ICS 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 5 cardinal signs of inflammation?
A
Rubor - redness - due to dilation of small BV
Dolor - pain - from stretching and distortion of tissues due to inflammatory oedema and pus putting pressure in an abscess cavity
Calor - heat - due to increased blood flow (hyperaemia) and systemic fever
Tumor - swelling - resulting from oedema and to a lesser extent the inflammatory cells migrating into the area
Loss of function
6
Q
What are the stages of acute inflammation?
A
Increase vessel calibre - inflammatory cytokines and endogenous chemical mediators (bradykinin, prostcyclin and NO) mediate vasodilation.
Fluid exudate - Vessels become leaky and protein rich fluid is forced out of the vessel leading to swelling
Cellular exudate - neutrophils become abundant in this exudate
7
Q
What is neutrophil action in acute inflammation?
A
- Margination - Due to increase in plasma viscosity and slowing of flow due to injury, neutrophils migrate to plasmatic zone
- Adhesion - selectins bind to neutrophil and cause rolling along the blood vessel margin
- Emigration and diapedesis - Movement of neutrophils out of the blood vessel through or in between the endothelium and basal lamina (other inflammatory cells follow)
- Chemotaxis - movement towards site of inflammation along chemical gradients
8
Q
What is the action of neutrophils at the site of inflammation?
A
Bind to the pathogen and start phagocytosis
Lysosomes move to fuse with the neutrophil to form the phagolysosome
This releases lytic enzymes to kill the pathogen.
Macrophages then clear the debris
9
Q
What are the outcomes of acute inflammation?
A
Resolution - initiating factor is removed and the tissue can return to normal structure and function
Suppuration - formation of pus (collection of leukocytes) surrounded by a pyogenic membrane to start the healing process (leads to scarring)
Organisation - Granulation tissue forms and you get the development of fibrosis
Progression - Excessive recurrent inflammation can become chronic and you get fibrotic tissue forming.
10
Q
What are granulomas?
A
Aggregates of epitheliod histocytes (mainly macrophages) at the site of inflammation to contain the pathogen
11
Q
How can acute inflammation be diagnosed histologically?
A
By looking for the presence of neutrophil polymorphs.
12
Q
Give 3 endogenous chemical mediators of acute inflammation.
A
- Bradykinin.
- Histamine.
- Nitric Oxide.
13
Q
What are 4 systemic effects of acute inflammation?
A
- Fever.
- Feeling unwell.
- Weight loss.
- Reactive hyperplasia of the reticuloendothelial system.
14
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.
15
Q
What cells are involved in chronic inflammation?
A
Macrophages and plasma cells (B and T lymphocytes).
16
Q
What cell can form when several macrophages try to ingest the same particle?
A
Multinucleate giant cell.
17
Q
Give 4 causes of chronic inflammation.
A
- Primary chronic inflammation.
- Transplant rejection.
- Recurrent acute inflammation.
- Progression from acute inflammation.
18
Q
What can cause primary chronic inflammation?
A
- Infective substances having resistance to phagocytosis e.g. TB, leprosy.
- Endogenous materials e.g. uric acid crystals. necrotic tissue
- Exogenous materials e.g. asbestos.
- Autoimmune diseases e.g. chronic gastritis, rheumatoid arthritis etc.
- Other chronic inflammatory diseases e.g. chronic inflammatory bowel disease.
19
Q
What are some macroscopic features of chronic inflammation?
A
- Chronic ulcer.
- Chronic abscess cavity.
- Granulomatous inflammation.
- Fibrosis.
20
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 of chronic inflammation
21
Q
What condition causes granulomas with central necrosis?
A
Caseous granuloma (soft cheese like)
Caused by TB
22
Q
What conditions cause granulomatous inflammation without central necrosis?
A
Sarcoidosis, leprosy, vasculitis, chrons disease
23
Q
What blood marker is released from granulomas?
A
ACE
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 cannot regenerate.
Myocardial cells
Neurons
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.
Laminar flow of blood
Endothelium is non-sticky
30
What are the 3 factors that can lead to thrombosis formation (virchow's Triad)
1. Change in vessel wall. (endothelial injury)
2. Change in blood constituents. (platelet aggregation, thrombus formation or fibrin deposition)
3. Change in blood flow. (stasis of blood flow)
31
Define embolus.
A mass of material (often a thrombus) that is carried in the vascular system that is able to become lodged in a vessel and block it.
32
Define ischaemia.
Decreased blood flow to tissues w/o other complications
33
Define infarction.
Decreased blood flow to a tissue that results in subsequent cell death.
34
Define Acute inflammation
Initial Response to tissue injury
Inflammation that is:
sudden onset,
lasts for a short duration and usually resolves
Involves Neutrophils and Monocytes
35
How do bacteria and viruses cause harm?
Bacteria - release exo/endotoxins that initiate the inflammatory pathways
Viruses - Intracellular replication causes cell death
36
What processes do the endogenous chemical mediators lead to?
Vasodilation
chemotaxis
increased vascular permeability
itching and pain
37
What are the main cell types in acute inflammation?
Neutrophil polymorphs
Macrophages
Fibroblasts
Endothelial cells
Lymphocytes
38
What are the main cell types in chronic inflammation?
Macrophages
Lymphocytes
Plasma cells
39
What is a multinucleated giant cell?
The cell that forms when several macrophages try to ingest the same pathogen and end up fusing together.
40
What are some differences between acute and chronic inflammation?
Chronic is persistent and the causative agent is often not removed
There tends to be less swelling
Inflammation and repair occurs at the same time
Fibrosis is a key feature
41
What is resolution?
Tissue restored to normal pre injury state tissue architecture is undamaged
tissue initiating factor is removed
42
What is lobar pneumonia
A bacterial infection caused by strep pneumonia one lobe of the lungs filled with pus and neutral polymorphs fill alveoli of the lungs this is resolved through antibiotics
43
What is healing by first intention?
1. Edges of incision are brought together using stitches?
2. The incision wound fills up with blood and a thrombus forms
3. Exudation of fibrinogen causes the formation of weak fibrin.
4. Epidermal growth, and collagen synthesis leads to a strong collagenous joint.
5. Epidermis grows over the top.
44
What is healing by second intention?
When there is a gap or whole in the skin and there is tissue loss.
1. small blood vessels move in from the edges of the gap
2. fibroblasts enter the site of trauma and make collagen - granulation tissue
3. fibroblasts organise tissue to form organised collagen fibrils
4. early thrombus scar forms
5. Epidermis grows over the top and leaves a scar.
45
What are the constituents of a thrombus?
Platelets. Red blood cells, fibrin.
46
What are the stages of thrombosis?
Vasospasm
Platelet aggregation - VWF binds exposed collagen and platletes bind to this via GP1b. Then platelets aggregate by binding to each other through GP2a/3b
Clotting cascade.
47
What stimulates platelet aggregation?
Endothelial damage changes localised blood flow from laminar to turbulent.
Platelets come into contact with the endothelium and stick.
48
What are the different types of thrombosis and what causes them?
Arterial thrombosis - atherogenesis
Venous thrombosis - venous stasis
49
How would you treat an arterial and venous thrombosis?
Arterial thrombosis - Antiplatelets
Venous Thrombosis - Anticoagulants
50
What are the fates of a thrombosis?
Resolution - thrombus degrades and returns to normal
Organisation - Leaves scar tissue behind
Embolism - fragments of thrombi break off and get lodged in the circulation
51
Define embolism.
A solid mass in the blood vessel which causes a blockage to the vasculature.
52
What happens to an embolus if it enters the venous system?
- Filtered by the lungs
- Travels through the vena cava, though the right hand side of the heart and lodge somewhere in the lungs depending on size
- Blood vessels in the lung split down to capillary size so act as a sieve
53
What happens to an embolus if it enters the arterial system?
It will travel anywhere downstream of its entry point
54
Where may an infarct have a reduced impact?
on areas with a dual blood supply
Brain,
Liver
Lungs
55
what is an atheroma?
Focal thickening of the tunica intima arteries produced through the movement of ldls from the lumen.
56
How is an atheroma formed?
The ldls caused a cascade of events which, mediated through inflammatory response and smooth muscle cells proliferation leads to the development of obstructive fibrolipid plaque.
57
What is atherosclerosis?
Atheromas are plaque build-ups which obstruct that flow of blood. Atherosclerosis is the condition caused by atheromas, marked by arteries narrowed with and hardened by plaque causing CV complications, such as angina, myocardial/ cerebral infarction
58
What is an atherosclerotic plaque made up of?
Fibrous tissue
Lipid component - Cholesterol
Lymphocytes
FOAM cells
59
What are the stages of atherosclerotic plaque formation?
1. Endothelial cell dysfunction
- Lots of cholesterol damages wall
- Endothelial cells directly injured
2. High levels of LDL in the blood
- Can freely pass in + out of the wall
- At high concentration LDLs accumulate in the arterial wall and undergo oxidation
3. Oxidised LDLs active the endothelial cells to:
- Release cytokines and growth factors
- Express adhesion molecule for **leukocytes**
- Attract macrophages + T helper cells
- Take up LDLs
4. Macrophages
- Engluf oxidised LDLs to form foam cells (inflammatory response)
5. Foam cells promote migration of smooth muscle cells from tunica media to tunica intima
- Increased population of smooth muscle cells leads to the increased sythesis of collagen (VIII) → hardened fibrous cap
6. When foam cells die their lipid content is released, causing the formation of a collagenous lipid plaque
7. Plaque occludes the lumen → leads to angina
8. Eventually the plaque ruptures → leads to thrombosis and complete occusion of the vessel lumen
60
How does Atherosclerosis compare in a high and low-pressure vessel?
Atherosclerosis is never present in low pressure systems (pulmonary circulation) -but will form in high pressure vessels such as the systemic circulation
61
Name some system specific complications of atherosclerosis.
- Obstruction/ occlusion of arteries in the head and neck = cerebral infarction
- Obstruction/ occlusion of coronary artery = myocardial infarction
- Obstruction/ occlusion of artery in the limbs = peripheral vascular disease or gangrene
- Obstruction/ occlusion og renal arteries = increased renin release → increased blood pressure
- Atherosclerosis in the aorta can cause an aortic aneurysm, a result of excessive dilation of the aorta to the point that it rupture. Results in sudden death
62
why does aspirin help a patient if they have atherosclerosis?
Aspirin inhibits platelet aggregation, therefore reducing plaque formation.
63
What are the risk factors for atherosclerosis?
Age
gender
FHx
smoking
sedentary lifestyle
High cholesterol
Hyperlipidaemia
Hypertension
Diabetes
64
Define apoptosis
Non inflammatory programmed cell controlled death.
65
What are the steps of apoptosis?
Pyknosis - nucleus condenses
Blebs form - cell membrane becomes irregular
Apoptotic bodies form
cell membrane breaks off into fragments for easy phagocytosis
66
What are the mediators of apoptosis?
Caspases
67
What regulates the activity of caspases?
