastic.
117
What are the 7 main features of benign neoplasms.
1. Localised.
2. Non-invasive.
3. Slow growth, low mitotic activity.
4. Close resemblance to normal tissue.
5. Normal nuclei.
6. Necrosis and ulceration are rare due to slow growth.
7. Exophytic growth.
118
What are the consequences of benign neoplasms?
1. Pressure on adjacent structures.
2. Obstruction to flow.
3. Transformation into malignant neoplasms.
4. Anxiety.
119
What are the 7 main features of malignant neoplasms.
1. INVASIVE!
2. Metastases.
3. Rapid growth, high mitotic activity.
4. Resemblance to normal tissue.
5. Poorly defined border due to invasive nature.
6. Necrosis and ulceration are common.
7. Endophytic growth.
120
What are the consequences of malignant neoplasms?
Destroy surrounding tissue, blood loss due to ulceration, pain, anxiety.
121
Define carcinoma.
MALIGNANT EPITHELIAL NEOPLASM!
122
Define sarcoma.
Malignant connective tissue neoplasm.
123
What is a rhabdomyoma?
Benign striated muscle neoplasm.
124
What is an adenoma?
Benign tumour of glandular epithelium.
125
What is a papilloma?
A non-glandular benign tumour.
126
What is a leiomyoma?
A benign smooth muscle neoplasm.
127
What is a neuroma?
A benign neoplasm of nerves.
128
What is a chondrosarcoma?
A malignant neoplasm of cartilage.
129
What is a liposarcoma?
A malignant neoplasm of adipose tissue.
130
What is a melanoma?
A malignant neoplasm of melanocytes.
131
What is a lymphoma?
A malignant neoplasm of lymphoid cells.
132
What is a mesothelioma?
A malignant neoplasm of mesothelial cells.
133
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.
134
What must the immune system do in order to be effective?
The immune system has to discriminate self from non-self.
135
Describe innate immunity.
Non-specific, instinctive, present from birth, first line of defence. It is focused around physical and chemical barriers and phagocytosis. No lymphocyte involvement.
136
Give examples of physical and chemical barriers used in innate immunity?
Skin, mucociliary escalator, gastric acid, hairs, lysozymes etc.
137
What is the function of lysozyme?
It destroys bacterial cell walls.
138
Describe adaptive immunity.
Specific, requires lymphocytes. Memory and quicker response.
139
Give examples of 3 polymorphonuclear leukocytes.
1. Neutrophils.
2. Basophils.
3. Eosinophils.
140
Give examples of 3 mononuclear leukocytes.
1. Monocytes.
2. B lymphocytes.
3. T lymphocytes.
141
In which primary lymphoid tissue do T cells mature?
Thymus.
142
In which primary lymphoid tissue do B cells mature?
Bone marrow.
143
How do T cells recognise antigens?
For T cells to recognise antigens they must be displayed by an antigen presenting cell and bound to MHC1/2. T cells can't recognise soluble antigens.
144
What is the function of T helper 1 (CD4)?
It helps the immune response against intracellular pathogens. Secretes cytokines.
145
What is the function of T helper 2 (CD4)?
It helps produce antibodies against extracellular pathogens. Secretes cytokines.
146
What is the function of Cytotoxic T cell (CD8)?
It can kill cells directly by binding to antigens; they induce apoptosis.
147
What is the function of T reg (FoxP3)?
They regulate the immune response.
148
Which cells express MHC1?
All nucleated cells express MHC1. e.g. a virus infected or cancer cell would express MHC1.
149
Which cells express MHC2?
Antigen presenting cells ONLY e.g. macrophages, B cells, dendritic cells.
150
Which MHC would an intracellular antigen (endogenous) lead to the expression of?
MHC1.
151
Which MHC would an extracellular antigen (exogenous) lead to the expression of?
MHC2.
152
What type of T cell binds to MCH1?
Cytotoxic T cells (CD8).
153
What type of T cells binds to MCH2?
Helper T cells (CD4).
154
What do B cells differentiate into?
Plasma cells. The plasma cells then produce antibodies.
155
What does a helper T cell bind to?
A T cell receptor which is bound to an antigen epitope which is bound to MHC2 on an APC.
156
Which interleukin is secreted when a helper T cell is bound to a T cell receptor?
IL-2. This then binds to an IL-2 receptor on the T cell and produces a positive feedback mechanism leading to division and differentiation.
157
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.
158
What happens to B cells that recognise 'self'?
They are killed in bone marrow.
159
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.
160
Give 3 functions of antibodies.
1. Neutralise toxins.
2. Opsonisation.
3. Activate classical complement system.
161
Which immunoglobulin is found in breast milk and other secretions?
IgA.
162
What are the 2 most common immunoglobulins?
IgG and IgM.
163
Which region of an antibody binds antigens?
The fab region.
164
Which region of an antibody binds to B cells?
The Fc region.
165
Name 4 types of cytokines.
1. Interferons.
2. Interleukins.
3. Colony stimulating factors.
4. Tumour necrosis factors.
166
What is the function of interferons?
Interferons produce antiviral proteins.
167
What is the function of interleukins?
Interleukins cause cell division and differentiation.
168
What is the function of colony stimulating factor (CSF)?
CSF causes division and differentiation of bone marrow stem cells.
169
What is the function of tumour necrosis factor (TNF)?
TNF mediates inflammation and cytotoxic reactions.
170
What is the function of chemokines?
Chemokines attract leukocytes to sites of infection.
171
Give examples of secondary lymphoid tissue.
The spleen, lymph nodes, mucosa associated lymphoid tissue - MALT.
