ICS (Part 2) Flashcards
1
Q
How do we treat micro-invasive carcinoma?
A
Micro-incision as it has not spread too far yet
2
Q
During invasion of basement membrane, what are the enzyme required?
A
-proteases (matrix metalloproteinases)
- collagenase
- cathepsin D
- urokinase-type plasminogen activator
3
Q
In situ carcinoma vs invasive carcinoma, whats the difference?
A
Invasive carcinoma invade through the basement membrane
4
Q
Describe how does a tumour metastasise?
A
- Tumour grows
- tumour invades basement membrane and extracellular matrix
- travel in the blood stream and lymphatics
- avoid being eaten up by the immune system
- stop somewhere and get out of the blood vessels
- start growing
- if it needs to be bigger than 1mm, then it needs to have its own blood supply
5
Q
How can therapy target the tumour cells to be localised and not spread to other places?
A
Target and restrict the cell motility
6
Q
State the 5 stages of metastases
A
- Invasion of basement membrane
- Intravastation
- Evasion of the host immune system
- Extravasation
- Growth and angiogenesis
7
Q
What does Avastin drug do in treating tumour?
A
Avastin blocks the VEGF-A, which will initially bind to VEGF receptor and grow capillary, so it stops angiogenesis
8
Q
How do you prescribe Avastin to macular degeneration?
A
Inject them directly into the eyeball
9
Q
How does tumour metastasis to the lung?
A
- tumours from the veins/abdomen goes into the veins
- They travel to the heart ventricles
- they travel to the lung
- Since the artery develop into capillaries in the lung, the tumour will lodge in the lung (act as a filter)
- tumour grows in the lung and invade the pulmonary venule
10
Q
Which tumour is more common at metastasizing to the lung?
A
Sarcoma
11
Q
What scan do you use to check whether there is metastases from a fracture in the neck of the femur of an old lady
A
chest X ray
12
Q
What are the tumours that are more common at metastasising to the bone?
A
- prostate
- breast
- thyroid
- lung
- kidney
13
Q
What are the tumours that are more common at metastasising to the liver?
A
- colon
- stomach
- pancreas
- carcinoid tumour of the intestine
14
Q
What do we do when patient went into coma suddenly?
A
- CT scan of the head
15
Q
What tumour tends to grow at people that are non-smoker?
A
Adenocarcinoma of the lung
16
Q
What does the cancer drug vinblastine do?
A
- bind and block the spindle fibres from dividing (antimicrotubule agent)
17
Q
What does the cancer drug etoposide do?
A
inhibits topoisomerase II
18
Q
What does the cancer drug ifosamide do?
A
inhibits DNA synthesis by cross linking
19
Q
What does cisplastin the cancer drug do?
A
inhibits DNA synthesis by cross linking
20
Q
What does conventional chemotherapy mean?
A
- not selective for tumour cells
– except that they might be dividing faster
21
Q
What are the side effects of conventional chemotherapy?
A
usually hits normal cells which are dividing
– myelosuppression (A condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets. Myelosuppression is a side effect of some cancer treatments. When myelosuppression is severe, it is called myeloablation.)
– hair loss
– diarrhoea
22
Q
Conventional chemotherapy are good for fast-dividing tumour out there such as?
A
– germ cell tumours of testis
– acute leukaemias
– lymphomas
– embryonal paediatric tumours
– choriocarcinoma
23
Q
Why do we want targetted chemotherapy?
A
- less side effect
- more effective
24
Q
How can we find the difference between cancer cells and normal cells to target drugs to the cancer cells?
A
- gene arrays
- proteomics
- tissue microarrays
25
Describe how can Growth Factor A contribute to cancer?
- growth factor a receptor lives on the CSPM on the cells
- when GF bind to receptor, switch on the intracellular signal, gene is upregulated
- more cell proliferation
- in cancer, too much GF-A receptor, thus more proliferation
- sometime you get a mutation for gene for GF-A receptor, nothing binds, still get signal and more cell proliferation,
26
How can we treat the Grow factor A error to prevet cancer?
- make a monoclonal anitbody, inject the person with a lot of antibody against GF A receptor, wont get activation
- small molecular inhibitor of GF-A inhibitor, bind to the inside surface of the receptor, block the signal going into the cells, the signals is activated tyrosine kinase, often called tyrosine kinase inhibitor
27
What are the example of monoclonal antibody that can target cancer cells?
- cetuximab ( binds competitively to extracellular domain of
EGFR, blocks production of VEGF, interleukin 8,
bFGF)
28
What does Herceptin drug act on?
monoclonal antibody against human
epidermal growth factor receptor 2:
Her-2
29
When is Her-2 gene amplified?
In 20-30% of breast cancer
30
Give an example of Herceptin?
trastuzumab
31
As what therapy can Herceptin be?
Adjuvant therapy
32
Give an example of small inhibitor of C-kit gene? (C-kit tyrosine kinase)
Gleevec (chronic myloid leukamia)
33
What do you know about Chimeric T cell receptors?
treated 9/10can kill all tumour, the problem with this one is take blood from pt, filter the immune T cells that are reacting v tumour, gene therapy, sot hat they recognise the tumour cells, grow them, then inject back to pt, initial problem is that they will bind to normal cells too, its now been approved for childhood leukamia, (curable for 90% via conventional chemotherapy, but for the 10% cant cure, use thus chimeric t cells receptors)
34
What are the cells first appear in accute inflammation?
Neutrophils polymorph
35
Which tumour doesnt spread and can be excised to treat?
Basal Cell Carcinoma (older patients particularly men)
36
What is the name of malignant tumour of striated muscle?
rhabdo-myo-sarcoma
37
What does not commonly metastasise to bone?
Liposarcoma
38
What do you call when a tumour is not invading the basement membrane?
Carcinoma in situ
39
What do you call for a benign tumour of glandular epithelium?
Adenoma
40
What is thrombosis?
formation of mass from blood constituent in an intact vessel in live human
41
Which of these tumours do not have a screening programme in UK?