Intrinsic:
Bcl2 family of enzymes:
Bcl2 - inhibits apoptosis
Bax - promotes apoptosis
Extrinsic:
Fas
Binding of Fas ligand to the fas receptor induces apoptosis
68
What is necrosis?
Inflammatory unprogrammed traumatic cell death that induces inflammation and repair.
69
Define genetic disease.
A genetic disease is one that occurs primarily from a genetic abnormality.
70
Define congenital disease.
A disease which is present at birth.
71
Define inherited disease.
Caused by inherited genetic abnormality, it may not manifest itself until later life.
72
Define an acquired disease.
Caused by non genetic environmental factors that usually occurs after birth.
73
Define atrophy.
Decrease in tissue size caused by the decreased in number of constituent cells or a decrease in their size.
74
Define hypertrophy.
Increase in tissue size caused by an increase in the size of the constituent cells.
75
Define hyperplasia.
Increase in tissue size caused by an increase in the number of the constituent cells.
76
Define metaplasia.
Change in differentiation of a cell from one fully differentiated type to a different fully differentiated type.
77
Define dysplaysia.
Morphological changes seen in cells in the progression to becoming cancer.
78
Define carcinogenesis
The transformation of normal cells to neoplastic cells through permanent genetic alterations or mutations
This is a multistep process
79
What is a carcinogen?
A mutagenic agent known to cause cancer
80
Define carcinogenic?
Cancer causing
81
Define Oncogenic?
Tumour causing
82
Define oncogenesis?
The process by which normal cells transform into neoplastic cells
83
What is a neoplasm?
An autonomous abnormal persistent new growth that continues to grow after the initial growth stimulus has been removed.
84
What can neoplasms arise from?
They can only arise from nucleated cells
(eg. not RBCs but could arise from their precursors)
85
What is a tumour?
Any abnormal swelling
86
What percentage of cancer risk is environmental?
85%
87
What host risk factors will increase the risk of cancer?
Race
Diet
Sex
Age
Inherited predisposition
premalignant conditions
Transplacental exposure
88
Give examples of how race can affect cancer risk?
Oral cancer increase risk in SE asia releated to chewing betal nut and reverse smoking
Skin cancer risk is decreased in people with black skin as an increase in melanin is protective against UV.
89
Give some examples of inherited predispositions that will increase cancer risk?
Familial polyposis coli - increase risk of bowel cancer
90
Give some examples of premalignant conditions that will increase the risk of cancer?
Colonic polyps
Ulcerative colitis
Undescended Testis
91
Give an example of how transplacental exposure increased the risk of cancer
The daughters of mothers who took diethylstilboestrol for morning sickness had and increased risk of developing vaginal cancer
92
Name 5 different categories of carcinogens?
Viral
Chemical
Ionising and non-ionising radiation
Hormones, parasites and mycotoxins
Miscellaneous
93
Give some examples of viruses that cause cancer?
Hepatitis B anda C - HCC
HHV8 (human herpes virus 8) - kaposi sarcoma
HPV - Squamous cell carcinoma
EBV - Burkitts Lymphoma
HIV - cerebral lymphoma
94
How can hormones cause cancer?
increase in oestrogen can cause endometrial cancer
95
What parasite can cause cancer?
Shistosoma causes bladder cancer
96
What miscellaneous materials can cause cancer?
Asbestos
Metals - arsenic
97
What type of cancer do polyaromatic hydrocarbons cause and what exposes people to these?
Lung and skin cancer
Smoking and mineral oils
98
What cancer do aromatic amines cause?
bladder cancer
People who work with dye or rubber
99
What cancer do nitrosamine cause?
Gut cancer
100
What type of cancer do alkylating agents cause?
Leukaemias
101
Define Neoplasia?
A lesion resulting from new and abnormal tissue growth which persists independent of its initiating stimulus.
102
What are the two types of neoplasia?
Benign and malignant
103
How can neoplasias be classified?
By behaviour
By histogenesis
104
What are the features of a benign tumour?
Slow growing - low mitotic activity
Well circimuscribed - no invasion to surrounding tissue
Resemble cell origin - rarely necrose or ulcerate
Exophytic - grow outwards
105
what are some long-term effects of benign tumours?
Pressure on adjacent tissues
Obstruction of ducts/hollow organs
produce hormones
Can be pre-malignant
Anxiety
106
What are the features of a malignant tumour?
Fast growing - high mitotic activity and division rate
Poorly defined, irregular infiltrative borders - invasion of surrounding tissues (metastasis)
Variable resemblance to cell of origin - commonly necrosing or ulcerating
Endophytic growth - grow inwards.
107
What are some complications of malignant tumours?
Pressure on adjacent structures
form secondary tumours
Obstructory
very painful
blood loss
108
What is the structure of a neoplasm?
Neoplastic cell
Stroma
109
What are the features of neoplastic cells?
Always derived from nucleated cells
Usually monoclonal
Growth pattern related to parent cell
Synthetic activity related to parent cell - eg. hormone producing.
110
What is the stroma of a neoplasm?
Supported by connective tissue framework that provides mechanical and nutritional support. usually blood vessels.
111
What factors promote angiogenesis?
VEGF
Fibrobalst growth factor
112
What is the behavioural classification of neoplasms?
Benign
Borderline - defy precise classification
Malignant
113
What are the main histological classifications of tumours?
epithelial
Connective tissue
Lymphoid
Haematopoietic
114
What cancer does not have a stroma?
Leukaemia
115
What is a benign non-glandular eplithelial neoplasm called?
Papilloma
116
What is a benign glandular epithelial neoplasm called?
Adenoma
117
What is a malignant epithelial neoplasm?
Carcinoma
118
What is a carcinoma?
A malignant epithelial neoplasm
119
What is the suffix for malignant connective tissue neoplasms?
Sarcoma
120
What is a benign neoplasm of adipocytes?
Lipoma
121
What is a benign neoplasm of adipocytes?
Lipoma
122
What is a benign neoplasm of Cartilage?
Chondroma
123
What is a benign neoplasm of bone
Osteoma
124
What is a benign neoplasm of vasculature?
Angioma
125
What is a benign neoplasm of striated muscle
Rhabdomyoma
126
What is a benign neoplasm of smooth muscle
Leiomyoma
127
What is a benign neoplasm of nerves
Neuroma
128
What is a well-differentiated tumour?
A tumour that closely resembles normal tissue.
These have a lower grade and tend to have a better prognosis.
129
If a neoplasm doesnt resemble normal tissue what is it said to be?
Poorly differentiated
higher grade and would carry a worse prognosis
130
What does the term anaplastic mean?
When the cell type of origin is unknown the tumour is anaplastic
131
What is a melanoma?
A malignant neoplasm of melanocytes
132
What is a mesothelioma?
A malignant neoplasm of mesothelial cells
133
What is a lymphoma?
A malignant neoplasm of lymphoid cells
134
What is burkitts lymphoma?
A B cell malignancy caused by EBV
135
What is kaposi sarcoma?
A vascular endothelial malignancy caused by Human herpes virus 8 and related to HIV
136
What is ewings sarcoma?
A bone malignancy
137
is a teratoma?
A cancer of all 3 embryonic germ layers
138
What is a blastoma?
A tumour of an embryo
139
What is the pathway of metastasis?
1. Detachment from primary tumour
2. Invasion of surrounding connective tissue
3. Intravasation into the lumen of blood vessels
4. Evasion of host defence
5. Adherence to blood vessel wall
6. Extravasation to a distant site
7. Proliferation of cells in new site/environment
140
What are the different methods of spread of a metastasis?
Haematogenous - via blood
Lymphatic - secondary formation in the lymph nodes
Transcoelomic - via exudative fluid accumulation across a body cavity. spread through pleural, pericardial and peritoneal effusions.
along nerves
Iatrogenic
141
What are the characteristics of a neoplastic cell?
Autocrine growth stimulation - overexpression of GF and mutations of tumour suppressor genes (p53)
Evasion of apoptosis
Telomerase - prevents telomeres shortening with each replication
Sustained angiogenesis - provides nutritional support.
142
What cancers commonly spread to bone?
BLT KP
Bladder
Lung
Thyroid
Kidney
Prostate
143
What is a neoplasm in situ?
When a neoplasm has proliferated but has not broken through the basement membrane to other tissues
144
When is a cancer considered to be invasive?
When it has breached its own tissue type into another area
145
What is a micro-invasive carcinoma?
A carcinoma that has only just broken through the basement membrane
146
What is invasion of a cancer dependent on?
Decreased cellular adhesion
abnormal increased cellular motility
Production of lytic enzymes to breakdown surrounding tissue
147
Define metastasis
The process by which a malignant neoplasm spreads from its primary site to produce secondary neoplasms at distant sites.
148
How do tumours invade surrounding tissues?
Proteases break down tissue surrounding neoplasm
tumour cell derived motility factors allow it to invade
149
How do tumours enter and exit blood vessels
(intravasion)
Collagenases break down the blood vessel wall and allow the neoplasm to enter
Adhesion receptors allow the tumour to stick to a specific area. collagenases again break the BV wall so the tumour can exit
150
How do neoplasms evade host defenses?
Aggregation with platelets
Shedding of surface antigens
Adhesion to other tumour cells
151
Why do malignant tumours often have a necrotic centre?
If neoplasms become too big and are too fast growing then they will outgrow the blood supply and so the centre of the tumour does not get enough nutrition and hence it will necrose.
152
What are some angiogenesis inhibitors?
Angiostatin
Endostatin
Vasculostatin
153
Describe the process for metastasis to the lung?
- If the carcinoma enters the venous system, it will travel through the blood vessels to the vena cava, right atrium, right ventricle and onto the pulmonary circulation
- From there, as the lung blood vessels act as a sieve, it will get stuck at some point (same process as thrombosis)
- If this new neoplasm site then grows into the venous system of the pulmonary circulation, it can travel anywhere in the body
154
Describe the process for metastasis to the liver?
- Liver receives 100% of blood from colorectal (remember first pass metabolism)
- Neoplasm may break off from digestive system and travel in the blood stream to the liver through the portal venous system
- Again, the liver blood vessels act as a sieve as they go down to capillary level
- Neoplasm will imbed at some point in the vasculature tree.
155
What cancers are screened for in the UK?
Cervical
Breast
Colorectal
156
Eosinophillic granulomas would be an indication of what?
Parasitic infection
157
What clotting facotrs make up the intrinsic, extrinsic and common coagulation cascade?
Intrinsic - 12, 11, 9, 8
Extrinsic - 3, 7
Common - 10 , 5, 2, 1
158
What cells are polymorphonuclear leukocytes?
Neutrophils
Eosinophils
Basophils
159
What cells are the mononuclear leukocytes?
Monocytes
T cells
B cells
160
Where is complement secreted from?
The liver
161
What are the 3 modes of action for complement?
Direct lysis - MAC
Chemotaxis - attract more leukocytes
Opsonisation - coat invading organisms
162
How can antibodies circulate in the blood
Bound to B cells
Free in plasma
163
Which part of the strucutre of an antibody is responsible for antigen binding?
FAB regions
Variable in sequence
Bind to specific antigens
164
What part of the structure of an antibody is responsible for antigen elimination?