172
Describe the process of phagocytosis.
1. Pathogen binds to neutrophil/macrophage.
2. Engulfment of pathogen.
3. Phagosome formation.
4. Lysosome fusion - phagolysosome.
5. Pathogen is destroyed.
173
Give 3 examples of O2 dependent mechanisms of killing.
1. Killing using reactive oxygen intermediates.
2. Superoxides can be converted to H2O2 and then to hydroxyl free radicals.
3. NO leads to vasodilation and increased extravasation and so more neutrophils etc are in the tissues to destroy pathogens.
174
What is the role of NO in killing pathogens?
NO leads to vasodilation and increased extravasation. This means more neutrophils etc pass into the tissues to destroy pathogens.
175
Why can superoxides be used to destroy pathogens?
Superoxides can be converted to H2O2 and then to hydroxyl free radicals. Hydroxyl free radicals are highly reactive and can destroy pathogens.
176
What mechanisms or cells are involved in O2 independent killing?
Defensins, lysozyme, pH, TNF.
177
Where are complement system plasma proteins derived from?
The liver.
178
What are the 3 main outcomes of complement system activation?
1. Pathogen lysis.
2. Increased phagocytosis.
3. Activation of leukocytes.
179
What activates the classical complement pathway?
Antibodies.
180
Briefly describe the classical complement pathway.
1. C1s cleaves C4 -> C4a and C4b.
2. C4b binds C2b forming C4b2b. C4b2b is a C3 convertase and is responsible for C3 -> C3a and C3b.
3. C4b2b binds C3b forming C4b2b3b.
4. C5,6,7,8 and 9 also bind and eventually you get MAC formation. MAC is a pore like channel in a membrane.
181
What compound prevents excessive activation of the classical complement pathway?
C1 inhibitor.
| - C1 inhibitor leads to a negative feedback loop.
182
What activates the lectin pathway?
Mannose binding protein.
183
What activates the alternative pathway?
Bacterial cell walls and endotoxin.
184
What are the 3 different pathways that make up the complement system?
1. Classical.
2. Lectin.
3. Alternative.
185
Briefly describe the alternative pathway.
1. C3 reacts slowly with H2O forming C3(H2O).
2. C3(H2O) binds factor B. This becomes a substrate for cleavage by factor D.
3. Factor B is split into Bb and Ba.
4. Bb sticks to C3(H2O) forming C3(H2O)Bb.
5. C3(H2O)Bb is a C3 convertase that cleaves C3 into C3b and C3a.
6. C3b then binds to pathogens and causes opsonisation for improved phagocytosis. Also leads to MAC formation.
186
Which complement plasma proteins have opsonic properties when bound to a pathogen?
C3b and C4b.
187
What is the function of MAC in a pathogens' membrane?
MAC is a leaky pore like channel. Ions and water pass through the channel and disrupt the intracellular microbe environment -> microbe lysis.
188
Which complement plasma proteins are pro-inflammatory and cause chemotaxis and activation of neutrophils and monocytes etc?
C3a and C5a.
189
What kind of immunity are PRR's and PAMP's associated with?
Innate immunity.
190
What are PRR's a receptor for?
PAMP's.
191
Name 3 receptors that make up the PRR family.
1. Toll-like receptors (TLR).
2. Nod-like receptors (NLR).
3. Rig-like receptors (RLR).
192
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.
193
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.
194
What disease could be caused by a non-functioning mutation in NOD2?
Crohn's disease.
195
What is the main function of RLR's?
RLR's detect intracellular double stranded RNA. This triggers interferon production and so an antiviral response.
196
TLR's are adapted to recognise damaged molecules. What characteristic do these damaged molecules often have in common?
They are often hydrophobic.
197
What kind of TLR's can be used in vaccine adjuvants?
TLR4 agonists.
198
Give examples of diseases that can be causes by PRR's failing to recognise pathogens.
1. Atherosclerosis.
2. COPD.
3. Arthritis.
199
Give examples of 3 extracellular PRR.
1. Mannose receptors.
2. Scavenger receptors.
3. TLR's.
200
What is the function of mannose and scavenger extracellular receptors?
The induce pathogen engulfment.
201
Give an example of an intracellular PRR.
NLR.
202
Where are circulating PRR secreted from?
Epithelia, phagocytes and the liver. They can activate the complement cascade and induce phagocytosis.
203
What happens when a PAMP binds to a PRR?
The innate immune response and inflammatory response is triggered.
204
What is extravasation?
Leukocyte (WBC) migration across the endothelium.
205
What do macrophages at the tissues secrete to initiate extravasation?
TNF alpha.
206
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 pass through the endothelium to the tissue to help fight infection.
207
What 2 compounds can act as C3 convertase?
1. C4b2b - produced in the classical and lectin pathways.
| 2. C3(H2O)Bb - produced in the alternative pathway.
208
What type of cancers results from transformations in the germ line?
Inheritable cancers (<10%).
209
What type of cancers results from transformations in somatic cells?
Non-inheritable cancers (>90%).
210
What factors can cause transformations in somatic cells?
Environmental factors e.g. UV, chemicals (smoking can cause lung cancer), pathogens (HPV can cause cervical cancer).
211
What are the 7 hallmarks for cancer?
1. Evade apoptosis.
2. Ignore anti-proliferative signals.
3. Growth and self sufficiency.
4. Limitless replication potential.
5. Sustained angiogenesis.
6. Invade surrounding tissues.
7. Escape immuno-surveillance.
212
What are the two types of tumour antigens and where are they found?
