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Medicine Phase 2a > ICS - Pathology, Immunity and Pharmacology > Flashcards

ICS - Pathology, Immunity and Pharmacology Flashcards

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1
Q

Define inflammation.

A

A local physiological response to tissue injury.

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2
Q

Give a benefit of inflammation.

A

Inflammation can destroy invading micro-organisms and can prevent the spread of infection.

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3
Q

Give a disadvantage of inflammation.

A

Inflammation can produce disease and can lead to distorted tissues with permanently altered function.

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4
Q

Define exudate.

A

A protein rich fluid that leaks out of vessel walls due to increased vascular permeability.

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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

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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

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7
Q

What is neutrophil action in acute inflammation?

A
  1. Margination - Due to increase in plasma viscosity and slowing of flow due to injury, neutrophils migrate to plasmatic zone
  2. Adhesion - selectins bind to neutrophil and cause rolling along the blood vessel margin
  3. Emigration and diapedesis - Movement of neutrophils out of the blood vessel through or in between the endothelium and basal lamina (other inflammatory cells follow)
  4. Chemotaxis - movement towards site of inflammation along chemical gradients
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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

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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.

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10
Q

What are granulomas?

A

Aggregates of epitheliod histocytes (mainly macrophages) at the site of inflammation to contain the pathogen

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11
Q

How can acute inflammation be diagnosed histologically?

A

By looking for the presence of neutrophil polymorphs.

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12
Q

Give 3 endogenous chemical mediators of acute inflammation.

A
  1. Bradykinin.
  2. Histamine.
  3. Nitric Oxide.
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13
Q

What are 4 systemic effects of acute inflammation?

A
  1. Fever.
  2. Feeling unwell.
  3. Weight loss.
  4. Reactive hyperplasia of the reticuloendothelial system.
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14
Q

Give 6 causes of acute inflammation.

A
  1. Microbial infections (bacteria and viruses).
  2. Chemicals (corrosives, acids/alkalis).
  3. Physical agents (trauma, burns, frost bite).
  4. Hypersensitivity reactions (TB).
  5. Bacterial toxins.
  6. Tissue necrosis.
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15
Q

What cells are involved in chronic inflammation?

A

Macrophages and plasma cells (B and T lymphocytes).

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16
Q

What cell can form when several macrophages try to ingest the same particle?

A

Multinucleate giant cell.

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17
Q

Give 4 causes of chronic inflammation.

A
  1. Primary chronic inflammation.
  2. Transplant rejection.
  3. Recurrent acute inflammation.
  4. Progression from acute inflammation.
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18
Q

What can cause primary chronic inflammation?

A
  1. Infective substances having resistance to phagocytosis e.g. TB, leprosy.
  2. Endogenous materials e.g. uric acid crystals. necrotic tissue
  3. Exogenous materials e.g. asbestos.
  4. Autoimmune diseases e.g. chronic gastritis, rheumatoid arthritis etc.
  5. Other chronic inflammatory diseases e.g. chronic inflammatory bowel disease.
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19
Q

What are some macroscopic features of chronic inflammation?

A
  1. Chronic ulcer.
  2. Chronic abscess cavity.
  3. Granulomatous inflammation.
  4. Fibrosis.
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20
Q

What is the Microscopic appearance of chronic inflammation?

A

Characteristically lymphocytes, plasma cells and macrophages
Exudation is not a common feature
Evidence of continuing destruction
Possible tissue necrosis

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21
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

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22
Q

What condition causes granulomas with central necrosis?

A

Caseous granuloma (soft cheese like)
Caused by TB

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23
Q

What conditions cause granulomatous inflammation without central necrosis?

A

Sarcoidosis, leprosy, vasculitis, chrons disease

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24
Q

What blood marker is released from granulomas?