Fc region
Constant sequence
binds to complement, Fc receptors on phagocytes or NK cells
165
What are the 5 classes of antibodies?
IgG
IgM
IgA
IgE
IgD
166
What is the structure, where it is found and its function for the IgG class of antibody?
Monomer - 2 heavy and 2 light chains
Most abundant in serum and tissues
Main Ab involved in adaptive immune response for secondary and memory responses.
Can cross the placenta
167
What is the structure, where it is found and its function for the IgM class of antibody?
Pentamer - dependent on J chain
Mainly found in the blood as they are too big to cross the vascular endothelium
Initial contact with Ag for immune response
High affinity low specificity Ab
168
What is the structure, where it is found and its function for the IgA class of antibody?
Dimer
Found at mucosal surfaces (secretory Ig)
also found in serum
Most abundant antibody in the total body
First line of defence
169
What is the structure, where it is found and its function for the IgE class of antibody?
50% found in blood. the rest bound to mast cells or basophils
Responsible for hypersenitivity reactions and anaphylaxis.
Important in parasitic infections
170
What is the structure, where it is found and its function for the IgD class of antibody?
Found on mature B cells
No effector functions identified
171
What are the different mechanisms of action of antibodies?
Agglutination - bind together in a clump
Neutralisation - antibodies cover the toxic sites of Ag to stop it binding
Lysis - Some antibodies can attack the cell membrane directly to rupture it.
Activate the classical complement pathway
172
What are cytokines?
Proteins secreted by immune and non-immune cells
173
What do interferons do?
Induce a state of viral resistance in uninfected cells and limit the spread of viral infection
174
What are the 3 types of interferons and which cells secrete them?
IFN alpha and beta
produced by virus-infected cells
IFN gamma
Produced by activated Th1 cells and this activates Macrophages
175
What do interleukins do?
Can be proinflammatory or anti-inflammatory
Cause cells to divide, differentiate and secrete factors
176
What do colony stimulating factors do?
Direct the division and differentiation of bone marrow stem cells
177
what do tumour necrosis factors do?
TNF alpha and beta
Mediate inflammation and cytotoxic reactions
178
What are chemokines?
proteins that direct the movement of cells from the blood stream to the tissues.
179
What is a foam cell?
Where a macrophage has phagocytosed LDL
180
What is innate immunity
Primitive
non-specific
rapid response
no memory is used or produced
Typically involves neutrophils and macrophages and complement activation along with physical and chemical barriers
181
What physical and chemical barriers are involved in the innate immune response
Physical barriers - skin, mucus, cilia
Chemical barriers - lysozymes in tears, stomach acid
182
What are pattern recognition receptors?
Receptors on immune cells that detect the presence of PAMPs
183
PAMPS and DAMPS?
Pattern-associated molecular patterns
Damage associated molecular patterns
184
What are Toll-like receptors?
A type of PRR that recognise structurally conserved molecules derived from microbes.
185
What components make up the innate immunity?
Physical and chemical barriers
Phagocytic cells -neutrophils, macrophages
Blood proteins - complement, acute phase proteins.
186
How can physical barriers be breached for allowing pathogens to entre the body?
Tissue trauma
Infection
187
What are the steps to the whole inflammatory response?
- Bleeding - acts to flush bacteria out of the site
- Coagulation - plugs the site to stop further antigens entering the system
- Acute inflammation - leukocyte recruitment
- Kill pathogens, neutralise toxins, limit pathogen spread
- Phagocytosis - clear debris
- Proliferation of cells to repair damage
- Remove thrombus - remodel extracellular matrix
- Re-establish normal function/structure of the tissue
188
What are 3 features of inflammation?
Increased blood supply
Increased Vascular permeability
Increased leukocyte extravasation
189
What cells detect presence of antigens in the blood?
Monocytes
neutrophils
190
What cells detect the presence of antigens in the tissues?
Macrophages
DCs
191
What are the 3 activation pathways for the complement system?
Classical - antibody binds to microbe
Alternative - C' binds to microbe
Lectin - activated by mannose-binding lectin bound to a microbe.
192
What are the 3 mechanisms of action of complement?
Direct lysis - Membrane attack complex (MAC)
Chemotaxis - C3a and C5a
Opsonisation - coat microbes to make them easier to phagocytose (C3b)
193
Describe the process of Extravasation of neutrophils in acute inflammation
1. E-selectin (an adhesion molecule on the capillary endothelium), is activated by IL-1 and TNF-α from damaged cells and binds to the glycoprotein CD15 on neutrophils in blood.
2. This causes neutrophils in the blood to slow down and roll along the endothelium lining.
3. ICAM-1 on endothelium (induced by LPS, IL-1, TNF-α) binds to integrin on neutrophil; the neutrophil stops.
4. Diapedesis: neutrophil squeezes through endothelium (holes caused by C3a, C5a, chemokines, histamines, prostaglandins, leukotrienes (causing smooth muscle contractions in the bronchioles))
194
What are 3 ways phagocytosis can be initiated?
Antibodies bound to antigens on microbes
C3b opsonised on microbes binds to complement receptor
Mannose receptor binds to carbohydrates on bacterial wall
195
What are the main steps in phagocytosis?
Binding
Engulfment (phagosome)
Phagolysosome
bacterial killing
clear debris
196
What are the 2 pathways that neutrophils and macrophages use to kill microbes?
Oxygen dependent
Oxygen independent
197
What is oxygen dependent killing of microbes?
Uses ROI (reactive oxygen intermediates)
Superoxide ions are converted to H2O2 and then to a hydroxide free radical
198
What is the oxygen independent mechanism of killing microbes?
Enzymes - lysozymes
proteins - defensins
pH
TNF
199
What are the 3 outcomes of phagocytosis?
Debris gets secreted by the phagocytic cell
cell components are converted to energy
Antigens are presented on cell surface via MHC II
200
What cells are APCs (antigen presenting cells)?
Dendritic cells
Macrophages
B cells
201
What is the function of a neutrophil?
70% of all WBC
key mediator of acute inflammation
Follow chemotaxic gradients of IL-8 (CXCL8)
Will eat and kill microbes
202
What is the function of macrophages?
Activated by IFN-y from Th1
Will phagocytes microbes and debris to remove them.
Secrete TNF-a, IL-1 and IL-2
Can act as APCs
Can either be circulating or resident to tissues
203
What is the function of eosinophils?
Contain MBP
Often in response to a parasitic infection.
204
What is the function of Basophils and mast cells?
IgE binding and upon re-exposure IgE crosslinking via FceR1
Degranulate to release histamine in Type 1 hypersensitivity reactions,
Mast cells are fixed at tissues
Basophils circulate in the blood.
205
What is the function of a natural killer cell?
NKs cells are a key role in viral cell killing
CD16 Fc receptors
When activated they release perforin to kill infected cells or malignant cells.
206
What is the function of a dendritic cell?
These cells act as APCs and provide an interface between the innate and adaptive immune system.
207
What are the 3 conditions that must be met to enable antigen presenting to function?
Primary receptor binding
co-stimulation molecules
Cytokine release
208
What does TLR 1 detect?
Gram positive bacteria
209
What does TLR 2 detect?
Gram positive bacteria such as lipopeptides, lipoteichoic acid
210
What does TLR 3 detect?
Endogenous viral infection and tissue necrosis
Responds to ds RNA
211
What does TLR 4 detect?
Gram Netagive Bacteria
detects endotoxin such as LPS
212
What does TLR 5 detect?
Flagellin
213
What does TLR 7 detect?
Single stranded RNA
214
What does TLR 8 detect?
Viral and bacterial pathogens
Important for detecting pyogenic bacteria
215
What does TLR 9 detect?
Non-methylated DNA
216
What is the adaptive immune response?
Specific and slower response
Needs to be activated first but then the second exposure has a much larger response
Provides immunological memory
Killing is usually antibody-mediated
Involves T and B lymphocytes.
217
Why do we need an adaptive immune response?
Microbes can evade innate immune responses
Intracellular viruses and bacteria hide from the innate immune system
Memory to specific antigens allows a faster response upon subsequent exposure to clear infection more effectively.
218
Which part of the adaptive immune system deals with intracellular and extracellular microbe
B cell (humoral - antibody) - extracellular
T cell (cell-mediated) - Intracellular
219
To recognise self from non-self what is required?
MHC proteins
220
What do T lymphocytes respond to?
Intracellular presented antigens
221
Where do T cells mature?
In the thymus
222
Where do B cells mature?
In the bone marrow
223
What is Thymic central tolerance?
Where T cells are tested to see if they recognise self antigens . if they produce an immune response they they are selected against and killed by T regulatory (Treg) cells
224
Where is MHC I found?
On all nucleated cells
225
Where is MHC II found?
On APCs Only
226
For intrinsic antigens (i.e. virus): which MHC class presents them, where is the MHC expressed, which T cells bind, what is the function of this T cell?
- MHC Class I
- All cells express MHC Class I (except for red blood cells) (every**one** expresses MHC Class **one**
- Tcytotoxic (CD8) cells
- Kill infected cell with intracellular pathogen directly
227
For extrinsic pathogens (i.e. extracellular pathogen): which MHC class presents them, where is the MHC expressed, which T cells bind, what is the function of this T cell?
- MHC Class II
- Only antigen presenting cells express MHC Class II
- Th (CD4) cells
- Help B cells make antibodies to extracellular pathogen and can help directly kill pathogen
228
What is required for full T cell activation?
Co-stimulatory molecules CD28 on the T cell binds to CD80/CD86 on the APC to fully activate the T cell
229
What is secreted from an activated T cell?
IL2
binds to the T cell receptor (autocrine)
230
What does T cell activation lead to?
Division
Differentiation (to CD4 or CD8)
Effector functions
Memory
231
What determines whether a T cell will differentiate into a Th1 or Th2 CD4 T cell?
Levels of IL-12
High IL-12 = Th1
Low IL-12 = Th2
232
What is the function of a Th1 CD4 T cell?
Travel to secondary lymphoid tissue
Secrete IFN gamma to help kill intracellular antigens
233
What is the function of a Th2 CD4 T-cell?
Binds to a B cell presenting an antigen and stimulates B cell divide (clonal expansion) and differentiation
Secretes IL-4 to stimulate differentiation
234
What is the function of a Cytotoxic CD8 T cell?
Kills cell directly.
Formation of perforin and granulysin which induce apoptosis in infected cells,
Secrete IFN gamma to inhibit viral invasion of neighboring cells to prevent viral spread
Secretion of chemokines to recruit more immune cells.
Express Fas-ligand to initiate apoptosis
235
Which membrane bound antibodies do B cells Express?
IgM or IgD monomers
236
How many types of antibodies can an individual B cell make?
1 Antibody specific to 1 antigen.
237
What happens if a B cell recognises self?
The B cell is killed in the bone marrow
238
How do B cells act as APCs?
Phagocytose the pathogen
Present the epitope on MHC II
Tcell binds to MHC II
lots of costimulatory molecules required such as CD80 and CD86
239
How is a B cell activated?