1. Tumour specific antigens; only found on tumour cells. Due to point mutations.
2. Tumour associated antigens; found on normal cells and over expressed on tumour cells.
213
What is cancer immunosurveillance?
When the immune system recognises and destroys transformed cells, this is an important host protection process.
214
What is cancer immunoediting?
When the immune system kills tumour cells changes are induced in the tumour, the tumour cells are 'edited' by natural selection. The tumour cells are then disguised from the immune system, they escape destruction and recurrence is possible.
215
What are the 3 E's of cancer immunoediting?
1. Elimination.
2. Equilibrium.
3. Escape.
216
Give an example of active cancer immunotherapy.
Vaccination e.g. killed tumour vaccine, purified tumour antigens, APC-based vaccines etc.
217
Give an example of passive cancer immunotherapy.
T cell transfer, anti-tumour antibodies.
218
Why is hypoxia a prominent feature of a lot of malignant tumours?
Malignant tumours grow rapidly and so outgrow their blood supply.
219
Give 3 reasons why hypoxic tumours have a poor prognosis for the patient.
1. Hypoxic tumours have growth factors for angiogenesis and so can receive nutrients for growth.
2. They suppress the immune system.
3. They are resistant to chemotherapy and radiotherapy.
220
Give 3 advantages of active immunity.
1. Induces immunological memory.
2. Produces high affinity antibodies.
3. It produces a persistent protective response against pathogens.
221
Give 2 advantages of passive immunity.
1. Immediate effect.
| 2. Useful treatment for acute dangers e.g. snake venom.
222
Give 3 disadvantages of passive immunity.
1. Short term.
2. No immunological memory produced.
3. Reaction is possible.
223
Describe the first immune response to initial exposure.
1. Innate immune response.
2. IgM predominates.
3. Low affinity.
224
Describe the second immune response following exposure to a pathogen encountered before.
1. Rapid and larger than the first.
2. High affinity IgG.
3. Adaptive immunity, T cell help.
225
Give 3 advantages of live vaccines.
1. Very effective, prolonged and comprehensive.
2. Immunological memory produced.
3. Often only 1 vaccine is needed.
226
Give 2 disadvantages of live vaccines.
1. Immunocompromised patients may become ill.
| 2. Vaccines often need to be refrigerated which can be a problem in remote areas.
227
Give 2 advantages of inactivated vaccines.
1. There is no risk of infection.
| 2. Storage is less critical.
228
Give 3 disadvantages of inactivated vaccines.
1. Inactivated vaccines tend to only activate the humoral response; there is a lack of T cell involvement.
2. The response is often weak.
3. Boosters are needed and so patient compliance may be poor.
229
What is the role of an adjuvant?
An adjuvant is a substance added to a vaccination to stimulate an immune response. They convince your immune system that you're infected.
230
What can be used as an adjuvant?
Toxoids, proteins, chemicals (aluminium salts) etc.
231
What are the 5 features of an ideal vaccine?
1. Safe.
2. Induces a suitable immune response.
3. Shouldn't require repeated boosters.
4. Generates immunological memory.
5. Stable and easy to transport.
232
Give 3 advantages of transplantation.
1. Improved quality of life.
2. Improves survival rates.
3. Cost effective.
233
Why are immunosuppressive agents needed to prevent rejection?
Transplanted organs are recognised as non self and therefore are seen as a threat. Graft v host disease; T-cells destroy graft cells.
234
On which chromosome are MHC proteins found?
Chromosome 6.
235
Describe the transplant cascade.
Donor -> organ preservation -> implantation -> re-perfusion -> organ function.
236
What are the main compounds involved in reperfusion injury?
Free radicals e.g. H2O2, O2-, OH-. They damage cell walls.
237
Define allorecognition.
The ability of an organism to distinguish its own tissues from those of another. Recognition of non-self antigens.
238
What are the consequences of transplant rejection?
Fibrosis and scarring.
239
Describe the immune responses to detection of graft antigens.
1. Innate immune response is activated.
2. T cell mediated cytotoxicity.
3. Ab mediated cytotoxicity.
4. Hypersensitivity.
5. Tolerance.
240
Give 6 ways of preventing transplant rejection?
1. Manage risk factors.
2. Tissue typing.
3. Cross match.
4. Immunosuppressive agents.
5. Sensitisation and desensitisation.
6. Tolerance.
241
Why is it important to get the balance right when using immunosuppressive agents?
Too much = infection.
| Too little = rejection.
242
What is involved in tissue typing?
1. Blood group matching.
| 2. HLA typing.
243
What is involved in cross matching?
Detecting anti HLA antibodies.
| Cell based assays and solid phase assays can be used.
244
Define tolerance with regards to transplant immunology.
Tolerance is the acquired modification to host immunity leading to drug free transplant survival with full immunocompetence.
245
Define xenotransplantation.
Transplantation of tissues from one species to another.
246
What is allergy?
An abnormal response to harmless foreign material.
247
What is atopy?
The tendency to develop allergies.
248
Which immunoglobulin is most commonly involved in allergic responses?
IgE.
249
Which cells are most commonly involved in allergic responses?
Mast cells! Also eosinophils and basophils.
250
What happens to IgE receptors when a 'threat' is identified?
The receptors cross-link.
251
Which cells express high affinity IgE receptors?
Mast cells, basophils and eosinophils.
252
What are the steps in an allergic response?
Allergen/threat is identified -> high affinity IgE receptors cross link -> IgE binds -> Mast cells are activated -> granules released -> histamine and cytokines. Cytokines induce a TH2 response.
253
What is the main IgE receptor cell?
MAST CELLS!