A. Lung cancer
B. Cervical cancer
C. Colorectal cancer
D. Breast cancer
A. Lung cancer
42
Which of the following is not known to be a human carcinogen?
A. Hepatitis C Virus
B. Ionising Radiation
C. Aromatic Amines
D. Aspergilus Niger
D. Aspergillus Niger
(hepatitis C virus> hepatocellular carcinoma; ionising radiation, all sorts of cancer ; aromatic amine > bladder carcinoma; aspergillus niger > blackmould is not a carcinogen, but aflatoxin B1> hepatocellular cancer)
43
What is the benign tumour of fat tissue?
lipoma
44
What do you call a malignant glandular tumour
Adenocarcinoma
45
Which of the following is not a feature of malignant tumours?
A. Vascular Invasion
B. Metastasis
C. Increased cell division
D. Growth related to overall body growth
D. growth related to overall body growth
(hamartoma only grow when teenager grows)
46
A transitional cell carcinoma in the bladder is a malignant tumour?
True/False
true
47
What do you call for a benign tumour of smooth muscle
Leiomyoma (tend to call fibroids when they are in tumour, can outgrow the blood supply, can cause acute abdomen syndrome)
48
Radon gas causes lung cancer?
True/False
True (since its radioactive) produce alpha particle, it actually only affect the lung but it damages the DNA (alpha travels like 1mm)
49
Asbestos is a human carcinogen?
true/false
true (blue asbestos > mesothelioma) tumour of pleural connective tissue
50
Which lifestyle factor is most likely to cause cancer?
A. Drinking half a bottle a wine per day
B. Being obese
C. Running for 20 mins twice a week
D. Smoking 20 cigarettes a day
D. Smoking 20 cigarettes a day
(20 cigarettes a day = 26X risk of lung cancer)
(alcohol> liver cirhhosis > hepatocellular carcinoma)
51
Which tumour has the shortest median survival?
A. Basal Cell Carcinoma of the Skin
B. Malignant melanoma of the skin
C. Breast cancer
D. Anaplastic carcinoma of the thyroid
D. Anaplastic carcinoma of the thyroid (only 2 months)
52
Ovarian cancer commonly spreads in the peritoneum?
True/False
true, the ovary lies right at the peritoneum, and its very difficult to deal with
53
Neoplasia = tumour
True/False?
FALSE!
54
What can be considered as tumour?
(any abnormal swelling)
Neoplasm
Inflammation
Hypertrophy
Hyperplasia
55
Define neoplasm
A lesion resulting from the autonomous or relatively autonomous abnormal growth of cells which persists after the initiating stimulus has been removed.
56
Why should we study neoplasia?
- it is in 25% of the population
- all ages
- increase risk with age
- high mortality rate
- 20% of all death
57
Most common cancer in man?
Prostate , Lung, Bowel
58
Most common cause of cancer death in man?
Lung, Prostate, Bowel
59
Most common cancer in woman?
Breast, lung, bowel
60
Most common cause of cancer death in woman
Lung, Breast, Bowel
61
What do you call it when the neoplasm is somewhere between benign and malignant?
borderline neoplasm
62
Neoplasm consists of 2 things. What are they?
- neoplastic cells
- stroma
63
Describe the 3 characteristics of neoplastic cells in neoplasm.
- Derived from nucleated cells (usually monoclonal)
- Growth pattern related to parent cells
- synthetic activities related to parent cells (collagen, mucin, keratin, hormones)
64
Describe the characteristics of the stroma of neoplasm.
- rich in fibroblast
- connective tissue framework
- mechanical support
- nutrition
65
What cell and tissue types would you therefore expect to find within a neoplasm’s stroma?
Malignant epithelium is the dark purple, paler part is the stroma
66
When the neoplasm is small, it derives the nutrient from diffusion, if want to grow more than how many mm, need vascular supply?
2mm
67
In malignant tissue, what do we tend to find in the middle part?
necrosis
68
Why should we classify neoplasm?
- To determine the appropriate treatment
- To provide prognostic information
- To allow universal understanding and communication
69
The appearance of the tumour is concordant with their behaviour.
true/false
FALSE!!
70
What are the methods of classification for neoplasm?
- behavioural classification (benign/malignant)
- histogenetic classification (cells of origin)
71
What are some characteristics of benign neoplasm?
- Localised, non-invasive
- Slow growth rate
- Low mitotic activity
- Close resemblance to normal tissue
- Circumscribed or encapsulated
- Nuclear morphometry is often normal
- Necrosis rare
- Ulceration rare
- Growth on mucosal surfaces often exophytic
72
What are some characteristics of malignant neoplasm?
- Invasive
- Metastases
- Rapid growth rate
- Variable resemblance to normal tissue
- Poorly defined or irregular border
- Hyperchromatic nuclei
- Pleomorphic nuclei
- Increased mitotic activity
- Necrosis common
- Ulceration common
- Growth on mucosal surfaces and skin often endophytic
- Encroach upon and destroy surrounding tissue
- Are poorly circumscribed
- Have a ‘crab-like’ cut surface (Latin: cancer)
73
Why should we worried about benign neoplasm?
They cause morbidity and mortality:
1. Pressure on adjacent structures
2. Obstruct flow
3. Production of hormones
4. Transformation to malignant neoplasm
5. Anxiety
74
Does all malignant neoplasm metastasise?
NO!! Invasion is the defining feature of neoplasm, NOT METASTASIS
75
Why worry about “malignant” neoplasms?
They cause morbidity and mortality:
1. Destruction of adjacent tissue
2. Metastases
3. Blood loss from ulcers
4. Obstruction of flow
5. Hormone production
6. Paraneoplastic effects (Paraneoplastic syndromes are a group of rare disorders that are triggered by an abnormal immune system response to a cancerous tumor known as a "neoplasm." Paraneoplastic syndromes are thought to happen when cancer-fighting antibodies or white blood cells (known as T cells) mistakenly attack normal cells in the nervous system. )
7. Anxiety and pain
76
If the cancer does not cause pain, can it still be cancerous?
yes!