A

ACE

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25
What is the difference between resolution and repair?
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.
26
Name 5 types of cells capable of regeneration.
1. Hepatocytes. 2. Osteocytes. 3. Pneumocytes. 4. Blood cells. 5. Gut and skin epithelial cells.
27
Name 2 types of cells that cannot regenerate.
Myocardial cells Neurons
28
Define abscess.
Acute inflammation with a fibrotic wall.
29
Define thrombosis.
Formation of a solid mass from blood constituents in an intact vessel in the living.
30
Give 2 reasons why thrombosis formation is uncommon.
Laminar flow of blood Endothelium is non-sticky
31
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)
32
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.
33
Define ischaemia.
Decreased blood flow to tissues w/o other complications
34
Define infarction.
Decreased blood flow to a tissue that results in subsequent cell death.
35
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
36
How do bacteria and viruses cause harm?
Bacteria - release exo/endotoxins that initiate the inflammatory pathways Viruses - Intracellular replication causes cell death
37
What processes do the endogenous chemical mediators lead to?
Vasodilation chemotaxis increased vascular permeability itching and pain
38
What are the main cell types in acute inflammation?
Neutrophil polymorphs Macrophages Fibroblasts Endothelial cells Lymphocytes
39
What are the main cell types in chronic inflammation?
Macrophages Lymphocytes Plasma cells
40
What is a multinucleated giant cell?
The cell that forms when several macrophages try to ingest the same pathogen and end up fusing together.
41
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
42
What is resolution?
Tissue restored to normal pre injury state tissue architecture is undamaged tissue initiating factor is removed
43
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
44
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.
45
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.
46
What are the constituents of a thrombus?
Platelets. Red blood cells, fibrin.
47
What are the stages of thrombosis?
- Vasospasm - Platelet adherence - Platelet Activation and platelet plug - Coagulation cascade
48
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
49
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
50
What stimulates platelet aggregation?
Endothelial damage changes localised blood flow from laminar to turbulent. Platelets come into contact with the endothelium and stick.
51
What are the different types of thrombosis and what causes them?
Arterial thrombosis - atherogenesis Venous thrombosis - venous stasis
52
How would you treat an arterial and venous thrombosis?
Arterial thrombosis - Antiplatelets Venous Thrombosis - Anticoagulants
53
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
54
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
55
Define embolism.
A solid mass in the blood vessel which causes a blockage to the vasculature.
56
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
57
What happens to an embolus if it enters the arterial system?
It will travel anywhere downstream of its entry point
58
Where may an infarct have a reduced impact?
on areas with a dual blood supply Brain, Liver Lungs
59
what is an atheroma?
Focal thickening of the tunica intima arteries produced through the movement of ldls from the lumen.
60
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.
61
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
62
What is a foam cell?
Where a macrophage has phagocytosed LDL
63
What is an atherosclerotic plaque made up of?
Fibrous tissue Lipid component - Cholesterol Lymphocytes FOAM cells
64
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
65
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
66
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
67
why does aspirin help a patient if they have atherosclerosis?
Aspirin inhibits platelet aggregation, therefore reducing plaque formation.
68
What are the risk factors for atherosclerosis?
Age gender FHx smoking sedentary lifestyle High cholesterol Hyperlipidaemia Hypertension Diabetes
69
Define apoptosis
Non inflammatory programmed cell controlled death.
70
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
71
What are the mediators of apoptosis?
Caspases
72
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
73
What is necrosis?
Inflammatory unprogrammed traumatic cell death that induces inflammation and repair.
74
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)
75
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.
76
Define genetic disease.
A genetic disease is one that occurs primarily from a genetic abnormality.
77
Define congenital disease.
A disease which is present at birth.
78
Define inherited disease.
Caused by inherited genetic abnormality, it may not manifest itself until later life.
79
Define an acquired disease.
Caused by non genetic environmental factors that usually occurs after birth.
80
Define atrophy.
Decrease in tissue size caused by the decreased in number of constituent cells or a decrease in their size.
81
Define hypertrophy.
Increase in tissue size caused by an increase in the size of the constituent cells.
82
Define hyperplasia.
Increase in tissue size caused by an increase in the number of the constituent cells.
83
Define metaplasia.
Change in differentiation of a cell from one fully differentiated type to a different fully differentiated type.
84
Define dysplaysia.
Morphological changes seen in cells in the progression to becoming cancer.
85