254
Which compound causes blood vessel dilation and vascular leakage in an allergic response?
Histamine.
255
What is the role of cytokine release in an allergic response?
They induce a TH2 response.
256
Which cells and which immunoglobulin is commonly involved in anaphylaxis?
- Mast cells and basophils.
| - IgE.
257
Give examples of anaphylactic systemic effects.
- CV: vasodilation, lowered BP.
- Resp: bronchial SM contraction, mucus.
- Skin: rash, swelling.
- GI: pain, vomiting.
258
Give 5 possible treatments for allergy and hypersensitivity.
1. Avoid allergens.
2. Desensitisation (immunotherapy, some risks).
3. Prevent IgE production (interfere with TH2 pathway).
4. Prevent mast cell activation.
5. Inhibit mast cell products (e.g. histamine receptor antagonists).
259
Which infection is most often seen in patients with hypogammaglobulinemia?
Streptococcus penumonia sinusitis.
260
Give 5 examples of PAMPs.
1. Lipopolysaccharides.
2. Endotoxins.
3. Bacterial flagellin.
4. Peptidoglycans.
5. dsRNA.
261
Which PRR responds to lipopolysaccharides?
TLRs.
262
Is production of interferons (anti-viral proteins) part of the elimination phase of complement activation?
No
263
Give 4 causes of acquired immunodeficiency.
1. Cancer.
2. HIV.
3. Having chemotherapy.
4. Taking immunosuppressants.
264
What signs and symptoms might a person with HIV present with?
Fever, weight loss, recurrent infections, respiratory infections, TB.
265
What immune system cells are affected in HIV?
There is CD4 deficiency and B cell defects too. The adaptive immunity is affected.
266
What is the name of the disease that is characterised by B cell deficiency?
Hypogammaglobulinaemia.
267
What infection is most commonly seen in patients with hypogammaglobulinaemia?
Streptococcus pneumonia.
268
Describe hyper IgM syndrome.
High numbers of IgM. IgM is non specific and has a low affinity. IgM is unable to class switch to more 'useful' immunoglobulins and so IgA, IgE and IgG numbers are low.
269
What are the consequences of complement deficiency?
Impaired opsonisation of encapsulated bacteria.
270
What is terminal complement deficiency and what are its consequences?
- Terminal complement deficiency is when there's a problem with C5-8 and so MAC isn't produced.
- The consequences of this are chronic Neisserial infections and recurrent meningitis.
271
What are the consequences of being deficient in C1 inhibitor?
Angioedema - facial swelling.
272
What are the consequences of being deficient in C1, 2 or 4?
Increased likelihood of autoimmune disease especially systemic lupus erythematosus.
273
What are the consequences of hyposplenism?
Reticuloendothelial function is decreased. This means the body has difficulty dealing with encapsulated bacteria e.g. streptococcus pneumonia.
274
What is thymic aplasia?
A deficiency in mature T cells.
275
How can immune function be assessed?
1. Looking at neutrophil numbers, morphology and flow cytometry.
2. Looking at B and T cell subsets, numbers and response to vaccines.
3. Genetic studies.
276
Give 3 examples of chronic inflammatory diseases.
1. Rheumatoid arthritis.
2. Crohn's disease.
3. TB.
277
Name 3 conventional therapies used in managing CID.
1. NSAIDs.
2. DMARDs.
3. Steroids.
278
What disease are DMARDs most commonly used in the management of?
Rheumatoid arthritis.
| DMARD - disease-modifying antirheumatic drug
279
How do NSAIDs work in relieving inflammation.
NSAIDs inhibit COX 1 and 2. COX 2 is needed for prostaglandin synthesis. Prostaglandins are responsible for inflammation and pain. Therefore NSAIDs reduce symptoms of inflammation and pain.
280
What is a disadvantage of long term NSAID use?
NSAIDs can cause gastric bleeding. They inhibit COX 1 which is needed for prostaglandin synthesis and prostaglandins are needed for gastric mucus production.
281
Give 2 advantages of biological agents in treating chronic inflammatory disease?
1. They're extremely specific.
| 2. A low dose is very effective.
282
Give 5 disadvantages of biological agents in treating chronic inflammatory disease?
1. They're very expensive.
2. There is a risk of contamination.
3. They're always injected.
4. They're immunosuppressive.
5. They need to be handled carefully to prevent denaturation.
283
What class of biological agent is often used in the treatment of rheumatoid arthritis when DMARDs fail?
TNF blockers - they bind to TNF to prevent it interacting with its receptors.
284
Name 3 TNF blockers.
1. Etanercept (TNF alpha specific).
2. Infliximab.
3. Adalimumab.
285
What compound is often combined with biological agents to make treatment cheaper?
Methotrexate.
286
Give a side effect of using TNF blockers.
Increased susceptibility to TB.
287
How do IL-6 blockers work?
IL-6 is an inflammatory cytokine. The biological agent binds to IL-6 so as to prevent it interacting with its receptor.
288
Name an IL-6 blocker.
Tocilizumab.
289
When are IL-6 blockers used?
They're used in the treatment of rheumatoid arthritis when TNF blockers fail.
290
What are the risks of using IL-6 blockers?
They dampen the immune response and so you have an increased risk of infection. There is also an incerased risk of shingles and chickenpox.
291
Name 4 classes of biological agents and give an example of a drug for each.
1. TNF blockers e.g. etanercept.
2. IL-6 blockers e.g. Tocilizumab.
3. Anti B lymphocytes e.g. rituximab.
4. T cell activation blockers e.g. abatacept.
292
In what region of the antibody is there reversible bonding between antibodies and antigens?