Th2 T cell binds to antigen presented via MHC class II
Co-stimulatory molecules bind CD80/CD86
T cell releases IL-4 and IL6
IL-4 induces B cell proliferation (clonal expansion)
IL-6 induces B cell differentiation into a plasma cell or memory cell
240
What is B cell somatic hypermutation?
A cellular mechanism where the immune system adapts to new foreign elements that confront it
241
What is B cell class switching?
Where an activated B cell changes its Ab production from IgM to either IgE, IgA or IgG depending on the functional requirements
242
What causes Somatic hypermutation?
AID
Activation induced Cysteine deaminase
243
What interleukin promotes class switching from IgM to IgA and IgE?
IL-4
244
What chromosome is the MHC protein found on?
Chromosome 6
245
What is the role of Tregs?
Regulatory T cells
These are important in immune tolerance and ensuring T cells are not autoreactive
246
What interleukin stimulates a naive T cell to become a Treg?
TGF-b and IL-2
Tregs secrete IL-10 which is anti-inflammatory
247
What Interleukin stimulates a naive T cell to become a Th17?
IL-17
248
What is passive immunisation?
The transfer of pre-formed antibodies
249
What are the two types of passive immunisation?
Natural - Transfer of preformed maternal antibodies across the placenta or through breast milk
Artificial - Treatment with pooled normal human IgG (immunoserum)
250
What would artificial immunisation be effective against?
Individuals with immunocompromisation
No time for active immunisation - against pathogens with a short incubation time
Anti-toxins or anti-venoms
251
What are the disadvantages of passive immunisation?
Does not provide immunological memory - no long term protection
IgG is cleared form the circulation
252
How do toxins act on a nerve cell to produce toxic effects?
Toxin prevents fusion of vesicles at the synapse so the neurotransmitters cannot get into the synapse
253
How does tetanus toxin act on the synapse?
Tetanus toxin inhibits the release of inhibitory neurotransmitters GABA and Glycine which prevents muscle relation
It causes muscle contraction and spasticity
254
How does Botulinum toxin act on the synapse?
Botulinum vesicles contain ACh which prevents muscle contraction
It causes muscle relaxation and flaccidity
255
What is active immunisation?
Manipulation of the immune system to generate a persistent protective response against pathogens by mimicking natural infection
256
What is the difference between innoculation and active immunisation?
Inoculation refers to the introduction of viable microorganisms into the individual to evoke an immune response
257
What are the advantages of active immunisation?
- Mobilises immune system to generate immunological memory - B and/or T cell memory
- Learned immunological behaviour → faster response
258
What are the stages of active immunisation?
Engage innate immune system
Mimicking agent elicits danger signals that TLRs etc
Activation of specialist APCs
Engage the adaptive immune system to generate memory T and B cells
259
What are the primary and secondary responses of active immunisation?
Initial response:
Relies on innate system
IgM predominates
Low affinity
Secondary response:
Rapid and large
High affinity IgG
Somatic hypermutation
260
Give an example of an artificial active immunity
Vaccinations
261
What are the different antigen options used in vaccines?
Whole organism - live attenuated or killed/inactived
Subunit - toxoids, antigenic extracts, recombinant protein
Peptides
DNA/RNA
Engineered virus
262
Give examples of a whole organism vaccination
Live attenuated - TB, Typhoid
Killed/inactivated - Influenza, Hep A
263
What are the advantages and disadvantages of Live attenuated vaccinations?
Adv:
Activates full natural immune response
Produces memory T and B cells
Long lasting and comprehensive protection
Often only requires a single immunisation
Disadv:
Immunocompromised at risk of infection
Complications could occur
Can lead to outbreaks in areas with poor sanitation
Require specific storage methods such as freezing
264
What are the advantages and disadvantages of dead/inactivated Vaccinations?
Adv:
No risk of infection
Storage is less important
Strong immune response is still possible
Disadv:
Tends to activate humoral response without T cell involvement
Immune response is weaker than live attenuated
Booster vaccinations required as a lack of memory is produced
265
What is an adjuvant
Any substance added to a vaccine to stimulate an enhanced immune response
266
Give an example of an adjuvant and explain how it functions
Aluminium salts:
Activate macrophages and lymphocytes
help APCs absorb antigen
extend the presence of antigen in the blood
potentiate opsonised phagocytosis
267
What cells are involved in the cell mediated immune repsonse?
Neutrophils and monocytes
Lymphocytes (T and B cells)
268
What is involved in the non-cellular humoral immune response?
Immunoglobulins (antibodies)
complement
Surfactant proteins
269
What immunoglobulin is made at the beggining of an infection?
IgM
270
What immunoglobulin is in high abundance upon second exposures?
IgG specific antibodies
271
What immunoglobulin is often involved with an allergic reaction?
IgE
272
What are the common features of anaphylaxis?
Rapid onset
Blotchy rash
Swelling of face and lips
Hypotension
Wheeze
Cardiac arrest if severe
273
What drugs can commonly cause hypersensitivity reactions?
Amiodarone
Bleomycin
Methotrexate
NSAIDs
Nitrofurantoin
Novel Ig treatments
274
Describe a Type 1 hypersensitivity Reaction
> 1️⃣ B-cells are stimulated (by CD4 and TH2 cells) to produce IgE antibodies specific to an antigen
> 2️⃣ IgE binds to mast cells and basophils via FcεRI - this is known as sensitisation.
> 3️⃣ Later exposure to the same allergen causes IgE cross-linking, resulting in anaphylactic degranulation of mast cells, therefore the release of inflammatory mediators - notably histamine, as well as leukotrine, prostaglandins, IL-4 ,IL-13, TNFa
> 4️⃣ Leads to acute anaphylaxis.
275
Give example of type 1 hypersensitivity reactions
Allergic Rhinitis (hayfever)
asthma
Nut,food and drug allergies
276
What is Atopy?
An inherited tendency to produce an exaggerated IgE response to an antigen
(hayfever, eczema, Asthma)
277
How are type one hypersensitivity reactions diagnosed?
Skin prick tests
Radioallergosorbent Tests (RASTs)
278
What is the treatment for hayfever?
Prevent exposure
Anti-histamines
steroids - reduce local inflammation
Desensitisation therapy - controlled, gradually increased exposure to the antigen
279
What is the treatment for acute anaphylaxis
Adrenaline 500mg IM (intramuscularly)
if necessary:
Antihistamines - Chlorphenamine
Cortisol - hydrocortisone
280
Describe a Type 2 hypersensitivity reaction
Antigen-Antibody complex on cell surface
IgG and IgM are directed against the self allergen. leads to cell lysis, tissue damage and loss of function through the classical complement pathway.
Antibody dependent cytotoxicity.
281
What can cause Type 2 hypersensitivity reactions?
Transplant rejection
Autoimmune diseases
282
Describe a Type 3 Hypersensitivity reaction?
Immune Complex Deposition:
Occur when immune complexes have not been adequately cleared by innate immune cells
IgG/IgA bind to free floating antigens
giving rise to complement activation and leukocyte recruitment.
Complexes are deposited in the tissue resulting in tissue damage
283
Give examples of Type 3 hypersensitivity reactions?
Systemic Lupus Erythematosus (SLE)
Post strep glomerulonephritits
Rheumatoid Arthritis
284
Describe a Type 4 hypersensitivity reaction?
> 1️⃣ CD4 and T-helper cells recognise antigens in complex with MHC class II on the surface of APCs.
> 2️⃣ The APC (commonly macrophages or monocytes) secrete IL-12 which stimulates the proliferation of CD4+TH-1 cells and their release of IL-2 and INF-y
> 3️⃣ IL2 and INF induce further TH-1 cytokine release.
> 4️⃣ Immune response leads to the activation of; CD8 T-cells - destroy target cells on contact; macrophages - produce hydrolytic enzymes and transform into multinucleated giant cells on presentation with certain intracellular pathogens
285
Give examples of Type 4 hypersensitivity reactions?
TB
Contact dermatitis
Sarcoidosis
286
What is involved in the diagnosis of drug hypersensitivity reactions?
Lung function tests
CT scans
Chest X rays
287
What is involved in the treatment of drug hypersensitivity reactions?
Withdraw offending drug
Give steroids for severe respiratory failure
288
What is autoimmunity?
Pathological response verses self antigens.
Caused by faulty immune tolerance or molecular mimickry
289
Give examples of organ specific Autoimmune disease?
T1DM - endocrine pancreas - beta cells
MS - oligodendrocytes of CNS
Pernicious anaemia - Parietal cells of the stomach - Loss of intrinsic factor - not Vit B12 absorption
Hashimoto's Thyroiditis - Anti-TPO Ab
Graves disease - TSH-R antibodies
Myasthenia Gravis - Anti ACh receptor antibodies
290
Give some non organ specific autoimmune diseases
Systemic Lupus Erythematosus
Autoimmune Haemolytic Anaemia
Immune Thrombocytopenic purpura
Rheumatoid Arthritis
291
Name different types of drug interactions
Synergism
Antagonism
Summation
Potentiation
292
Define synergism?
Interaction of 2 compounds leads to a greater combined effect
(1+1>2)
293
Define Antagonism
Interaction of 2 compounds where one may block another from working so the overall net effect is 0
(1+1=0)
294
Define Summation
Interaction of 2 compounds with similar pharmacodynamics combine to give an increased expected effect
(1+1=2)
295
Define Potentiation
Where one compound may increase the potency of another drug without affecting its own state
(1+1=1+1.5)
296
What are some host risk factors for drug interactions?
Old age
Polypharmacy
Genetics
Hepatic Disease
Renal Disease
297
What are some drug risk factors for drug interactions?
Drugs with a narrow therapeutic index
Drugs with a steep dose response curve
Drugs with a saturable metabolism
298
What are the 2 major routes of drug administration?
Enteral - Gut involved (eg. oral)
Parenteral - Bypasses the gut (eg. IV, IM, SC)
299
Define Pharmacokinetics
What happens to the drug within the body
300
What are the different pharmacokinetic mechanisms?
ADME
Absorption
Distribution
Metabolism
Excretion
301
What factors affect a drugs absoprtion?
Gut motility
Acidity
Solubility
Complex formation
Direct action on enterocytes
302
What factors affect drug distribution?
Protein binding
Chemical properties (water soluble/lipid soluble)
Blood flow to area
303
What factors affect a drugs metabolism?
Drugs are metabolised by the liver or the kidneys
Liver - hydrophobic compounds - CYP450 enzymes - Phase1/2 metabolism
Induction or inhibition of CYP450
Kidney - small water-soluble compounds
304
What factors affect a drugs excretion?
Renal factors
Its pH dependent
Weak bases are cleared faster if urine is acidic
Weak acids are cleared faster if urine is basic
(can use this to aid overdose eg. treat aspirin overdose with bicarbonate)
305
How are drugs metabolised?
By the liver mostly
Phase 1 - microsomal enzymes increase reactivity by adding groups
Phase 2 - non-microsomal enzymes conjugate compounds to increase hydrophilicity
306
What is CYP450 induction/inhibition and what can affect this?