Define carcinogenesis
The transformation of normal cells to neoplastic cells through permanent genetic alterations or mutations This is a multistep process
86
What is a carcinogen?
A mutagenic agent known to cause cancer
87
Define carcinogenic?
Cancer causing
88
Define Oncogenic?
Tumour causing
89
Define oncogenesis?
The process by which normal cells transform into neoplastic cells
90
What is a neoplasm?
An autonomous abnormal persistent new growth that continues to grow after the initial growth stimulus has been removed.
91
What can neoplasms arise from?
They can only arise from nucleated cells (eg. not RBCs but could arise from their precursors)
92
What is a tumour?
Any abnormal swelling
93
What percentage of cancer risk is environmental?
85%
94
What host risk factors will increase the risk of cancer?
Race Diet Sex Age Inherited predisposition premalignant conditions Transplacental exposure
95
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.
96
Give some examples of inherited predispositions that will increase cancer risk?
Familial polyposis coli - increase risk of bowel cancer
97
Give some examples of premalignant conditions that will increase the risk of cancer?
Colonic polyps Ulcerative colitis Undescended Testis
98
Give an example of how transplacental exposure increased the risk of cancer
The daughters of moths who took diethylstilboestrol for morning sickness had and increased risk of developing vaginal cancer
99
Name 5 different categories of carcinogens?
Viral Chemical Ionising and non-ionising radiation Hormones, parasites and mycotoxins Miscellaneous
100
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
101
How can hormones cause cancer?
increase in oestrogen can cause endometrial cancer
102
What parasite can cause cancer?
Shistosoma causes bladder cancer
103
What miscellaneous materials can cause cancer?
Asbestos Metals - arsenic
104
What type of cancer do polyaromatic hydrocarbons cause and what exposes people to these?
Lung and skin cancer Smoking and mineral oils
105
What cancer do aromatic amines cause?
bladder cancer People who work with dye or rubber
106
What cancer do nitrosamine cause?
Gut cancer
107
What type of cancer do alkylating agents cause?
Leukaemias
108
Define Neoplasia?
A lesion resulting from new and abnormal tissue growth which persists independent of its initiating stimulus.
109
What are the two types of neoplasia?
Benign and malignant
110
How can neoplasias be classified?
By behaviour By histogenesis
111
What is 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
112
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
113
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.
114
What are some complications of malignant tumours?
Pressure on adjacent structures form secondary tumours Obstructory very painful blood loss
115
What is the structure of a neoplasm?
Neoplastic cell Stroma
116
What are neoplastic cells?
Always derived from nucleatedcells Usually monoclonal Growth pattern related to parent cell Synthetic activity related to parent cell - eg. hormone producing.
117
What is the stroma of a neoplasm?
Supported by connective tissue framework that provides mechanical and nutritional support. usually blood vessels.
118
What factors promote angiogenesis?
VEGF Fibrobalst growth factor
119
What is the behavioural classification of neoplasms?
Benign Borderline - defy precise classification Malignant
120
What are the main histological classifications of tumours?
epithelial Connective tissue Lymphoid Haematopoietic
121
What cancer does not have a stroma?
Leukaemia
122
What is a benign non-glandular eplithelial neoplasm called?
Papilloma
123
What is a benign glandular epithelial neoplasm called?
Adenoma
124
What is a malignant epithelial neoplasm?
Carcinoma
125
What is a carcinoma?
A malignant epithelial neoplasm
126
What is the suffix for malignant connective tissue neoplasms?
Sarcoma
127
What is a benign neoplasm of adipocytes?
Lipoma
128
What is a benign neoplasm of adipocytes?
Lipoma
129
What is a benign neoplasm of Cartilage?
Chondroma
130
What is a benign neoplasm of bone
Osteoma
131
What is a benign neoplasm of vasculature?
Angioma
132
What is a benign neoplasm of striated muscle
Rhabdomyoma
133
What is a benign neoplasm of smooth muscle
Leiomyoma
134
What is a benign neoplasm of nerves
Neuroma
135
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.
136
If a neoplasm doesnt resemble normal tissue what is it said to be?
Poorly differentiated higher grade and would carry a worse prognosis
137
What is the difference between the stage and the grade of a tumour?
Stage - size of the tumour and how far it has spread from its original site Grade - the appearance of the tumour, How well it resembles normal tissue
138
What does the term anaplastic mean?
When the cell type of origin is unknown the tumour is anaplastic
139
What is a melanoma?
A malignant neoplasm of melanocytes
140
What is a mesothelioma?
A malignant neoplasm of mesothelial cells
141
What is a lymphoma?
A malignant neoplasm of lymphoid cells
142
What is burkitts lymphoma?
A B cell malignancy caused by EBV
143
What is kaposi sarcoma?
A vascular endothelial malignancy caused by Human herpes virus 8 and related to HIV
144
What is ewings sarcoma?
A bone malignancy
145
is a teratoma?
A cancer of all 3 embryonic germ layers
146
What is a blastoma?
A tumour of an embryo
147
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
148
What are the different methods of spread of a metastasis?
Haematogenous - via blood Lymphatic - secondary formation in the lymph nodes Transcolemic - via exudative fluid accumulation. spread through pleural, pericardial and peritoneal effusions. along nerves Iatrogenic