Complementarity determining region (CDR).
| - Hydrogen bonds and VDW's etc form cumulative weak interactions that together form a strong force.
293
True or False. The heavy and light chains of an antibody are coded for by the same gene.
False. Distinct sets of genes code for the heavy and light chains.
294
What region determines Ig class?
The constant region!
295
What is the result of recombination in the Ig region?
Class switching.
296
Describe complement fixation.
An antibody binds multiple antigens so as to bring the Fc regions together. The complement pathway is initiated in this process and you get MAC formation.
297
Which compound is responsible for signalling when an antigen binds to an antibody?
Tyrosine kinase.
298
What immunoglobulin do naive antibodies express?
IgM.
299
Describe the process of class switching.
Antigen engagement and T cell help will result in class switching. A different FC region is used and there is affinity maturation.
300
What do T cells recognise?
PEPTIDES
301
Describe somatic hypermutation.
1. Random mutations in CDR.
2. Amino acid sequences are effected meaning Ab-Ag affinity is altered.
3. High affinity B cell clones are selected via natural selection.
302
Briefly describe the steps involved between T cell stimulation and plasma cell differentiation.
1. T cells are stimulated.
2. Cytokine release.
3. B cell proliferation.
4. Somatic hypermutation.
5. High affinity B cell clones differentiate into plasma cells and memory cells.
303
Give 4 uses of antibodies in medicine.
1. Diagnostic tools.
2. Immunoassays, Ab's are used to measure the presence of a molecule.
3. Flow cytometry, Ab's label cells in suspension.
4. Therapeutic uses, monoclonal Ab's can act as specific antagonists for biological targets e.g. HERCEPTIN.
304
Give an example of a proton pump inhibitor.
Omeprazole.
305
Give an example of a statin.
Simvastatin.
306
Give an example of an ACE inhibitor.
Enalapril.
307
Give an example of a COX inhibitor.
Aspirin and paracetamol.
308
Give an example of a β2 adrenoceptor agonist.
Salbutamol.
309
Give an example of a β1 adrenoceptor blocker.
Atenolol.
310
Give an example of a Ca2+ channel blocker.
Amlodipine.
311
Give an example of a broad spectrum antibiotic.
Amoxicillin.
312
Give an example of an opiate analgesic.
Tramadol.
313
What do most drugs target?
Proteins!
314
Name 4 receptors that drugs target.
1. Ligand gated ion channels.
2. GPCR.
3. Kinase linked.
4. Cytosolic/nuclear.
315
Give an example of a ligand gated ion channel.
Nicotinic Ach receptor.
316
Give an example of a GPCR.
Muscarinic and β2 adrenoceptor.
| GPCR's usually interact with adenylate cyclase or phospholipase C
317
Give an example of a kinase linked receptor.
Receptors for growth factors.
318
Give an example of a cytosolic/nuclear receptor.
Steroid receptors; steroids affect transcription.
319
What are agonists?
Agonists bind to a receptor and to activate it.
320
What are antagonists?
Antagonists decrease the effect of an agonist. They show no response at a receptor.
321
Describe the shape of a log dose-response curve.
Sigmoidal.
322
What does EC50 tell us about a drug?
Its potency!
323
What is EC50?
The concentration of drug that gives half the maximal response.
324
Would a drug with a lower EC50 have a lower or greater potency?
Greater potency.
325
What does Emax tell us about a drug?
Efficacy.
326
Which is more efficacious, a full agonist or partial agonist?
A full agonist is more efficacious because a full agonist can give a 100% response.
327
Would an antagonist shift a dose-response curve to the left or right?
The antagonist would shift the dose-response curve to the RHS. The drug therefore becomes less potent.
328
Drug action: define affinity.
How well a ligand binds to a receptor.
329
Drug action: define efficacy.
How well a ligand activates a receptor; how well it induces a conformational change.
330
What is the effect of fewer receptors on drug potency?
Fewer receptors will shift the dose-response curve to the RHS, this means drug potency will be reduced.
331
What is the effect of fewer receptors on receptor response?
Receptor response is still 100% due to receptor reserve. (Partial agonists don't have receptor reserve).
332
What is the affect of less signal amplification on drug response?
Less signal amplification gives a reduced drug response.
333
Describe allosteric modulation.
An allosteric modulator binds to a different site on a receptor and influences the role of an agonist.
334
What is inverse agonism?
Where an agonist has a negative effect at a receptor.
335
Does an antagonist show efficacy?
No. An antagonist has affinity but zero efficacy. An agonist however demonstrates affinity and efficacy.
336
Pharmacology: define tolerance.
A reduction in the effect of a drug overtime. This can be due to continuous use of repeatedly high concentrations.
337
What 3 ways can a receptor be desensitised?
1. Uncoupled (an agonist would be unable to interact with a GPCR).
2. Internalised (endocytosis, the receptor is taken into vesicles in the cell).
3. Degraded.
338
Can aspirin be described as a selective drug?
No. Aspirin is non-selective, it acts on COX1 and COX2.
339
What is the function of COX1 and COX2?
They cyclise and oxygenate arachidonic acid and produce prostaglandin H2.
340
What does prostaglandin H2 form when it interacts with synthases?
Prostanoids.
341
Define pro-drugs and give an example of one.
Drugs that need to be activated enzymatically e.g. ACE inhibitors, enalapril.
342
How do ACE inhibitors work?
Angiotensinogen is converted to angiotensin 1 via renin. Angiotensin 1 is then converted to angiotensin 2 via ACE. ACE inhibitors prevents angiotensin 1 binding and so you don't get angiotensin 2 formation.