Induction - Drug A induces CYP450 = Increased metabolism of drug B - so drug B has reduced effects
Inhibition - Drug C blocks metabolism of drug D = increase free drug D in plasma - increases drug Ds effects
Can be inhibited by food or drugs
307
Give an example of compounds that will inhibit CPY450/enzymes?
Metronidazole - inhibits Alcohol Dehydrogenase - prevents ethanol metabolism - increases drunkenness
308
How do Avocado and grapefruit affect drug pharmacokinetics?
Avocado - affects solubility - High fat content increases absorption of warfarin (anticoagulant)
Grapefruit juice - Inhibits CYP3A4 which increases the bioavailability of drugs with a high first pass metabolism
309
Define Pharmacodynamics
The effect that a drug has on the body
310
What do drugs usually target?
Give examples of different types?
PROTEINS!!
Receptors
Enzymes
Transporters
Ion Channels
311
What are the different effects of a ligand?
Agonists
Partial Agonist
Antagonist - Competitive or non-competitive
312
Name some mechanisms through which drug interactions can take place?
Pharmacokinetic mechanism
Pharmacodynamic mechanism
313
Give examples of receptor based drug interactions
Agonists - Alcohol + benzodiazepine at a GABA A receptor causes a summative effect
Antagonists - Beta Blockers and asthma - make asthma worse
314
Give examples of how signal transduction can lead to drug interactions?
Giving beta blockers to a diabetic
At B3 receptor - alters blood glucose control
At B2 receptor - suppresses hypoglycaemia
So a diabetic would lose their hypoglycaemic awareness
315
Define Bioavailability?
Amount of drug taken up into systemic circulation unaltered as a proportion of the amount administered
316
How can we avoid drug interactions?
Prescribe rationally
BNF/NICE guidelines
Ward pharmacists
Patient information leafles
317
What are some important drug side effects to know?
Simvastatin - Rhabdomyolysis
Warfarin - bleeding
SSRIs - Serotonin syndrome
NSAID + ACEi + Furosemide - renal failure
318
Define a receptor?
A component of a cell that interacts with a specific ligand and initiates a change in biochemical events leading to ligand-observed effects
319
What is the difference between a target cell and non-target cell?
> Target cell → contains receptors required for a specific ligand to bind and elicit a response
> Non-target cell → does not contain receptors required for specific ligands to being and elicit a response
320
What are the different types of receptors targeted by drugs?
Ligand gated ion channels
G-protein coupled receptors (GPCRs)
Kinase-linked receptors
Cytosolic/nuclear receptors
321
How do ligand gated ion channels work and give an example?
Ion channels are opened through the the binding of a ligand (e.g. neurotransmitter) to an orthosteric site → triggers a conformational change resulting in the conducting state.
Nicotinic ACh Receptor
322
How do GPCRs work?
1️⃣Binding of ligand to the extracellular binding domain causes the Gα-subunit to undergo a conformational change.
2️⃣Change allows Gα to bind GTP (release GDP)
3️⃣Binding of GTP causes the another conformation change which results in the separation of the G-protein into a Gα and Gβγ-subunit
4️⃣Gα and Gβγ-subunits are able to actively continue the signal transduction pathway
5️⃣Activate effector molecules to initiating signal cascades via secondary messengers
Adenylate cyclase - cAMP pathway
Phospholipase C - phosphatidylinositol pathway
323
What are the 3 types of GPCR?
Gs - stimulatory - activates Adenylate cyclase
Gi - Inhibitory - Inhibits Adenylate Cyclase
Gq - Activates PLC - increases IP3 and DAG
324
Give examples of different GPCRs
Muscarinic 3 receptor - Gq GPCR
B2 Adrenoceptor - Gs GPCR
325
How do kinase linked receptors work and give an example?
1️⃣Ligand binding causes or stabilises receptor dimerisation
2️⃣This allows tyrosine in the cytoplasmic portion of each receptor monomer to be transphosphoylated by its partner receptor
3️⃣Phosphorylation of specific tyrosine residues within the activated receptor creates ligand-specific signalling protein binding sites (e.g. a phospholipase C binding site)
4️⃣Binding to these binding sites causes signalling protein phosphorylation and activation → initiation of signal transduction pathway
Receptors for Growth Factors
326
How do cytosolic/nuclear receptors work and give an example?
1️⃣Steroid ligand freely move into the cell cytoplasm
2️⃣Steroid ligand binds to receptor on nuclear membrane - often form dimers
3️⃣In the nucleus, the steroid complex acts as a transcriptional factors, functioning to augment or supress transcription of particular genes by binding to DNA
Breast cancer drugs - Tamoxifen
327
What is an agonist?
A compound that binds to a receptor to activate it
It has both affinity and efficacy
328
What is an antagonist?
A compound that binds to a receptor but shows no response at the receptor
It has affinity but no Efficacy
These block the effects of agonists
329
What is a partial agonist?
A agonist which, no matter how much it is exposed to the receptor, a maximal response is never reached
Does not have full efficacy
330
What are the 2 types of antagonist?
Competitive - Binds to the active site. (Decreases Potency but does not affect efficacy)
Non-competitive - Binds to an allosteric site (Decreases both potency and efficacy)
331
What is the Emax?
The maximum response that can be achieved
(The Efficacy)
332
What is the EC50?
The concentration of a drug that gives half the maximal response
It tells us about potency
333
What does the EC50 tell us about?
How potent a drug is
334
Would a drug with a lower EC50 have a lower or greater potency?
Greater Potency
335
Which is more efficacious, a full agonist or partial agonist?
A full agonist is more efficacious as a full agonist has the capability of inducing a 100% response.
336
Define efficacy?
How well a ligand activates a receptor
how well it induces a conformational change
337
Define Affinity
How well a ligand can bind to a receptor
338
What are the two subtypes of Cholinergic receptors and what are their respective agonists and antagonists?
- Muscarinic (mAchR) - GPCR
Agonist → muscarine
Antagonist → atropine
- Nicotinic (nAchR) - Ion channel
Agonist → nicotine
Antagonist → curare
339
What is the effect of fewer receptors on drug potency?
Fewer receptors will shift the dose-response curve to the right → potency reduced
340
What is a receptor reserve?
Where an agonist needs to activate only a small fraction of the existing receptors to produce the maximal system response
341
What is the effect of less signal amplificiation on drug response?
Less signal amplification gives a reduced drug response
342
Describe allosteric modulation?
An allosteric modulator binds to a different site (the allosteric site) on a receptor and influences the role of an agonist.
343
What is inverse agonism?
When the binding of a drug to the same receptor as the agonist induces an opposite pharmacological response to that of the agonist - the inverse agonist changes the function of the receptor.
344
Define tolerance?
A reduction in the effect of a drug overtime
Due to continuous use, repeated use or use at high concentrations
345
What 3 ways can a receptor become desensitised?
Uncoupled - agonist unable to interact with the GPCR
Internalised - The receptor is taken into the cell via endocytosis
Degraded
346
What is the drug target for statins?
HMG-CoA reductase
347
What is the action of statins?
Block the rate limiting step in the cholesterol pathway
348
what is the end effect of statin use?
Lipid lowering
Prevent CVD
Reduce CVD and mortality of those at risk
349
What is the Renin-angiotensin aldosterone system responsible for?
Blood pressure control
350
What is the function of ACE inhibitors?
Reduces the production of angiotensin II
Reduces blood pressure
351
What is the function of L-DOPA in parkinsons?
It is a dopamine precursor
It can freely cross the BBB and thus be given as part of a treatment for parkinsons
352
What are the mechanisms of action of Co-Careldopa (carbidopa)?
DOPA decarboxylase inhibitor
Reduces L-DOPA metabolism to dopamine in the periphery
More can pass into the brain to be metabolised here
(carbidopa does not cross the BBB)
353
What is the mechanism of action of tolcapone and entacapone?
Catechol-O-methyl transferase (COMT) inhibitor
prevents breakdown of L-DOPA and dopamine
354
Can tolcapone cross the BBB?
Yes
355
What is the mechanism of action of selegiline and rasagiline?
Monoamine oxidase - B (MOA) inhibitors
Prevent the breakdown of dopamine
356
What are the 3 types of protein ports?
uniporters - use ATP to move molecule through
Symporters - use the passive transport of one molecule to pull another through
Antiporters - use the passive transport of one molecule to move another molecule the opposite way
357
What does amiloride act on and what is its function?
Epithelial sodium channel (ENaC)
Stops reabsorption of water in the kidney
Used as an antihypertensive
358
What does thiazide act on and what is it function?
NaCl cotransporter
Stops reabsorption of water in the DCT of the nephron
Used as an antihypertensive
359
What class of drug is amlodipine?
Angioselective calcium channel blocker
360
What is the mechanism of action of amlodipine?
Blocks the activation of calcium channels
Inhibits the contraction of cardiac muscle and vascular smooth muscle
Reduces TPR and leads to a decrease in overall BP
361
What is the mechanism of action of lidocane and what class of drug is it?
Anaesthetic
use-dependent blockage of VG-Na channels
Sodium channels need to activate in order for lidocaine to act on them
Blocks transmission of APs
Reduces Arrhymthmias
362
How do potassium channel blockers help in T2DM?
Block of potassium cause membrane depolarisation in pancreatic beta cells
opens calcium channels which cause exocytosis of insulin
363
Give 3 examples of potassium channel blockers used to treat T2DM?
Repaglinide
Nateglinide
Sufonylureal
364
What do barbiturates do and give an example of a drug in this class?
Phenobarbitone
GABA receptor agonists
GABA is an inhibitory ionotropic receptor
365
What is the mechanism of action of digoxin?
Blocks the action of NA/K/ATPase mainly in myocardial tissue
this increases level of Na in the cell
Decreases the action of Na-Ca exchanger
Increases amount of Ca in the cell
Increases the length of contraction and reduces heartrate
366
What do proton pump inhibitors do an give an example?
Omeprazole
Act on the stomach by decreasing gastric acid production by irreversible inhibition.
Decrease the pH of gastric acid
367
What does the rate of metabolism determine?
Duration and intensity of a drugs pharmacological action
368
What is Cytochrome P450?
Major microsomal enzyme in the liver
Most drugs are inactivated by CYP however some require CYP to be activated
369
What are the different categories of opioids?
Naturally occurring
Simple chemical modifications
Synthetic opioids
Synthetic partial agonists
370
What are the naturally occurring opioids?
Morphine (from the opium poppy)
Codeine
371
What are the simple chemical modifications class of opioids?
Diamorphine (2x stronger than morphine)
Oxycodone (1.5x more potent than morphine)
Dihydrocodeine (1.5x more potent that codeine)
372
What are the modern synthetic opioids?
Fentanyl
Alfentanil
Remifentanil
373
give an example of a synthetic partial agonist opioid?
Buprenorphine
374
What drug is the antagonist to opioids and is important to treat overdose with?
Naloxone - acts on the u receptor
375
What percentage of oral morphine is metabolised in first pass metabolism?