149
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.
150
What cancers commonly spread to bone?
BLT KP Breast Lung Thyroid Kidney Prostate
151
What is a neoplasm in situ?
When a neoplasm has proliferated but has not broken through the basement membrane to other tissues
152
When is a cancer considered to be invasive?
When it has breached its own tissue type into another area
153
What is a micro-invasive carcinoma?
A carcinoma that has only just broken through the basement membrane
154
What is invasion of a cancer dependent on?
Decreased cellular adhesion abnormal increased cellular motility Production of lytic enzymes to breakdown surrounding tissue
155
Define metastasis
The process by which a malignant neoplasm spreads from its primary site to produce secondary neoplasms at distant sites.
156
How do tumours invade surrounding tissues?
Proteases break down tissue surrounding neoplasm tumour cell derived motility factors allow it to invade
157
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
158
How do neoplasms evade host defenses?
Aggregation with platelets Shedding of surface antigens Adhesion to other tumour cells
159
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.
160
What are some angiogenesis inhibitors?
Angiostatin Endostatin Vasculostatin
161
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
162
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.
163
What cancers are screened for in the UK?
Cervical Breast Colorectal
164
Eosinophillic granulomas would be an indication of what?
Parasitic infection
165
What cells are polymorphonuclear leukocytes?
Neutrophils Eosinophils Basophils
166
What cells are the mononuclear leukocytes?
Monocytes T cells B cells
167
Where is complement secreted from?
The liver
168
What are the 3 modes of action for complement?
Direct lysis - MAC Chemotaxis - attract more leukocytes Opsonisation - coat invading organisms
169
How can antibodies circulate in the blood
Bound to B cells Free in plasma
170
Which part of the strucutre of an antibody is responsible for antigen binding?
FAB regions Variable in sequence Bind to specific antigens
171
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
172
What are the 5 classes of antibodies?
IgG IgM IgA IgE IgD
173
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
174
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
175
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 First line of defence
176
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
177
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
178
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
179
What are cytokines?
Proteins secreted by immune and non-immune cells
180
What do interferons do?
Induce a stateof viral resistance in uninfected cells and limit the spread of viral infection
181
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
182
What do interleukins do?
Can be proinflammatory or anti-inflammatory Cause cells to divide, differentiate and secrete factors
183
What do colony stimulating factors do?
Direct the division and differentiation of bone marrow stem cells
184
what do tumour necrosis factors do?
TNF alpha and beta Mediate inflammation and cytotoxic reactions
185
What are chemokines?
proteins that direct the movement of cells from the blood stream to the tissues.
186
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
187
What physical and chemical barriers are involved in the innate immune response
Physical barriers - skin, mucus, cilia Chemical barriers - lysozymes in tears, stomach acid
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What are pattern recognition receptors?
Receptors on immune cells that detect the presence of PAMPs
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PAMPS and DAMPS?
Pattern-associated molecular patterns Damage associated molecular patterns
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What are Toll-like receptors?
A type of PRR that recognise structurally conserved molecules derived from microbes.
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What is the TLR responsible for detecting Gram +tve Bacteria and Lipoteichoic acid/peptidoglycan?
TLR 2
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What is the TLR Responsible for detecting Gram Negative Bacteria and Lipopolysaccharide (LPS)
TLR-4
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What components make up the innate immunity?
Physical and chemical barriers Phagocytic cells -neutrophils, macrophages Blood proteins - complement, acute phase proteins.
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How can physical barriers be breached for allowing pathogens to entre the body?
Tissue trauma Infection
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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
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What are 3 features of inflammation?
Increased blood supply Increased Vascular permeability Increased leukocyte extravasation
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What cells detect presence of antigens in the blood?
Monocytes neutrophils
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What cells detect the presence of antigens in the tissues?
Macrophages DCs
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What are the 3 activation pathways for the complement system?
Classical - antibody binds to microbe antigen and then Complement Alternative - C'3b Bb that enhances activation of the complement system Lectin - activated by mannose-binding lectin binding to mannose on pathogen.