Pain is the late presenting feature of the cancer, just because it doesnt hurt, it doesnt mean its not cancerous
77
Neoplasms may arrive from which 3 cell types?
1. Epithelial cells
2. Connective tissues
3.Lymphoid/haematopoietic organs
78
What do you call for benign tumour of non-glandular, non-secretory epithelium?
papilloma
79
What do you call for benign tumour of glandular or secretory epithelium?
Adenoma
80
What do you call for malignant tumour of epithelial cells?
Carcinoma
81
What do you call for Carcinomas of glandular epithelium?
Adenocarcinoma
82
Example of benign connective tissue neoplasm
- Lipoma: adipocytes
- Chondroma: cartilage
- Osteoma: bone
- Angioma: vascular
- Rhabdomyoma: striated muscle
- Leiomyoma: smooth muscle
- Neuroma: nerves
83
What are the examples of malignant connective tissue neoplasms?
- Liposarcoma adipose tissue
- Rhabdomyosarcoma striated muscle
- Leiomyosarcoma smooth muscle
- Chondrosarcoma cartilage
- Osteosarcoma bone
- Angiosarcoma blood vessels
84
Where the cell-type of origin is unknown, the tumour is said to be?
anaplastic (soor poorly differentiated until you dont know the subtype (they are all maligannt with bad prognosis))
85
Not all ‘-omas’ are neoplasms: what are the examples?
- granuloma (a growth of inflammation)
- myecetoma (Growth of fungal common in the lung)
- tuberculoma (Massive inflamed tissue in the lung due to TB)
86
Not all malignant tumours are carcinoma or sarcoma , such as?
1. melanoma: malignant neoplasm of melanocytes
2. Mesothelioma: malignant neoplasm of mesothelial cells
3. Lymphoma: malignant neoplasm of lymphoid cells
87
Tumours named after the person who first recognised/described them, such as?
- Burkitt’s lymphoma (a type of non-Hodgkin lymphoma (NHL) due to EBV)
- Ewing’s sarcoma (a rare type of cancer that affects bones or the tissue around bones. )
- Grawitz tumour (renal cell carcinoma)
- Kaposi’s sarcoma (a disease in which cancer cells are found in the skin or mucous membranes that line the gastrointestinal (GI) tract, from mouth to anus, including the stomach and intestines; caused by herpesvirus-8)
88
What is teratoma?
A teratoma is an ovarian germ cell tumor made up of several different types of tissue, such as hair, muscle, teeth, or bone.Teratomata typically form in the ovary, testicle, or coccyx.
89
What are the 2 main constituents of both innate and adaptive immunity?
1. Cells
2. Soluble factors
90
What are the few characteristics about innate immunity?
- non-specific
- 1st line of defence
- Provides barrier to antigen
- Instinctive
- Present from birth
- Slow response
- No memory
- Does not depend on immune recognition by lymphocytes
91
What are the few characteristics about adaptive immunity?
- Specific
- Response specific to antigen
- Learnt behaviour
- Memory to specific antigen
- Quicker response
92
What is blood consisted of?
1. White blood cells (middle layer buffy coat)
2. Plasma (upper fluid, straw-coloured)
- Water 90%, electrolytes, proteins, lipids, sugars etc.
3. erythrocytes, platelets (Haematocrit) (lowest layer 45%)
93
What is serum?
plasma without fibrinogen and other clotting factors
94
What are the three types of polymorphonuclear leukocytes?
Neutrophil, Eosinophil, Basophil
95
What are the 3 types of mononuclear leukocytes?
Monocytes, T cells , B cells
96
What is the precursor cells of all white blood cells?
haematopoietic stem cells
97
What are the different types of T cells?
T-regs
T-helper (CD4) (Th1 & Th2)
Cytotoxic (CD8)
Th17
98
Which cells is responsible for the
1. Allergic
2. Parasitic
3. Kidney shape nucleus
4. Produce a lot of histamine?
1. eosinophil
2. basophil
3. monocyte
4. mast cells
99
Whar are the other cells of immune system ?
1. Mast cells
2. Natural killer cells
3. Dendritic cells (Kupffer in the liver and Langerhans in the skin)
100
What are the 3 main soluble factors in the blood?
1. Complement
2. Antibodies
3.
101
What is it called for the Group of ~20 serum proteins secreted by the liver that need to be activated to be functional?
Complement
102
What are the 3 activation pathway/mode of action of complement system?
- Direct lysis
- Attract more Leukocytes to site of infection
- Coat invading organism
103
What are the 2 forms of antibody?
- Soluble (secreted)
- Cell surface (B cells)
104
What are the 5 different type of antibodies?
IgG, IgA, IgM, IgE, IgD
105
What are the 2 light chains of antibody?
- Kappa chain
- Lamda chain
106
What are the most common type of antibody?
IgG, 75%
107
What are the binding sites and common region in an antibody called?
Fab region, Fc region
108
How many binding sites does one antibody have?
two
109
Why is IgM restricted to blood?
Its in a oenta shape and too big !!
110
Which antibody can be a monomer or dimer, the dimer is important as it get secreted, combating pathogen outside the body?
IgA
111
Which antibody is soluble and can bind to leucocyte?
IgD
112
Which antibody is for allergic reaction?
IgE
113
What are the 5 types of cytokines?
- Interferons (induce a state of antiviral resistance in
uninfected cells )
- Interleukins (Can be pro-inflammatory (eg. IL1) or anti-inflammatory (eg. IL-10)
Can cause cells to divide, to differentiate and to secrete
factors)
- Colony Stimulating Factors
(Involved in directing the division and differentiation of bone marrow stem cells – precursors of leukocytes)
- Tumour Necrosis Factors (TNFa & b)
(Mediate inflammation and cytotoxic reactions)
- Chemokines (Mediate inflammation and cytotoxic reactions)
114
What are innate immunity composed of?