50%
Hence, you would half the dose if giving by s/c; IM; IV etc 10mg oral morphine = 5mg s/c;IM;IV - you will need to write two separate prescriptions!
376
What are the main routes of administration of opioids?
Parenteral:
IM
SC
IV (fastest)
Epidural
Transdermal patches - fentanyl
377
What is important about IV PCA?
Intravenous patient-controlled analgesia
important that only the patient administers the dose as this is a protective mechanism against respiratory distress. If the patient administers too much then they will fall asleep before they get to respiratory distress and hence prevent them administering more drug.
378
What is the difference between potency and efficacy?
Potency: Strength of binding affinity of the drug for the receptor
Efficacy: is it possible to get a maximal response with the drug or not?
379
What is the difference between tolerance and dependence?
Tolerance: ↓ regulation of receptors with prolonged drug use
Dependence: what happens when you stop: physical and psychological effects
380
What is the mechanism of action of opioids?
They use the existing pain modulation system - endorphins and enkephalins
Work via GPCRs
Inhibit the release of pain neurotransmitters at the midbrain and spinal cord
Can modulate pain perception (euphoria) to change the emotional aspect of pain.
381
What is the main opioid receptor?
u, Mu or MOP
382
What are the main side effects of opioids?
1. Respiratory distress
2. Sedation
3. Nausea and Vomiting
4. Constipation
5. Itching
6. Immune suppression
7. Endocrine effects
383
How would you treat opioid induced respiratory depression?
With Naloxone
384
What enzyme metabolises codeine and what is it metabolised to?
CYP2D6 metabolises codeine to morphine
(codeine is a prodrug)
385
What is morphine metabolised to?
Morphine-6-glucoronide (more potent than morphine)
386
Describe the dose response curve to morphine
As dose increases response increases. This association is initially rapidly and then the graph plateaus. It is not sigmoidal!
387
What is tramadol?
A weak opioid agonist (slightly stronger than codeine)
Also acts as a SSRi and noradrenaline reuptake inhibitor.
388
What systemic effects can be controlled by manipulating cholinergic and adrenergic pathways?
Control blood pressure; raise in shock, lower in hypertension
Control heart rate; speed up lethal bradycardias, slow down dangerous tachycardias
Anaesthetic agents; muscle relaxants
Regulation of airway tone; treat life-threatening bronchospasms
Control GI functions; treat diarrhoea and constipation
Reduce pressure in the eye; prevent glaucoma causing blindness
389
How does the structure of the Somatic NS and the Autonomic NS differ?
- Somatic Nervous System - a neurone comes from CNS to innervate skeletal muscle
- Autonomic Nervous System - there are two nerves in the series; the pre- and postganglionic fibres. The parasympathetic ganglia have short postganglionic fibres (near target); the sympathetic ganglia have long postganglionic fibres (near spinal cord)
390
What nerves are the Parasympathetic NS made up of?
- Oculomotor (CN III)
- Facial (CN VII)
- Glossopharyngeal (CN IX)
- Vagus (CN X)
- Further outflow via *sacral nerve* innervations of the pelvis
391
What neurotransmitter and receptor are associated with the Parasympathetic nervous system?
Acetylcholine acting on muscarinic receptors
392
What neurotransmitter is released by the preganglionic nerve fibres within the ANS?
Acetylcholine acting on N2 receptors
393
What neurotransmitter is released by the post ganglionic nerve fibres within the sympathetic NS?
Noradrenaline acting on alpha/beta adrenoceptors
394
What neurotransmitter is released in the somatic NS at the effector cells?
Acetylcholine acting on N1 receptors
395
give examples of non-adrenergic/cholinergic autonomic transmitters?
Sympathetic - ATP, Neuropeptide y
Parasympathetic - NO, VIP
396
What nervous system pathway does cholinergic pharmacology deal with?
Manipulation of the parasympathetic pathway
397
What does nicotine stimulate?
Stimulates all automimic ganglia via preganglionic nicotinic receptors
Activates both the SNS and PNS
398
What does muscarine stimulate?
Activates the muscarinic receptors specific to the PNS
399
What type of receptor are muscarinic and nicotinic receptors?
Muscarinic - GPCR - M1-5
Nicotine - Ligand gated ion channels
400
Where are the different subtypes of muscarinic receptors found?
M1 - Brain
M2 - Heart
M3 - Glandular and smooth muscle (lungs and GI tract)
M4 - Mainly CNS
M5 - Mainly CNS
401
What is the effect of muscarinic agonists at the M2 receptors?
Slows the heart rate
402
What is the effect of muscarinic agonists at the M3 receptors?
Causes bronchoconstriction of smooth muscle
Will increase sweating, saliva and GI motility.
403
What is the difference between a selective and non-selective drug?
A selective drug will act on a specific subunit of a receptor type (eg. B2 receptors only)
A non-selective drug will act on all receptors of a certain type (eg. B1 and B2 receptors)
404
What is pilocarpine?
A muscarinic agonist
Stimulates salivation - treats Sjogrens syndrome
Contracts iris smooth muscle - treats glaucoma by draining aqueous humour
405
What is a side effect of pilocarpine?
Slows the heart
(non-selective muscarinic agonist)
406
What is atropine?
A muscarinic antagonist
Prevents bradycardia - used to treat bradycardia in cardiac arrest
Dry secretions perioperatively
407
What drugs are used in the treatment of bronchoconstriction?
Drugs that block the M3 receptors - anticholinergics/anti-muscarinics
Short acting (SAMA) - Ipratropium bromide
Long acting (LAMA) - Tiotropium
408
What other roles can anticholinergics play?
Solifenacin - treat overactive bladder
Mebeverine - Treat IBS
409
Give 2 examples of ACh action in the CNS?
Motion sickness - ACh stimulates vomiting centre in the brain
Worsen Parkinsons symtpoms - ACh increases dopamine re-uptake
410
How is ACh synthesised?
Acetyl CoA combined with Choline; mediated by Choline Acetyl Transferase
411
What enzyme is responsible for ACh breakdown in the synaptic cleft?
Acetylcholinesterase
412
What is the action of the botulinum toxin at the NMJ?
Botulinum inhibits Ach release at the NMJ → Cause paralysis/decrease muscle contractions - cosmetic and antispasmodic uses
413
What is the purpose of competitive antagonists at the NMJ?
Competitive antagonists block Ach receptors → muscle relaxants, adjuncts to general anaesthesia (pancuronium)
414
What is the action of depolarising agonists?
Act as blockers as they cause receptor desensitisation
415
What are AChE inhibitors used for?
prevent the breakdown of Ach in the synaptic cleft. Used to increase the amount of Ach available in the synaptic cleft to compete with depolarising blockers or receptor deficiencies
416
What is Myasthenia Gravis and how is it treated?
A diseases associated with the autoimmune destruction of nAchR, resulting in weakness; treated using acetylcholinesterase inhibitors to increase the amount of Ach available to limited nAch receptors
417
What are some side effects of anticholinergics?
- Worsening memory/ confusion
- Constipation
- Dry mouth
- Blurred vision
418
What are organophosphates?
Used in insecticides and nerve gases
They are irreversible AChE inhibitors
Cause muscle tremors, twitching, salivation and confusion.
419
Give some examples of AChE inhibitors?
Neostigmine
Pyridostigmine
Rivastigmine
420
What is Curare and Pancuronium?
An nACh-R antagonist
421
What does overstimulation of Ach at the NMJ lead to?
Cholinergic Crisis (SLUDGE)
Salivation
Lacrimation
Urination
Defecation
GI distress
Emesis
422
What nervous system pathway does adrenergic pharmacology deal with?
Sympathetic nervous system
423
What are the principle catecholamines involved in the sympathetic nervous system?
- **Noradrenaline**; released from sympathetic nerve fibre ends → important in the management of shock in ICU
- **Adrenaline;** released from adrenal glands → important for management of anaphylaxis
- **Dopamine;** precursor of noradreanline, which is the precursor of adrenaline
424
What is the synthetic pathway of catecholamines?
Tyrosine
DOPA
Dopamine
Noradrenaline
Adrenaline
425
What is the primary function of α1 adrenoceptors?
Vasoconstriction (contraction of BV)
Bladder contraction
Dilation of pupils
426
What is the primary function of α2 adrenoceptors?
Responsible for pre-synaptic inhibition - prevents NAd release
Used in analgesia
427
What neurotransmitter predominates in α1 and α2 interactions?
α1 - Noradrenaline
α2 - Adrenaline = noradrenaline
428
What is the primary function of β1 adrenoceptors?
Increased cardiac effects to increase SV and CO
Increase ionotropy (force of contraction)
Increase chronotropy (heart rate)
Increase Dromotropy (electrical conduction)
Increase renin secretion
429
What neurotransmitter predominates in β1, β2 and β3 interactions?
β1 - Noradrenaline = adrenaline
β2 - Adrenaline
β3 - Noradrenaline
430
What is the primary function of β2 adrenoceptors?
Decrease SM tone - Bronchodilation
Vasodilation (partly)
431
What are the primary functions of β3 adrenoceptors?
Increased Lipolysis
Bladder - detrusor muscle relaxation
432
Where are the various adrenoceptors located?
α1 - Vascular smooth muscle, pupil
α2 - Presynaptic neurone (CNS Acting)
β1 - Heart
β2 - Lungs
β3 - Bladder detrusor muscle (and increase lipolysis)
433
What is the role of adenylate cyclase?
Converts ATP to cyclic AMP (cAMP) to activate PKA
434
What do α1 adrenergic agonists do?
Vasoconstriction; used for treatment of septic shock
435
What do α1 adrenergic antagonists (alpha blockers) do?
Vasodilation; lowers blood pressure (doxazosin)
436
What disease could an α1 adrenergic antagonist be used in the treatment of?
Benign prostatic hyperplasia; tamsulosin blocks α1 receptors in the prostate
437
What do β1 adrenergic agonists do?
Increase heart rate and chronotropic effects; used for treating conditions like septic shock
(dobutamine)
438
What do β1 adrenergic antagonist do?
Reduce CO and reduce renin secretion; lower blood pressure
(Bisoprolol, Atenolol, Metoprolol)
439
What diseases could an β1 adrenergic antagonist be used in the treatment of?
Hypertension, angina and arrhythmia.
440
What do β2 agonists do?
Muscle relaxation; life-saving treatment for asthma and delay onset of premature labour
441
What do β3 agonists do?
Smooth muscle relaxation; relaxation of detrusor muscle to reduce over-active bladder symptoms
442
Give examples of cardioselective beta blockers and non-selective beta blockers?
Cardioselective (against B1) - Atenolol, Metoprolol
Non-selective - Propanolol
443
What is the suffix for:
Murine Antibodies
Chimeric Antibodies
Humanised Antibodies
Human Antibodies
Murine Antibodies - omab
Chimeric Antibodies - ximab
Humanised Antibodies - zumab
Human Antibodies - umab
444
Where are DA (dopamine receptors) most found?
Nucleus accumbens in the brain
445
What is the main excitatory and main inhibitory neurotransmitter in the CNS?