200
What are the 3 mechanisms of action of complement?
Direct lysis - Membrane attack complex (MAC) Chemotaxis and mast cell degranulation- C3a and C5a Opsonisation - coat microbes to make them easier to phagocytose (C3b)
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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. Emigration: neutrophil squeezes through endothelium (holes caused by C3a, C5a, chemokines, histamines, prostaglandins, leukotrienes (causing smooth muscle contractions in the bronchioles)) 5. Diapedesis - RBCs also follow neutrophils and migrate out of the vessel
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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
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What are the main steps in phagocytosis?
Binding Engulfment (phagosome) Phagolysosome bacterial killing clear debris
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What are the 2 pathways that neutrophils and macrophages use to kill microbes?
Oxygen dependent Oxygen independent
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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
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What is the oxygen independent mechanism of killing microbes?
Enzymes - lysozymes proteins - defensins pH TNF
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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
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What cells are APCs (antigen presenting cells)?
Dendritic cells Macrophages B cells
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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
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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
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What is the function of eosinophils?
Contain MBP Often in response to a parasitic infection.
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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.
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What is the function of a natural killer cell? What is their receptor?
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.
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What is the function of a dendritic cell?
These cells act as APCs and provide an interface between the innate and adaptive immune system.
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What are the 3 conditions that must be met to enable antigen presenting to function?
Primary receptor binding co-stimulation molecules Cytokine release
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What does TLR 1 detect?
Gram positive bacteria
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What does TLR 2 detect?
Gram positive bacteria such as lipopeptides, lipoteichoic acid
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What does TLR 3 detect?
Endogenous viral infection and tissue necrosis Responds to ds RNA
219
What does TLR 4 detect?
Gram Netagive Bacteria detects endotoxin such as LPS
220
What does TLR 5 detect?
Flagellin
221
What does TLR 7 detect?
Single stranded RNA
222
What does TLR 8 detect?
ssRNA Viral and bacterial pathogens Important for detecting pyogenic bacteria
223
What does TLR 9 detect?
Non-methylated DNA (ssDNA)
224
Which TLRs are intracellular receptors?
TLR 3, 7, 8, 9 These will detect genetic material and are intracellularly located
225
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.
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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.
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Which part of the immune system deals with intracellular and extracellular microbe
B cell (humoral - antibody) - extracellular T cell (cell-mediated) - Intracellular
228
To recognise self from non-self what is required?
MHC proteins
229
What do T lymphocytes respond to?
Intracellular presented antigens
230
Where do T cells mature?
In the thymus
231
Where do B cells mature?
In the bone marrow
232
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
233
What is the common T cell marker? What is the Marker of T cell activation?
CD3 CD25
234
Where is MHC I found?
On all nucleated cells
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Where is MHC II found?
On APCs Only
236
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
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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
238
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
239
What is secreted from an activated T cell?
IL2 binds to the T cell receptor (autocrine)
240
What does T cell activation lead to?
Division Differentiation (to CD4 or CD8) Effector functions Memory
241
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
242
What is the function of a Th1 CD4 T cell?
Travel to secondary lymphoid tissue Cell mediated response - control macrophages and monocytes Secrete IFN gamma to help kill intracellular antigens
243
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
244
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
245
Which membrane bound antibodies do B cells Express?
IgM or IgD monomers
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How many types of antibodies can an individual B cell make?
1 Antibody specific to 1 antigen.
247
What happens if a B cell recognises self?
The B cell is killed in the bone marrow
248
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
249
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
250
What is the Mature B cell marker?
CD20