- Physical and chemical barriers
- Phagocytic cells (neutrophils and macrophages)
- Blood proteins (complement, acute phase)
115
What are the examples of physical barriers for innate immunity?
- lysosyme in tears and other secretions
- skin
- low pH and commensals of vagina
- removal of particles by rapid passage of air over turbinate bones
- mucus and cilia at the bronchus
- acid and rapid pH change at gut
- flushing of urinary tract
116
What are the inflammatory response if the physical barriers are breached?
- Stop bleeding (coagulation)
- Acute inflammation (leukocyte recruitment)
- Kill pathogens, neutralise toxins, limit pathogen spread
- Clear pathogens/dead cells (phagocytosis)
- Proliferation of cells to repair damage
- Remove blood clot – remodel extracellular matrix
- Re-establish normal structure/function of tissue
117
Define acute inflammation
Complete elimination of a pathogen followed by resolution of damage, disappearance of leukocytes and full regeneration of tissue
118
Define chronic inflammation
Persistent, un-resolved inflammation
119
What sense microbes in blood?
- In blood – Monocytes, Neutrophils
120
What sense microbes in tissue?
- Macrophages, Dendritic cells
121
What is PRR and where isit ?
– Pattern Recognition Receptors (on cells)
122
What is PAMP and where is it?
- Pathogen-Associated Molecular Patterns
(on microbe)
123
What cells are involved during the 3 mode of activation of Complement system?
- Lyse microbes directly (MAC)
Chemotaxs (C3a and C5a)
Opsonisation (C3b)
124
What are the 5 different processes of phagocytosis?
1. Binding of bacterium
2. Engulfment of bacteria
3. Phagosome formation
4. Phagolysosome formation
5. MHC presentation
125
Why do we need adaptive immunity?
1. Microbes evade innate immunity (proteases, decoy proteins, etc)
2. Intracellular viruses and bacteria ‘hide’ from innate immunity
3. Need memory to specific antigen – ‘seen it before so faster response’
- Cell Mediated - T cells - intracellular microbes
- Humoral (Ab) - B cells - extracellular microbes
126
What cells do cell-mediated immunity need?
- Antigen Presenting Cells (APC)
- T cells
- Major Histocompatibility Complex (MHC)
- Intrinsic/Endogenous (intracellular) antigens
- Extrinsic/Exogenous (extracellular) antigens
127
What are the 3 examples of APC?
- Macrophages
- Dendritic Cell
- B cells
128
What is it called when T cells that recognise self are killed in the foetal thymus as they mature
(called T cell selection)
129
T Cell Receptor (TCR) recognises foreign antigens in association with ?
Major Histocompatibility Complex (MHC)
130
What are CD4 related to? (Th, ie T helper cells)
- Extrinsic/ Extracellular (phagocytosis)
- Class 2 MHC (APC only)
- Help B cells make Ab to extracellular pathogen, can help directly killa
131
What are CD8 related to? (Tk, ie T killer cells)
- Intrinsic/ Intracellular (virus)
- Class 1 MHC (all cells)
- Tc (T cytotoxic cells)
- Kill infected cell with intracellular pathogen
132
State briefly how does T cells differentiate?
1. Naive T cells differentiate into CD4 and CD8?
2. CD4 divided into TH1 (when there is high IL12), and into TH2 (when there is low IL12)
3. TH1 helps kill intracellular pathogen
4. TH2 helps Antibody production
133
What happens in CD8 activation?
- CD8 + MHCI/peptide = Tc / CTL(Cytotoxic T Lymphocyte)
- CTL forms proteolytic granules &
releases perforins and granulysin
- Also induces apoptosis (cell suicide)
134
What happens in CD4 activation?
- APC presents Antigen with MHC II to a naïve CD4 T cell
- Stimulation with high levels of IL-12 activate naïve cells to CD4 Th1 cells
- Th1 cells travel to secondary lymphoid tissue (spleen, lymph nodes)
- Activated CD4 Th1 cells proliferate (clonal expansion, memory T cells)
- Th1 cell recognises Antigen on infected cells via TCR (CD4)
- Th1 secretes INFγ – stop virus spread, activates macrophages
135
What happened in B cell activation?
- B cells express membrane bound Ig (IgM or IgD monomer)
- Each B cell can only make one Ab that will only bind one epitope on one Antigen
- We are born with more than 10power 9 immature B cells – enough to detect every single possible epitope on all antigens - ever!
- B cells that recognise self are killed in bone marrow
135
What happened in B cell activation?
- B cells express membrane bound Ig (IgM or IgD monomer)
- Each B cell can only make one Ab that will only bind one epitope on one Antigen
- We are born with more than 10power 9 immature B cells – enough to detect every single possible epitope on all antigens - ever!
- B cells that recognise self are killed in bone marrow
136
Explain how B Cells Present Ag to T Cells via MHC II?
- mIgM (or mIgD) binds Ag
- Phagocytosis
- Peptide displayed on surface with MHC II
- TCR of naive Th (CD4) binds to MHC II
- Lots of other co-stimulatory molecules required.
137
Explain how T cells help B cells?
- APC eats Ag (extrinsic) and presents it to naïve CD4+ T cells (via MHC II)
- These turn into primed Th2 cells
- Th2 cells bind to B cells that are presenting Ag (via MHC II). This Ag has been captured using the mIgR on cell surface.
- Th2 cell now secretes cytokines (IL-4, IL-5, IL-10 and IL-13 ( )
- These cause B cells to divide – CLONAL EXPANSION and differentiate into:
- Plasma cells (AFC = antibody forming cell) and
Memory B cells (Bm)
138
What does antibody do?
- Neutralise toxin by binding to it
- Increase opsonisation – phagocytosis
- Activate complement
139
How does handling of pathogen works when there are viruses?
- cellular shut-down
- self-sacrifice
- cellular resistance
140
Does all creatures have adaptive immune system?