Excitatory - glutamate
Inhibitor - GABA
446
Give an example of a GABA agonist and what it may be used to treat?
Benzodiazepines (eg. Diazepam, Lorazepam)
Treats:
Anxiety
Sleep disorders
Alcohol withdrawal
447
Give an example of a Histamine (H1 and H2) receptor antagonist and what they would be used to treat?
H1 Antagonist - Loratidine - treats allergy (T1 hypersensitivity)
H2 antagonist - cimetidine, Ranitidine - Treats GORD/reflux (Reduces gastric acid)
448
What is an adverse drug reaction (ADR)?
An unwanted, harmful reaction following the administration of a drug or combination of drugs under normal conditions of use, and is suspected to be related to the drug
Rxn has to be noxious and unintended
449
Are side effects and ADRs the same?
No! side effects are predictable
A side effect is an unintended effect of a drug related to the pharmacological properties and can include unexpected benefits of treatment (e.g. PDE5 inhibitors (viagra), used for erectile dysfunction, is also found to improve urinary flow).
450
What are the patient risk factors for ADRs?
- Gender (F>M)
- Elderly
- Neonates
- Polypharmacy
- Genetic predisposition
- Hypersensitivity/ allergies
- Hepatic/ renal impairment
- Adherence problems
451
What are the drug risk factors for ADRs?
- Steep dose-response curve
- Low therapeutic index
452
What are some potential causes for ADRs?
- Pharmaceutical variation
- Receptor abnormalities
- Abnormal biological system unmasked by drug
- Abnormalities in drug metabolism
- Immunological
- Drug-drug interactions
- Multifactorial
453
What drugs commonly cause ADRs?
- Antibiotics (penicillin)
- Anti-neoplastics
- Cardiovascular drugs
- Hypoglycaemics
- NSAIDs
- CNS drugs
454
What body systems are commonly affected by ADRs?
- Gastrointestinal
- Renal
- Haemorrhagic (i.e. NSAIDs in patients on warfarin can cause gastric ulcer causing a catastrophic bleed)
- Metabolic
- Endocrine
- Dermatologic
455
Give examples of common ADR presentations
- Confusion
- Nausea
- Balance problems
- Diarrhoea
- Constipation
- Hypotension
456
How are ADRs categorised?
- Toxic effects - above therapeutic range
- Collateral effects - at normal therapeutic range
- Hypersusceptibility effects - below therapeutic range (e.g. tiny does of penicillin causing anaphylaxis)
457
What is the Rawlins Thompson System of ADRs?
Type A - Augmented
Type B - Bizarre
Type C - Chronic
Type D - Delayed
Type E - End of use
Type F - Failure
458
Describe a Type A ADR
*Augmented (or pharmacological).*
- Common and predictable from physiological effects of the drug; often dose related.
(eg. Anticoagulants causing haemorrhage)
Treatment is reduce drug dose
459
Describe a Type B ADR
*Bizarre (or idiosyncratic).*
- Not predictable, not dose dependent and cannot be readily reversed
- For example, immunological mechanisms and hypersensitivity reactions such as anaphylaxis to penicillin
Tx is to withdraw drug immediately
460
Describe a Type C ADR?
*Chronic.*
- Occurs after long term therapy
(eg. Nephropathy caused by long term NSAID use)
461
Describe a Type D ADR?
Delayed
Occurs many years after treatment
(eg. teratogenesis caused by thalidomide)
462
Describe a Type E ADR?
End of use
Complications of stopping medication (withdrawal)
eg. opioids
463
Describe a Type F ADR?
Failure of therapy
(eg. Failure of the oral contraceptive pill in the presence of enzyme inducer drugs)
464
What does the acroyn DoTS mean?
Dose relatedness - Toxic, collateral or hypersusceptibility
Timing - fast rxns, or late Rxns
Susceptibility - Patient factors
465
When should you suspect an ADR?
- Symptoms after a new drug is started
- Symptoms after dosage increase
- Symptoms disappear when drug is stopped
- Symptoms reappear when drug is restarted
466
Define Drug hypersenstivity?
Reproducible symptoms or signs that are initiated by the exposure to a drug at a dose tolerated by normal subjects
467
Give explanations for the main features of anaphylaxis?
- Occurs within minutes of drug exposure and lasts 1-2 hours
- Vasodilation - flushing
- Increased vascular permeability - fluid centrally shifted peripherally; swelling and oedema
- Angio-oedema - swelling of the face and throat
- Central cyanosis - bluish discolouration of the hands or feet
- Bronchoconstriction - wheeze, SOB
- Urticaria - itchy, aggressive rash (80-90%)
- Hypotension - known as anaphylactic shock
- Cardiac arrest
468
What is non-immune anaphylaxis?
- Anaphylaxis occuring with no prior exposure - due to the direct degranulation of mast cells
- Clinically identical as immunological anaphylaxis and the treatment is the same.
469
How is anaphylaxis managed?
- Commence basic life support (ABCDE)
- Stop the drug if currently being infused
- Adrenaline (IM) 500mg - second dose after five miuntes if patient is not initially responding.
- High flow oxygen
- IV fluids - fluid shifts peripherally; IV fluids maintain intravascular volume
- IV Antihistamine (Chlorphenamine 10mg)
- IV Hydrocortisone (100 to 200mg)
470
What does adrenaline do during anaphylaxis Treatment?
- Vasoconstriction - increases peripheral vascular resistance; increases BP and coronary perfusion via α1-adrenoreceptors
- Stimulation of β1-adrenoreceptors; produces positive ionotrophic (strength) and chronotropic (speed) effects on heart
- Stimulation of β2-adrenoreceptors; reduces oedema and bronchodilation
- Attenuates further release of mediators from mast cells and basophils by increasing intracellular cAMP → reduced release of inflammatory mediators
471
Define Absorption (pharmacokinetics)
The process of transfer from the site of administration into the general or systemic circulation
472
What are the routes of drug administration?
po - oral
iv - intravenous
pr - rectal
sc - subcutaneous
im - intramuscular
in - intra-nasal
top - topical
sl - sublingual
inh - inhaled
neb - nebulised
et - endotracheal
473
How do drugs cross membranes to reach their target sites?
Passive diffusion
Facilitated diffusion
Active transport
non-ionic diffusion
Pinocytosis
474
What is drug ionisation?
A property of a drug: they can be weak acids (e.g. aspirin) or weak bases (e.g. propranolol). Drugs with ionisable groups exist in equilibrium between charged ionised and uncharged forms
475
What is the strength of drug ionisation dependent on?
The strength of the ionisable group
pH of the solution
476
What are other terms used to describe ionised drugs vs. unionised drugs?
Water soluble vs. lipid soluble respectively
477
What is the pKa of a drug?
The pH at which half of the substance is ionised and half is unionised
478
Drugs that are weak acids are best absorbed where?
The stomach
(eg. Aspirin is a weak acid and so becomes less ionised in the stomach due to the low gastric pH.)
479
Drugs that are weak bases are best absorbed where?
The intestines
480
What is the effect of an increase in pH on a weak acid?
The weak acid will become more ionised
481
What is the effect of an increase in pH on a weak base?
The weak base will become less ionised.
482
What is the effect of a decrease in pH on a weak acid?
The weak acid will become less ionised
483
What is the effect of a decrease in pH on a weak base?
The weak base will become more ionised
484
What route of drug administration has a bioavailability of 1?
IV - all the drug administered will go into the plasma
485
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.
486
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
487
What equation can be used to determine the degree of ionisation at a specific pH?
Henderson Hasselbach.
pH = log[A-]/[HA] + pKa.
488
What can enhance non ionic diffusion?
Non ionic diffusion can be enhanced if adjacent compartments have pH difference.
489
Give an example of a proton pump inhibitor.
Omeprazole
490
Give an example of a statin
Simvastatin
Atorvostatin
491
Give an example of an ACE inhibitor?
Enalapril
492
Give an example of a COX inhibitor?
Aspirin
Ibuprofen
493
Give an example of a beta 2 adrenoceptor agonist?
Salbutamol
494
Give an example of a beta 1 adrenoceptor antagonist?
Atenolol
495
Give an example of a Calcium channel blocker?
Amlodipine
496
Give an example of a broad spectrum antibiotic?
Amoxicillin
497
Give an example of an opiate analgesic?
Tramadol
498
What pharmaceutical properties can affect the rate of drug absorption?
Pharmaceutical form - syrup/pill
Ability to disintegrate
Ability to dissolve
499
What physiochemical properties of a drug affects the rate of drug absorption?
Solubility
pH
Molecular weight
500
What physiological variables can affect the rate of drug absorption?
Available Surface area
Contact time of drug with receptors
Concentration of drug at absorption site
Absorption site - level of blood flow
Drug interactions
Transporter systems
501
What is first pass metabolism?
Where a drug is metabolised at a specific site prior to reaching its site of action or the systemic circulation that results in an overall reduced dose/bioavailability
502
Define distribution (pharmacokinetics)
The process by which the drug is transferred (reversibly) from the general circulation to the tissues as the blood concentration increases and then returns from the tissues to the blood when the blood concentration falls.
503
What is important about drugs binding to proteins in the plasma?
Binding lowers the free conc of a drug and acts as a depot releasing the bound drug when the plasma conc drops through redistribution or elimination.
504
What is the most common protein that drugs bind to?
Albumin
505
What type of drugs pass easily into the brain?
Lipid soluble
Some drugs use SLC (solute carrier) transporters that supply the brain with carbohydrate and AAs e.g. L-DOPA used in Parkinson's
506
How are water soluble and lipid soluble drugs eliminated?
Water soluble: directly by the kidney
Lipid soluble: must be metabolised to water soluble products
507
What are the phases of metabolism?
Phase 1:
Transform the drug to a more polar molecule by unmasking or adding functional groups through oxidation, reduction or hydrolysis reactions.
This is usually carried out by CYP450 microsomal enzymes
Phase 2:
Conjugation reactions where there is a major increase in hydrophilicity to make the drug easily excreted via the kidney.
Often uses conjugates such as glucuronic acid, glutathione.
508
What is first order kinetics?
Rate of metabolism is directly proportional to Drug concentration
Where a constant fraction of drug is eliminated per unit time
509
What is zero order kinetics?
If an enzyme system that removed a drug is saturated the rate of removal of the drug is constant and unaffected by an increase in concentration e.g. ethanol follows zero order kinetics once alcohol dehydrogenase has been saturated.
510
Define half-life
The time taken for a concentration of a drug to reduce by half.
511
What would be the bioavailability of an oral drug?
F<1 as they are incompletely absorbed and undergo incomplete first pass metabolism.
512
If a drug has an oral bioavailability of 0.1, and the IV dose has a bioavailability of 1, what is the oral dose needed to be to be effective?
10x the oral dose
513
What is the volume of distribution and how is it calculated?
A measurement of how a drug is dispersed in the body related to the measured plasma concentration.
Amount of drug in the body / Measured plasma concentration
514
Do water soluble or lipid soluble drugs have a higher volume of distribution?