(Angiotensin 2 is a vasoconstrictor and so ACEi can be used in the treatment of hypertension).
343
Give an example of a β lactam antibiotic.
Penicillin and amoxicillin.
344
How do β lactam antibiotics work?
The inhibit transpeptidase and so prevent bacterial cell wall synthesis.
345
How do diuretics work?
They inhibit 'synporters' in the loop of henle. This leads to increased H2O excretion and decreased salt reabsorption and so BP decreases.
346
Give an example of loop of henle diuretics.
- Furosemide, act on the ascending loop.
| - Thiazides, act on the distal tubule.
347
How can drugs be developed?
1. Serendipity, by chance. e.g. penicillin.
| 2. Rational drug design. e.g. propranolol.
348
Describe how rational drug design works.
Rational drug design is focused on developing an antagonist from an agonist. It looks at solubility, electrostatic charge and bulk.
349
How do you determine whether insulin is long or short acting?
Small changes in amino acid sequence will determine whether insulin is long or short lasting - RECOMBINANT PROTEIN!
350
Name 3 things that the chemical properties of a drug can influence?
1. Administration.
2. Distribution.
3. Elimination.
351
As the difference in concentration falls what happens to the rate of reaction?
The rate of reaction will slow down.
| Rate is proportional to the concentration of drug
352
What is the association between diffusion and concentration gradient?
Diffusion is proportional to concentration gradient; this is a first order process and represents an exponential function.
353
How many litres of water are there in the following body compartments:
a) Plasma.
b) Interstitial space.
c) Intracellular space.
a) 3L.
b) 11L.
c) 28L.
354
What are the 5 ways by which fluid can move between compartments?
1. Simple diffusion.
2. Facilitated diffusion.
3. Active transport.
4. Movement through extra-cellular spaces.
5. Non-ionic diffusion.
355
What can influence the degree of ionisation of weak acids and weak bases?
pH.
356
What equation can be used to determine the degree of ionisation at a specific pH?
Henderson Hasselbach.
| pH = log[A-]/[HA] + pKa.
357
What can enhance non ionic diffusion?
Non ionic diffusion can be enhanced if adjacent compartments have pH difference.
358
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.
359
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.
360
What is the effect of an increase in pH on a weak acid?
The weak acid will become more ionised.
361
What is the effect of an increase in pH on a weak base?
The weak base will become less ionised.
362
What is the effect of a decrease in pH on a weak acid?
The weak acid will become less ionised.
363
What is the effect of a decrease in pH on a weak base?
The weak base will become more ionised.
364
Define bioavailability.
The amount of drug taken up as a proportion of the amount administered. It is a reflection of uptake.
365
What route of drug administration has a bioavailability of 1?
IV infusion, all the drug administered will go into the plasma.
366
Explain what would happen to the bioavailability of aspirin if gastric pH increased.
The bioavailability would decrease. Aspirin would be more ionised and so wouldn't diffuse across the gut into the plasma as rapidly this would mean aspirin uptake would decrease.
367
Give 2 factors that drug distribution in the plasma depends upon.
1. Chemical properties.
| 2. Molecular size.
368
Write an equation for the volume of distribution (Vd).
Vd = amount of drug administered/concentration of drug in plasma.
369
If a drug had a high Vd what would that tell us about the drug?
This would indicate that the drug was highly lipid soluble and that most of the drug had moved into the intracellular space, less was in the plasma.
370
What is the relationship between plasma concentration and Vd?
Plasma concentration is inversely proportional to Vd.
371
Give 3 factors that can increase gastric pH.
1. Ingesting alkaline foods.
2. Antacids.
3. Omeprazole (PPI).
372
Give the two definitions for clearance.
1. The volume of plasma from which a drug is completely removed per unit time.
2. The rate at which plasma drug is eliminated per unit plasma concentration.
373
Write an equation for renal clearance.
Renal clearance = Rate of appearance in urine / plasma concentration.
374
What are the two ways by which drugs can be eliminated in the kidneys?
1. Glomerular filtration.
| 2. Active secretion.
375
What are the possible dangers of kidney damage with regards to renal clearance?
Kidney damage results in decreased renal clearance and so there is danger of accumulation, over dosage and toxicity.
376
What compound do many lipid soluble drugs combine with to increase their hydrophilicity?
Glucuronic acid.
377
Define hepatic extraction ratio (HER).
The proportion of a drug removed by one passage through the liver.
378
What is the limiting factor when a drug has a high HER?
Hepatic blood flow, perfusion limited.
379
What is the limiting factor when a drug has a low HER?
Diffusion limited. A low HER is slow and not efficient.
380
What happens to high and low HER drugs when enzyme induction is increased?
The clearance of low HER drugs increases. There is minimal effect on high HER drugs.
381
Where do phase 1 hepatic metabolism reactions occur?
In the smooth endoplasmic reticulum.
382
What enzyme usually catalyses phase 1 reactions?
CYP450.
383
What is a phase 2 hepatic metabolism reaction?
Phase 2 reactions involve conjugation and glucuronidation etc.
They usually inactivate products and increase hydrophilicity for renal excretion.
384
Give 3 advantages of IV infusion.
1. Steady state plasma levels are maintained.
2. Highly accurate drug delivery.
3. IV infusion can be used for drugs that would be ineffective when administered via an alternative route.
385
Give 3 disadvantages of IV infusion.
1. Expensive.
2. Needs constant checking.
3. Calculation error likely.
386
Give an advantage of a drug having a low Vd.
It is easy to reach steady state and plasma concentration is ‘responsive’ to dose rate.