- NO!! Only vertebrae have it
141
What are the different pattern of pathogens (related to pathogen associated molecular pattern PAMP)
* Limited characteristics
* Gram +ve/-ve
* dsRNA (double-stranded RNA)
* CpG motifs
142
What are the 2 types of PRR (Pathogen Recognition Receptor)?
- Secreted and circulating PRRs
- Cell-associated PRRs (more traditional receptors)
143
What are the difference between gram positive and gram negative bacteria?
- Gram-negative bacteria are surrounded by a thin peptidoglycan cell wall, which itself is surrounded by an outer membrane containing lipopolysaccharide. Gram-positive bacteria lack an outer membrane but are surrounded by layers of peptidoglycan many times thicker than is found in the Gram-negatives.
144
What are the different types of secreted and circulating PRRs?
* Antimicrobial peptides secreted in lining fluids, from
epithelia, and phagocytes.
* Defensins, cathelicidin
* Lectins and collectins: carbohydrate-containing
proteins that bind carbohydrates or lipids in microbe
walls. Activate complement, improve phagocytosis.
* Mannose binding lectin (deficiency syndromes),
surfactant proteins A and D
* Pentraxins. Proteins like CRP, which have some antimicrobial actions, can react with the C protein of pneumococci, activate complement, and promote phagocytosis.
145
What are cell-associated PRRs?
* Receptors that are present on the cell membrane
or in the cytosol of the cells.
* Recognise a broad range of molecular patterns.
* such as Toll-Like Receptors (TLR)
146
What does TLR4 do?
TLR4 has been long recognized as the sensing receptor for gram-negative lipopolysaccharide (LPS). In addition, it also binds endogenous molecules produced as a result of tissue injury. Hence, TLR4 represents a key receptor on which both infectious and noninfectious stimuli converge to induce a proinflammatory response.
147
What are other membrane-bound PRRs?
* Family of receptors that may participate in pathogen recognition and particularly in pathogen
phagocytosis, the C-type Lectin receptors
* Mannose receptor on macrophages (fungi).
* Dectin-1, Dectin-2. Widespread on phagocytes, helps recognise beta glucans in fungal walls.
148
Not all pathogen are extracellular, state some examples?
* Viruses multiply in the cytoplasm of cells
* Bacteria such as Salmonella burst out from the
phagolysosome and multiply in the cytoplasm of
macrophages
149
What is NLR?
- Nod-like receptors.
- Rapidly expanding family of another 22 human proteins that detect intracellular microbial pathogens.
- Detection of peptidoglycan, muramyl dipeptide,etc.
- Best known are NOD1, NOD2
150
State some features of NOD2?
- Widespread expression
* Recognises muramyl dipeptide (MDP), a breakdown product of peptidoglycan
* Activates inflammatory signalling
pathways
* Non-functioning mutations: Crohn’s
disease
* Hyperfunctioning mutations: Blau
syndrome (rare, chronic granulomatous inflammation of skin, eyes and joints)
151
State some characteristics of NOD2?
* Widespread expression
* Recognises muramyl dipeptide (MDP), a breakdown product of peptidoglycan
* Activates inflammatory signalling
pathways
* Non-functioning mutations: Crohn’s
disease
* Hyperfunctioning mutations: Blau
syndrome (rare, chronic granulomatous inflammation of skin, eyes and joints)
151
State some characteristics of NOD2?
* Widespread expression
* Recognises muramyl dipeptide (MDP), a breakdown product of peptidoglycan
* Activates inflammatory signalling
pathways
* Non-functioning mutations: Crohn’s
disease
* Hyperfunctioning mutations: Blau
syndrome (rare, chronic granulomatous inflammation of skin, eyes and joints)
152
What are RLRs and state the features of RLR?
- Riglike helicases = RLRs
- Best known are RIG-I and MDA5, who’s roles are to detect intracellular double-stranded viral RNA and
DNA.
- They couple effectively to activation of interferon production, enabling an antiviral response
- NOD2 can also activate anti-viral signalling
152
What are RLRs and state the features of RLR?
- Riglike helicases = RLRs
- Best known are RIG-I and MDA5, who’s roles are to detect intracellular double-stranded viral RNA and
DNA.
- They couple effectively to activation of interferon production, enabling an antiviral response
- NOD2 can also activate anti-viral signalling
153
In homeostasis, Blood neutrophil numbers may be dependent upon what and not dependent upon what?
- dependent upon TLR4 signalling
- not dependent upon LPS (lipopolysaccharide)
154
Link TLR to damage recognition?
* TLRs also adapted to recognise a range of endogenous damage molecules, which may share
characteristics of hydrophobicity.
* Appearance of host molecules in unfamiliar contexts can activate TLRs.
* TLR signalling by cellular damage products activates immunity to initiate tissue repair and perhaps enhance local antimicrobial signalling.
155
Link TLR to damage recognition?
* TLRs also adapted to recognise a range of endogenous damage molecules, which may share
characteristics of hydrophobicity.
* Appearance of host molecules in unfamiliar contexts can activate TLRs.
* TLR signalling by cellular damage products activates immunity to initiate tissue repair and perhaps enhance local antimicrobial signalling.
156
What are the example of damage molecules? (Both Intracellular and Extracellular)
* Extracellular molecules: fibrinogen, hyaluronic acid, tenascin C
* Intracellular molecules: for example, HMGB1, mRNA, heat shock proteins
157
How can the relationship of PRR and adaptive immunity be put into application?
- Activation of TLRs and other PRRs drives cytokine production by antigen-presenting cells that can increase the likelihood of successful T cell
activation
- TLR4 agonists already used as vaccine adjuvants.
- TLR7/8/9 adjuvants in development.
158
Give 3 examples how can PRR relate to diseases?
* Recognition of host molecules in autoimmune disease
* Failure to recognise pathogens or increased inflammatory responses
* Atherosclerosis, arthritis, COPD, inflammatory bowel disease, etc.