Lipid soluble - these will move into the tissues more readily
Water soluble - highly protein bound and will be confined to the blood
515
Define Clearance?
The volume of plasma from which a drug is completely removed per unit time
The rate at which a plasma drug is eliminated per unit plasma concentration
516
Give the equation for renal clearance?
Renal clearance = Rate of appearance in urine / plasma concentration.
517
Define hepatic extraction ratio (HER).
The proportion of a drug removed by one passage through the liver.
518
What is the limiting factor when a drug has a high HER?
Hepatic blood flow, perfusion limited
519
What is the limiting factor when a drug has a low HER?
Diffusion limited. A low HER is slow and not efficient.
520
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.
521
What is steady state?
A balance between drug input and elimination
522
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.
523
What are APUDomas?
Neuroendocrine tumours
524
Describe T cell Activation
Naive T cell with the TCR binds to the epitope of the antigen presented via MHC on the APC
Co stimulatory molecule CD28 binds to CD80/CD86 on the APC to allow for full activation of the T cell.
The T cell will release IL-2 which then rebinds to the T cell IL-2-R to initiate T cell differentiation via autocrine mechanism.
The T cell will divide into Th1 or TH2 depending on the IL-12 concentration present at the time of differentiation.
525
What cytokines are released from Th1 cells and Th2 cells
Th1 - IL2 and INFy
Th2 - IL-4, IL-5, IL-6, IL-10
526
Give 3 functions of antibodies.
1. Neutralise toxins.
2. Opsonisation.
3. Activate classical complement system.
527
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.
528
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.
529
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.
530
What is the function of these complement proteins:
MAC
C3a and C5a
C3b
MAC - Lyse microbes directly
C3a /C5a - Chemotaxis
C3b - Opsonisation
531
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.
532
Which complement plasma proteins are pro-inflammatory and cause chemotaxis and activation of neutrophils and monocytes etc?
C3a and C5a.
533
Which complement plasma proteins have opsonic properties when bound to a pathogen?
C3b and C4b.
534
Name 3 receptors that make up the PRR family.
1. Toll-like receptors (TLR).
2. Nod-like receptors (NLR).
3. Rig-like receptors (RLR).
535
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.
536
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.
537
What disease could be caused by a non-functioning mutation in NOD2?
Crohn's disease.
538
What is the main function of RLR's?
RLR's detect intracellular double stranded RNA. This triggers interferon production and so an antiviral response.
539
TLR's are adapted to recognise damaged molecules. What characteristic do these damaged molecules often have in common?
They are often hydrophobic.
540
What kind of TLR's can be used in vaccine adjuvants?
TLR4 agonists.
541
What is extravasation?
Leukocyte (WBC) migration across the endothelium.
542
What do macrophages at the tissues secrete to initiate extravasation?
TNF alpha.
543
Describe the process of extravasation.
1. Macrophages at tissues release TNF alpha.
2. The endothelium is stimulated to express adhesion molecules (eg. GAG) and to stimulate chemokines.
3. Neutrophils bind to adhesion molecules (ICAM-1); 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.
544
Define Adsorption and give an example
Where a compound clings to the surface of another molecule
eg. In paracetamol overdose you could prescribe activated charcoal to stick to the paracetamol to prevent its absorption from the gut.
545
How would you treat paracetamol overdose?
If less than 1hour since ingestion:
Give Activated charcoal with N-acetylcysteine
If longer than an hour since ingestion:
give N-acetylcysteine
546
Describe the difference between tolerance and desensitisation
- Tolerance - reduction in drug effect over time (continuously repeated high conc)
- Desensitisation - receptors become degraded / uncoupled / internalised
547
Which common condition often diagnosed in childhood is a contraindication of beta-blockers and why?
Asthma
Beta blockers cuase bronchoconstriction
548
Give 3 differences between apoptosis and necrosis.
Apoptosis is programmed cell death whereas necrosis is unprogrammed.
Apoptosis tends to effect only a single cell whereas necrosis effects a large number of cells.
Apoptosis is often in response to DNA damage. Necrosis is triggered by an adverse event e.g. frost bite.
549
What is the role of p53 protein?
p53 protein looks for DNA damage, if damage is present p53 switches on apoptosis.
550
Define chronic inflammation.
Subsequent and prolonged tissue reactions to injury.
551
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.
552
What kind of drugs can be used in targeted chemotherapy?
Monoclonal antibodies (MAB) and small molecular inhibitors (SMI).
553
What enzymatic cascade systems does plasma contain?
1. The complement system.
2. The kinin system.
3. The coagulation system.
4. The fibrinolytic system.
554
Give examples of 3 extracellular PRR.
1. Mannose receptors.
2. Scavenger receptors.
3. TLR's.
555
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.
556
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.
557
What is cancer immunosurveillance?
When the immune system recognises and destroys transformed cells, this is an important host protection process.
558
What are the 3 E's of cancer immunoediting?
1. Elimination.
2. Equilibrium.
3. Escape.
559
Which infection is most often seen in patients with hypogammaglobulinemia?
Streptococcus penumonia sinusitis.
560
Give 5 examples of PAMPs.
1. Lipopolysaccharides.
2. Endotoxins.
3. Bacterial flagellin.
4. Peptidoglycans.
5. dsRNA.
561
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.
562
Give a side effect of using TNF blockers.
Increased susceptibility to TB.
563
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.
564
Name an IL-6 blocker.
Tocilizumab.
565
When are IL-6 blockers used?
They're used in the treatment of rheumatoid arthritis when TNF blockers fail.
566
What factors govern drug action?
Receptor related:
Affinity
Efficacy
Tissue Related:
Receptor number
Signal amplification
567
Give 4 properties of the 'ideal drug'.
1. Small Vd (high bioavailability)
2. Drug broken down effectively by enzymes.
3. Predictable dose:response relationship.
4. Low risk of toxicity.
568
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.
569
Give examples of adverse muscarinic agonist effects.
DUMBELS:
1. Diarrhoea.
2. Urination.
3. Miosis.
4. Brachycardia.
5. Emesis (vomiting).
6. Lacrimation.
7. Salivation.
570
Which enzymes inactivate catecholamines?
MAO and COMPT.
571
Define pain.
An unpleasant sensory and emotional experience associated with actual or potential tissue damage.
572
Give 3 advantages of pain.
1. Gives a warning for tissue damage.
2. Immobilisation for healing.
3. Memory establishment.
573
Define acute pain.
Pain caused by nociceptor activation. It is of short duration,
574
Define chronic pain.
Pain that is on-going or persistent, it lasts for >3-6 months.
575
Define neuropathic pain.
Pain caused by a primary lesion or dysfunction of the nervous system.
576
Define nociceptive pain.
Pain caused by actual or potential damage to non neural tissue, it is due to nociceptor activation.
577
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.
578
Give 4 risk factors for hypersensitivity.
1. Protein based macromolecules.
2. Female > male.
3. Immunosuppression.
4. Genetic factors.
579
Why are drug interactions such a big problem today?
1. Ageing population.
2. Polypharmacy.
3. Increased use of over the counter drugs.
580
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.
581
What are the 3 actions of NSAIDS?
1. Anti-inflammatory.
2. Analgesic.
3. Anti-pyrexic.
(AAA).
582
What are the effects of a competitive antagonist?
Decreases potency of a drug but does not affect the efficacy
583
What are the effects of a non-competitive antagonist?
Decreases both the potency and efficacy.
584
Give examples of alpha 1 blockers and what they can be used to treat
Doxazosin - Decrease BP
Phenoxybenzamine - Treats phaeochromocytoma
585
What drugs are CYP450 Inducers and what does that do to drug effects?
Drug effects reduced
PCBRAS:
Phenytoin
Carbamazepine
Barbiturates
Rifampicin
Alcohol (chronic use)
Sulfonylureas
586
What drugs are CYP450 Inhibitors and what does that do to drug effects?
Drug effects increased
ODEVICES:
Omeprazole
Disulfiram
Erythromycin
Valproate
Isoniazid
Ciprofloxacin
Ethanol (acute)
Sulphonamides
587
What is the Microscopic appearance of chronic inflammation?
Characteristically lymphocytes, plasma cells and macrophages
Exudation is not a common feature
Evidence of continuing destruction
Possible tissue necrosis
588
What is the Role of platelets?
No nucleus, derived from megakaryocytes
Contain alpha granules and dense granules
Alpha granules are involved in platelet adhesion, e.g. fibrinogen
Dense granules cause platelets to aggregate, e.g. ADP
Platelets are activated, releasing their granules when they come into contact with collagen
If this happens within an intact vessel, a thrombus is formed
589
What is the Role of platelets?
No nucleus, derived from megakaryocytes
Contain alpha granules and dense granules
Alpha granules are involved in platelet adhesion, e.g. fibrinogen
Dense granules cause platelets to aggregate, e.g. ADP
Platelets are activated, releasing their granules when they come into contact with collagen
If this happens within an intact vessel, a thrombus is formed
590
What are the clinical features of an arterial and venous thrombus?
Arterial thrombi:
Loss of pulse distal to thrombus
Area becomes cold, pale and painful
Possible gangrene
Venous thrombi:
Tender
Area becomes reddened and swollen
591
What are the different types of necrosis?
Coagulative necrosis:
Most common type
Can occur in most organs
Cause by ischaemia
Liquefactive necrosis:
Occurs in the brain due to its lack of substantial supporting stroma
Caseous necrosis:
Causes a ‘cheese’ pattern
TB is characterized by this form of necrosis
Gangrene:
Necrosis with rotting of the tissue
Affected tissue appears black due to deposition of iron sulphide (from degraded haemoglobin)
592
What is the TLR responsible for detecting Gram +tve Bacteria and Lipoteichoic acid/peptidoglycan?
TLR 2
593
What is the TLR Responsible for detecting Gram Negative Bacteria and Lipopolysaccharide (LPS)
TLR-4
594
What is the common T cell marker?
What is the Marker of T cell activation?
CD3
CD25
595
What is the Mature B cell marker?
CD20
596
What drugs act on Alpha 2 receptors and what could they be used for?
Conidine/ alpha-methyldopa
CNS acting vasodilators
597
Give examples of Non-selective NSAIDs?
Diclofenac
Ibuprofen
Naproxen
High Dose Aspirin
Inhibit both COX1/COX2 to reduce conversion of Arachidonic acid to prostaglandins
598
Give Examples of Selective NSAIDs?
Celecoxib
Specifically Targets COX2
Low dose Aspirin - Targets COX1
599
Give an example of a phosphodiesterase inhibitor?
Dipyridamole - stimulates prostacyclin and inhibits thromboxane A2
600
Give an Example of a Direct Factor Xa inhibitor?
DOACs
Apixaban
Rivaroxaban
601
Give an Example of an indirect Anti-thrombin inhibitor?
Heparin - activates anti-thrombin to inhibit thrombin and Factor Xa
602
Give an example of a Vitamin K antagonist?
Warfarin Decreases Factor II (prothrombin) and is an antagonist to Vitamin K
Therefore reduces Vit K dependent clotting factors (2, 7, 9, 10)