387
Give 4 properties of the 'ideal drug'.
1. Small Vd.
2. Drug broken down effectively by enzymes.
3. Predictable dose:response relationship.
4. Low risk of toxicity.
388
What are the advantages of pulsatile secretion as opposed to steady state?
1. Enhanced responsiveness.
| 2. More information can be conveyed.
389
What is the principal neurotransmitter in the body?
Acetylcholine.
390
What receptor does Ach interact with in the somatic nervous system?
Post-synaptic nicotinic receptors at the neuromuscular junction.
391
What type of receptor are nicotinic receptors?
Ligand gated ion channels.
392
Briefly describe how Ach is synthesised.
Acetyl CoA, choline and choline acetyl trasnferase combine to form acetylcholine. Ach is taken up into a vesicle in the presynpatic cleft and will be released following Ca2+ influx.
393
What enzyme is responsible for acetylcholine breakdown in the synaptic cleft?
Acetylcholinesterase.
394
Describe the action of botulinum toxin at the NMJ,
Botulinum toxin inhibits Ach release at the NMJ. Protease degrade vesicle proteins.
395
Describe the action of competitive antagonists at the NMJ.
They block Ach receptors. Competitive antagonists are muscle relaxants, adjuncts to general anaesthesia.
396
Describe the action of depolarising agonists (blockers) at the NMJ.
Depolarising agonists cause receptor desensitisation.
397
Describe the action of anticholinesterases at the NMJ.
There is increased Ach in the synaptic cleft. Ach can then compete with depolarising blockers.
398
What type of receptor are muscarinic receptors?
GPCR.
399
Give examples of adverse muscarinic agonist effects.
1. Diarrhoea.
2. Urination.
3. Miosis.
4. Brachycardia.
5. Emesis (vomiting).
6. Lacrimation.
7. Salivation.
400
Give 2 examples of Ach action in the CNS.
1. Motion sickness; Ach stimulates the vomiting centre in the brain.
2. Ach leads to increase dopamine re-uptake and so can worsen the symptoms of Parkinson's.
401
Briefly describe catecholamine synthesis.
Tyrosine -> L-DOPA -> Dopamine -> Noradrenaline -> Adrenaline.
402
Where does the conversion from Dopamine to Noradrenaline happen?
In a vesicle in the pre-synpatic neurone.
403
Which enzymes inactivate catecholamines?
MAO and COMPT.
404
Which protein does α1 interact with to activate phospholipase C?
Gq.
405
What is the primary function of α1?
α1 leads to vasoconstriction.
406
Which protein does α2 interact with in order to inhibit adenylate cyclase synthesis?
Gi.
407
What is the primary function of α2?
α2 is responsible for pre-synaptic inhibition; it inhibits NAd release.
408
What protein does β1,2,3 interact with in order to activate adenylate cyclase?
Gs.
409
What is the role of adenylate cyclase?
It converts ATP to cyclic AMP, this then leads to PKA synthesis.
410
What are the primary functions of β1?
1. Increased cardiac effects e.g. force, rate and conduction.
2. Increased renin secretion.
411
What are the primary functions of β2?
1. Bronchodilation.
| 2. Vasodilation.
412
What are the primary functions of β3?
1. Increase lipolysis.
| 2. Bladder relaxation.
413
What would an α1 adrenergic antagonist do?
1. Vasodilation.
| 2. Relaxation of bladder neck = reduced resistance to bladder outflow.
414
What disease could an α1 adrenergic antagonist be used in the treatment of?
Benign prostatic hyperplasia.
415
What would a β1 adrenergic antagonist do?
1. Reduce CO.
| 2. Reduce renin secretion.
416
What diseases could an β1 adrenergic antagonist be used in the treatment of?
Hypertension, angina and arrhythmia.
417
Define pain.
An unpleasant sensory and emotional experience associated with actual or potential tissue damage.
418
Give 3 advantages of pain.
1. Gives a warning for tissue damage.
2. Immobilisation for healing.
3. Memory establishment.
419
Define acute pain.
Pain caused by nociceptor activation. It is of short duration,
420
Define chronic pain.
Pain that is on-going or persistent, it lasts for >3-6 months.
421
Define neuropathic pain.
Pain caused by a primary lesion or dysfunction of the nervous system.
422
Define nociceptive pain.
Pain caused by actual or potential damage to non neural tissue, it is due to nociceptor activation.
423
Are A delta fibres myelinated or unmyelinated?
Myelinated.
424
Are C fibres myelinated or unmyelinated?
Unmyelinated.
425
Describe the type of pain that A delta fibres conveys.
Quick, sharp, localised.
426
Describe the type of pain that C fibres conveys.
Slow, dull, spread out.
427
Describe pain wind up.
A perceived increase in pain intensity over time when a stimulus is repeatedly delivered. It is caused by C fibre stimulation.
428
Describe the gate control theory.
Non-noxious stimuli trigger larger A beta fibres, these override smaller pain fibres and 'close the gate' to pain transmissions to the CNS.
429
What is pain treatment focused on?
1. Reducing excitatory neurotransmitters and nerve excitation.
2. Enhancing inhibitory neurones.
430
What are released in the presence of pain?
Endorphines.
431
What is an adverse drug reaction?
A noxious and unintended response to a drug.
432
Rawlins-Thompson system: Describe a type A adverse drug reaction.
- Augmented.
- Very common.
- Predictable from physiological effects of the drug.
- Often dose related.
433
Rawlins-Thompson system: Describe a type B adverse drug reaction.
- Bizarre.
- Unpredictable.