159
Relate PRR to possible therapy
* Enhance TLR signalling: improve immunity, adjuvants
* Inhibit TLR signalling: sepsis syndromes, inflammation, arthritis
* Modify adaptive immune response: bias Th and Treg responses
160
What percentage of anaesthetists in the UK are doctors?
99%
161
Anaesthetists are involved in how much portion of patients in hospital care
2/3
162
What are the 3 main sectors about pharmacology?
1. Physiochemical
2. Pharmacodynamics (drugs effect on body)
3. Pharmacokinetics (body effects on drug)
163
How do you treat paracetamol overdose?
paracetamol absorption can be reduced by 83% by "activated charcoal" administered within five minutes
164
What are the 4 main sectors in pharmacodynamics?
1. Summation
2. Synergism
3. Antagonism
4. Potentiation
- Summation: 1 +1 = 2, total effect is the sum of the effect put together, “additive/summative”
- Synergism: 1+1>2 , the effect is more than you would expect from the summated effect, paracetamol and morphine (analgesic), look at the table
- Antagonism: 1+1 =0, “antagonism or blockage”, salbutamol is beta 2 agonist, smooth muscle relaxation, beta blockers, all of them are non-selective, beta 1 is within the heart, beta blocker generally want to slow the heart rate down, used in heart failure etc, difficulty in the asthmatic patient is that a non-selective beta blocker will act on the beta 2 in the lung, that is the example of blockage due to the counteraction of the drugs,
- Potentiation:
1+1= 1+1.5 “potentiation, one of the drugs has it effect increased
165
What are the 4 main sectors in pharmacokinetics?
ADME
1. Absorption
2. Distribution
3. Metabolism
4. Excretion
166
What is bioavilibility?
The proportion of a drug or other substance which enters the circulation when introduced into the body and so is able to have an active effect.
167
Describe motility in pharmocology.
Drugs may affect gastrointestinal motility and, therefore, absorption of other concomitantly administered drugs.
168
Describe acidity in pharmacology.
> All drugs exist in ionised and unionised form, ph, alkali or acidic, local anaesthetic is alkali drug, aspirin etc is acidic drugs
> ionised drug cant get across phospholipid bilayer , unionised drug can get acrossed, proton pump inhibitor
169
Describe "distribution" in pharmacology.
The drugs can go anywhere, this is a phenemoenon called protein binding, as an anaesthetic, want to turn off the brain, consider onset and offset of the drug, when u guve 2 drugs that are protein binding, need to think twice, warfarin and amiodarone!!
170
Whats wrong with prescribing both warfarin and amiodarone?
Amiodarone is a potent inhibitor of the enzymes responsible for warfarin metabolism. The combination of amiodarone and warfarin potentiates the effect of warfarin and prolongs the International Normalized Ratio (INR), increasing the risk of bleeding.
171
The patient on warfarin is given IV amiodarone for unstable, fast AF. The amiodarone is likely to continue for the next 2-3days. The patient is now stable with no signs of instability. Put the following order of priority from most to least sensible.
1. Check INR regurlarly (An INR test measures the time for the blood to clot.)
2. Reduce warfarin
3. Check patient
4. CT head to rule out ischemic stroke
5. Check warfirin level
6. Barium swallow to look for upper GI bleeding
172
Describe morphine metabolism route
Morphine > CYP450 > Morphine + Gluconoride
173
What happens when phenytoin acts on CYP450 in the morphine metabolism pathway?
Phenytoin acts on CYP450, morphine accumulate, hard to eliminate,
174
What happen when metronidazole acts on CYP450 during drug metabolism pathway?
metronidazole reduces the effect of CYP450, slow down the process of eliminating the morphine, its not metabolised quickly
175
What would enzyme induction do to warfarin?
warfarin get metabolised into its active component, increase INR, bleeding, ischemic stroke
176
What is furosemide, and what does it interact with?
diuretics, affect the loop of henle, interact with GENTIMICIN, its an anitbiotic, gent on its own causes renal failure, both causes autotoxicity, we need to make sure it doesnt happen, have to be very careful on the dosage
177
How do you treat aspirin overdose?
treat with sodium bicarbonate, alkaline the urine causes the aspirin not to be absorbed,
178
Define drug
A medicine or other substance which has a physiological effect when ingested or otherwise introduced into the body.
179
Define pharmacology.
The branch of medicine concerned with the uses, effects, and modes of action of drugs
180
Define druggability.
A biological target that is known to or is predicted to bind with high affinity to a drug, it must alter the function of the target with a therapeutic benefit to the patient
181
What are the different types of drug targets?
- receptors
- enzymes
- transporters
- ion channels
182
What are the top 3 drugs prescribed?
1. Statin
2. Thyroid Hormone
3. Proton Pump Inhibitor
183
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.
184
Are ligands exogenous or endogenous?
Ligands can be both exogenous (drugs) or endogenous (hormones, neurotransmitter, etc)
185
What are the communicating chemicals in human body?
1. Neurotransmitter (AcH, serotonin)
2. Autacoids (local) (cytokines, histamine)
3. Hormones (testosterone, hydrocortisone)
186
What are the 4 main types of neurotransmitter?
1. Ligand-gated ion channels (nicotine ACh receptor
2. G-protein coupled receptors (beta-adrenoceptors)
3. Kinase-linked receptors (receptors for growth factors)
4. Cytosolic/nuclear receptors (steroid receptors)
187
The change in charge in ligand-gated ion channels can be mediated by?
- an influx of any kind of cation (+ve)
- an efflux of any kind of anion (-ve)
188
What is the largest and most diverse group of membrane receptors in eukaryotes (7 membrane-spanning regions)
G-protein coupled receptors (made up of 4% of all genes! targeted by >30% of drugs)
- Ligands include light energy, peptides, lipids, sugars and proteins
189
Talk about G protein
- also known as Guanine nucleotide-binding proteins
- hydrolyse GTP to GDP
- act as a molecular switch
190
State the G protein, coupled, 2nd messengers for the receptor M3R.
Gq as the G protein, PLC (phospholipase as the enzyme), IP3/DAG as 2nd messengers
191
State the G protein, coupled, 2nd messengers for the receptor beta2 -AR (adrenegic receptor)
Gs as the G protein, AC (adenylyl cyclase) as the enzyme, cyclic AMP as the 2nd messenger
192
Talk about 3 features of kinase-linked receptors?
- Kinases are enzyme that catalyse 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.
193
Talk about nuclear receptors.
- Steroid hormones
- Work by modifying gene transcription
- Zinc fingers that can bind to DNA
- Tamoxifen (Breast cancer) acts as a selective oestrogen receptor modulator (SERM), or as a partial agonist of the oestrogen receptors
194
Imbalance of chemicals/receptors can lead to pathology, such as ?
Chemicals:
- Allergy: increased histamine
- Parkinson's: reduced dopamine
Receptors:
- Myasthenia gravis: loss of ACh receptors
- mastocytosis: increased c-kit receptor
195
Receptor characterisation is essential in therapeutic development, state the 3 relevant steps.
1. Identify the receptor involved in a pathophysiological response
2. Develop drugs that act at the receptor
2. Quantify drug action at that receptor
196
What is an agonist in receptor ligands?
- A compound that binds to a receptor and activates it
197
What is an antagonist in receptor ligands?
- A compound that reduces the effect of an agonist
198
What is the 2-state model of receptor activation?
- Drugs activate receptors by inducing or supporting a conformational change in the receptor from "off" to "on"
199
What shape is the log concentration response curve?
Sigmoidal
200
Describe EC50 (potency)
The concentration that gives half the maximal response
201
What is efficacy (Emax)?
The maximum response achievable
202
What is intrinsic activity?
- 68 / 100 = 0.68
- Intrinsic activity or efficacy refers to the ability of a drug-receptor complex to produce a maximum functional response
203
What are the 2 types of antagonism?
- competitive antagonism (binds to the same site)
- non-competitive antagonism (binds to the allosteric site on the receptor to prevent activation of the receptor)
204
What are the agonist and antagonist for 1. muscuranic ACh receptor and 2. Nicotinic ACh receptor?
1. For muscuranic AChR
- muscarine as agonist
- atropine as antagonist
2. for nicotimic AChR
- Nicotine as agonsit
- curare for antagonist
205
What type of receptor is histamine receptor?
- G-protein coupled receptors
206
What are the factors governing drug action? In terms of ...
1. Receptor-related
2. Tissue-related?
1. Receptor-related
- affinity
- efficacy
2. Tissue-related
-receptor number
-signal amplification
207
What is affinity?
- Describes how well a ligand binds to the receptor. Affinity is a property that is shown by both agonists and antagonists
208
What is efficacy?
Describe how well a ligand activates the receptor.
209
What has both affinity and efficacy?
Agonists
210
What has affinity but zero efficacy?
Antagonists
211
What is isoprenaline?
A non-selective beta adrenoreceptor agonist analogue of adrenaline
- relaxation of pre-contracted human bronchial rings
212
What is the irreversible antagonist of beta adrenoreceptor?
Bromoacetyl alprenolol menthane (BAAM)
213
What is receptor reserve?
Some agonists needs to activate only a small fraction of the existing receptors to produce the maximal system response.
This holds for a full agonist in a given tissue reserve can be large or small; depends on tissue.
No receptor reserve for a partial agonist even with 100% occupancy, maximal response not seen
214
What are the other types of receptor ligand interaction?
1. Allosteric modulation
2. 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)
215
What is tolerance (slow)?
- Reduction in agonist effect over time
- Continuously, repeatedly, high concentrations
216
What is desensitisation (rapid)?
- uncoupled
- internalized
- degraded
217
Should we talk about specificity or selectivity?
- No compound is every truly specific
- selective is a better term to describe activity
218
What is the difference between isoprenaline and salbutamol?
- isoprenaline is a non-selective b-adrenoreceptor agonist
- salbutamol is a selective b2 adrenoreceptor agonist
219
What is an enzyme inhibitor?
An enzyme inhibitor is a molecule that binds to an enzyme and (normally) decreases its activity.
An enzyme inhibitor prevents the substrate from entering the enzyme's active site and prevents it from catalyzing its reaction.
220
What are the 2 types of 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.
221
State what does statin do?
Block the rate limiting step in the Cholesterol pathway
A class of lipid-lowering medications that reduces the levels of “bad cholesterol”
For the primary prevention of cardiovascular disease
Reduce cardiovascular disease (CVD) and mortality in those who are at high risk.
222
What is RAAS 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
223
What does ACE inhibitor do?
Inhibiting ACE reduces ATII production and therefore causes a reduction in blood pressure
224
What are the symptoms of parkinson disease?
1. Hypokinesia (slower muscle movement)
2. Tremor at rest
3. Muscle rigidity, motor inertia
4. Cognitive impairment
5. Degenerative disease of basal ganglia
6. Early degeneration of dopaminergic neurons in the nigrostriatial pathway leading to autonomic dysfunction and dementia
225
Relate L-DOPA to Parkinson's disease.
- L-DOPA produced from the amino acid L-Tyrosine as a precursor for neurotransmitter (dopamine) biosynthesis - crosses the Blood Brain Barrier
226
What are the different therapeutic drugs for Parkinson's Disease?
1. Peripheral DDC Inhibitor
-Blocks DDC in the periphery generating more for the CNS pathway
2. Peripheral COMT Inhibitor
- Prevents breakdown of L-DOPA generating more for the CNS pathway
3. Central COMT Inhibitors
- Function within the CNS to keep Dopamine levels up
4. Mono Amine Oxidase B Inhibitor
- Prevents Dopamine breakdown and increases availability
5. Central Dopamine Receptor Agonists
- Antagonise dopamine receptors (not enzyme inhibitors)
227
What are the different types of drug and ions transport?