- Immunological mechanisms and hypersensitivity.
- Often there is a history of allergy.
434
Rawlins-Thompson system: Describe a type C adverse drug reaction.
- Chronic.
| - Occurs after long term therapy.
435
Rawlins-Thompson system: Describe a type D adverse drug reaction.
- Delayed.
| - Occurs many years after treatment.
436
Rawlins-Thompson system: Describe a type E adverse drug reaction.
- End of use.
| - Withdrawal reaction after long term use; complications of stopping medication.
437
What is the treatment for a type A adverse drug reaction?
Reduce the dose.
438
What is the treatment for a type B adverse drug reaction?
Withdraw drug immediately!
439
Describe type 1 hypersensitivity.
IgE mediated hypersensitivity. Acute anaphylaxis. IgE becomes attached to mast cells, IgE cross linking leads to mast cell degranulation -> histamine.
440
Describe type 2 hypersensitivity.
IgG mediated cytotoxicity.
441
Describe type 3 hypersensitivity.
Immune complex deposition; immune complexes have not been adequately cleared by innate immune cells, giving rise to an inflammatory response.
442
Describe type 4 hypersensitivity.
T cell mediated.
443
Give 6 features of anaphylaxis.
1. Rapid onset.
2. Blotchy rash.
3. Swelling of face and lips.
4. Wheeze.
5. Hypotension.
6. Cardiac arrest if severe.
444
What can cause a type 1 hypersensitivity reaction?
Pollen, cat hairs, peanuts etc. (allergies).
445
What can cause a type 2 hypersensitivity reaction?
Transplant rejection.
446
What can cause a type 3 hypersensitivity reaction?
Fungal.
447
What can cause a type 4 hypersensitivity reaction?
TB.
448
What is the treatment for anaphylaxis?
1. Commence basic life support (ABC).
2. Stop infusion of drug.
3. Give adrenaline and anti-histamines.
449
Give 4 risk factors for hypersensitivity.
1. Protein based macromolecules.
2. Female > male.
3. Immunosuppression.
4. Genetic factors.
450
Why are drug interactions such a big problem today?
1. Ageing population.
2. Polypharmacy.
3. Increased use of over the counter drugs.
451
Give 5 patient risk factors for drug interactions.
1. Old age.
2. Polypharmacy.
3. Renal disease.
4. Hepatic disease.
5. Genetics.
452
Give 3 drug related risk factors for drug interactions.
1. Narrow therapeutic index.
2. Steep dose/response curve.
3. Saturable metabolism.
453
Name 3 types of drug interaction.
1. Synergy; interaction of 2 compounds leads to a greater combined effect.
2. Antagonism; one drug blocks another.
3. Other.
454
How might drug interactions affect drug metabolism?
If a drug inhibits or induces CYP450 it might affect the metabolism of another drug.
455
How does avocado affect CYP450? And what drug might this impact on?
Avocado is a CYP450 inductor. Warfarin is likely to be affected and the risk of blood clots will be increased.
456
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. Ca2+ channel blockers and immunosuppressants.
457
Are weak acids cleared quicker if urine is more acidic or more alkali?
Weak acids are cleared quicker if urine is more alkali.
458
Are weak bases cleared quicker if urine is more acidic or more alkali?
Weak bases are cleared quicker if urine is more acidic.
459
What drug acts as an antagonist at the μ receptor?
Naloxone.
460
What enzyme is needed to metabolise codeine?
Codeine is a pro drug and needs to be metabolised by CYP2D6.
461
What is the bioavailability of morphine taken orally?
50%.
462
10mg of morphine is taken orally. What is the equivalent dose if given parenterally?
5mg.
463
What is morphine metabolised to?
Morphine 6 glucuronide.
464
Where might μ receptors be found?
In the epidural space and CSF.
465
Give 5 side effects of opioid use.
1. Respiratory depression.
2. Sedation.
3. Nausea.
4. Vomiting.
5. Constipation.
466
Describe the dose-response curve for morphine.
As dose increases response increases. This association is initially rapidly and then the graph plateaus. It is not sigmoidal!
467
Name a protein that can inhibit apoptosis.
BCL-2; it inhibits pro-apoptotic proteins e.g. caspase and therefore inhibits apoptosis.
468
What disease might develop in someone with a non-functional BCL-2 protein?
Cancer.
469
Where are mast cells found?
They are only found in tissues, not in the blood!
470
What is dobutamine used in the treatment of and at what receptor is it an agonist?
Dobutamine is a beta 1 agonist. It is used in the treatment of heart failure.
471
Define physiological antagonism.
A substance that produces effects that counteract the effects of another substance.
472
What are the 3 actions of NSAIDS?
1. Anti-inflammatory.
2. Analgesic.
3. Anti-pyrexic.
(AAA).
473
Name a local anaesthetic.
Lidocaine.
474
How do local anaesthetics work?
They inhibit pain by stopping impulse conduction in sensory nerves.
475
What drug inhibits ACh release at the NMJ?
Botulinum toxin.
| It is used to treat urinary incontinence and also cosmetically as a muscle relaxant.
476
Give 3 cytokines secreted by TH2.
1. IL-4.
2. IL-6.
3. IL-13.
4. IL-5.
5. IL-10.
477
What is the name of the variable region on an antibody?
Fab region.
478
Name 3 cytokines secreted by TH1.
1. IL-2.
2. Gamma-interferon.
3. TNF-beta.
479
Name 2 cytokines secreted by TREG.
1. IL-10.
| 2. TGF-beta.
480
Define adenocarcinoma.
A malignant neoplasm of glandular epithelium.