Passive
- Symporter
(Na/K/2Cl , NaCl)
- Channels
(Na, Ca, K, Cl )
Active (requires energy)
- ATP-ases
(Na/K, K/H)
228
What are the different types of protein ports?
1. Uniporters: use energy from ATP to pull molecules in.
2. Symporters: use the movement in of one molecule to pull in another molecule against a concentration gradient.
3.Antiporters: one substance moves against its gradient, using energy from the second substance (mostly Na+, K+ or H+) moving down its gradient.
229
Talk about an example of symporter!
The Na-K-Cl cotransporter (NKCC) is a protein that transports Na, K, and Cl into cells
Move ions in the same direction
Functions in organs that secrete fluids.
Furosemide (a so-called loop diuretic - used for hypertension and edema)
Acts by inhibiting the luminal NKCC in the thick ascending limb of the loop of Henle
Binding to the NKCC causes sodium, chloride, and potassium loss in urine
230
Ion channels exist in many tissues, such as ?
Epithelial (Sodium) – heart failure
Voltage-gated (Calcium, Sodium) – nerve, arrhythmia
Metabolic (Potassium) – diabetes
Receptor Activated (Chloride) - epilepsy
231
What is ENaC?
An (apical) membrane-bound heterotrimeric ion channel selectively permeable to Na+ ions
Causes reabsorption of Na+ ions at the collecting ducts of the kidney's nephrons (also in colon, lung and sweat glands)
232
What are the drugs related to ENaC?
Blocked by the high affinity diuretic amiloride (often used with Thaizide).
Thaizide targets Na+Cl− cotransporter that reabsorbs Na and Cl from tubular fluid
Used as a anti-hypertensive
233
Where are Voltage-gated (Calcium) channels found?
Voltage-gated ion channels (VDCC) are found in the membrane of excitable cells (e.g., muscle, glial cells, neurons, etc.)
At physiologic or resting membrane potential, VDCCs are normally closed.
They are activated (i.e., opened) at depolarized membrane potentials (action potential).
Ca2+ enters the cell, resulting in activation of Ca-sensitive K channels, muscular contraction, excitation of neurons etc.
234
What are the drugs for Voltage-gated (Calcium) inhibition ?
Amlodipine is an angioselective (Why is that important?) Ca channel blocker that inhibits the movement of Ca ions into vascular smooth muscle cells and cardiac muscle cells
This inhibits the contraction of cardiac muscle and vascular smooth muscle cells
Amlodipine inhibits Ca ion influx across cell membranes, with a greater effect on vascular smooth muscle cells
Causes vasodilation and a reduction peripheral vascular resistance, thus lowering blood pressure
Also prevents excessive constriction in the coronary arteries
235
In excitable cells voltage-gated Na+ channels have three main conformational states. What are they?
closed, open and inactivated.
236
Whta blocks the Voltage gated (Sodium) Channels?
Lidocaine (anaesthetic) blocks transmission of the action potential. Also blocks signaling in the heart reducing arrhythmia.
237
What does Voltage gated (Potassium) Channels regulate?
- Regulate insulin in Pancreas: Islets of Langerhans
- Increased glucose leads to block of ATP dependent K+ channels.
- Repetitive firing of action potentials increases Ca+ influx and triggers insulin secretion
- Repaglinide, nateglinide and sulfonylureal lower blood glucose levels by blocking K+ channels to stimulate insulin secretion.
- Used for treatment of type II diabetes
238
What is the example of Ligand-gated ion channels (ionotropic receptors), open to allow ions to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand)
GABA-A receptor (post-synaptic)
- Barbiturates increase the permeability of the channel to chloride
239
What drug inhibit Sodium Pump (Na/K ATP-ase) and used for atrial fibrillation, atrial flutter, and heart failure
digoxin
- This inhibition causes an increase in intracellular Na, resulting in decreased activity of the Na-Ca exchanger and increases intracellular Ca.
- This lengthens the cardiac action potential, which leads to a decrease in heart rate.
240
Where is the proton pump located?
- The gastric hydrogen potassium ATPase or H+/K+ ATPase is the proton pump of the stomach.
- responsible for the acidification of the stomach and the activation of the digestive enzyme pepsin
241
What drug block the proton pump in the stomach?
Proton pump inhibitors: Omeprazole (1st in class) - inhibits acid secretion independent of cause.
Irreversible inhibition of H/K ATP-ase - drug half-life 1h, but works for 2-3 days
Omeprazole metabolised at acid pH – enteric coated granules (alters own bioavailability)
242
What are xenobiotics?
compounds foreign to an organism's normal biochemistry, such any drug or poison.
243
What does pharmacokinetics tell us?
Pharmacokinetics gives us information about how drugs will function at certain doses and for how long.
244
What does pharmacokinetics tell us?
Pharmacokinetics gives us information about how drugs will function at certain doses and for how long.
245
What is bioavailbility?
This is the fraction (%) of an administered drug that reaches the systemic circulation.
If a drug can’t reach its intended site of action then it will have limited therapeutic utility!
246
Where is CYP located?
in the inner membrane of mitochondria or in the endoplasmic reticulum of cells.
247
CYPs are the major enzymes involved in drug metabolism, accounting for about how many percentages of the total metabolism.
75%
248
What is afferent?
carries signals toward the brain or spinal cord
249
What is efferent?
carries signals away from the brain or spinal cord
250
What can efferent system be divided into?
1. Autonomic (Smooth muscles)
2. Somatic (Skeletal muscles)
251
What can autonomic system be divided into?
1. sympathetic
2. Enteric
3. parasympathetic
252
What can autonomic system be divided into?
1. sympathetic
2. Enteric
3. parasympathetic
253
State 3 features of Somatic nervous system?
1. Single neuron between CNS and skeletal muscle
2. Innervates Skeletal Muscles
3. Leads to muscle excitation (not inhibition)