251
What is the process of a B cell from Naive B cell to differentiation?
Naive B cell Clonal Expansion Somatic Hypermutation T cell activates B cell B cell selection and class switching Differentiation into plasma cell or memory
252
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
253
What causes Somatic hypermutation?
AID Activation induced Cysteine deaminase
254
What interleukin promotes class switching from IgM to IgA and IgE?
IL-4
255
What chromosome is the MHC protein found on?
Chromosome 6
256
What is the role of Tregs?
Regulatory T cells These are important in peripheral immune tolerance and ensuring T cells are not autoreactive. Release IL-10 (anti-inflammatory)
257
What interleukin stimulates a naive T cell to become a Treg?
TGF-b and IL-2 Tregs secrete IL-10 which is anti-inflammatory
258
What Interleukin stimulates a naive T cell to become a Th17?
IL-17
259
What is passive immunisation?
The transfer of pre-formed antibodies
260
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)
261
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
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What are the disadvantages of passive immunisation?
Does not provide immunological memory - no long term protection IgG is cleared form the circulation
263
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
264
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
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How does Botulinum toxin act on the synapse?
Botulinum vesicles contain ACh which prevents muscle contraction It causes muscle relaxation and flaccidity
266
What is active immunisation?
Manipulation of the immune system to generate a persistent protective response against pathogens by mimicking natural infection
267
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
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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
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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
270
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
271
Give an example of an artificial active immunity
Vaccinations
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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
273
Give examples of a whole organism vaccination
Live attenuated - TB, Typhoid Killed/inactivated - Influenza, Hep A
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When is the 6in1 Vaccine give? What conditions are vaccinated against within the 6in1?
Given to Babies 3 times at 8, 12, 16 weeks Vaccinates against: Diphtheria Tetanus Pertussis Polio Hib (haemophilus) HepB
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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
276
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
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What is an adjuvant
Any substance added to a vaccine to stimulate an enhanced immune response
278
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
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What cells are involved in the cell mediated immune repsonse?
Neutrophils and monocytes Lymphocytes (T and B cells)
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What is involved in the non-cellular humoral immune response?
Immunoglobulins (antibodies) complement Surfactant proteins
281
What immunoglobulin is made at the beggining of an infection?
IgM
282
What immunoglobulin is in high abundance upon second exposures?
IgG specific antibodies
283
What immunoglobulin is often involved with an allergic reaction?
IgE
284
What are the common features of anaphylaxis?
Rapid onset Blotchy rash Swelling of face and lips Hypotension Wheeze Cardiac arrest if severe
285
What drugs can commonly cause hypersensitivity reactions?
Amiodarone Bleomycin Methotrexate NSAIDs Nitrofurantoin Novel Ig treatments
286
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.
287
Give example of type 1 hypersensitivity reactions
Allergic Rhinitis (hayfever) asthma Nut,food and drug allergies
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What is Atopy?
An inherited tendency to produce an exaggerated IgE response to an antigen (hayfever, eczema, Asthma)
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What is Anergy?
A condition in which the body's immune system fails to react to an antigen Immunological hypo-responsiveness
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How are type one hypersensitivity reactions diagnosed?
Skin prick tests Radioallergosorbent Tests (RASTs)
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What is the treatment for hayfever?
Prevent exposure Anti-histamines steroids - reduce local inflammation Desensitisation therapy - controlled, gradually increased exposure to the antigen
292
What is the treatment for acute anaphylaxis
Adrenaline 500mg IM (intramuscularly) if necessary: Antihistamines - Chlorphenamine Cortisol - hydrocortisone
293
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.
294
What can cause Type 2 hypersensitivity reactions?
Transplant rejection Autoimmune diseases
295
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
296
Give examples of Type 3 hypersensitivity reactions?
Systemic Lupus Erythematosus (SLE) Post strep glomerulonephritits Rheumatoid Arthritis
297
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 IFNy activates macrophages > 4️⃣ can phagocytose or form granulomas and activate CD8 T cells
298
Give examples of Type 4 hypersensitivity reactions?
TB Contact dermatitis Sarcoidosis
299
What is involved in the diagnosis of drug hypersensitivity reactions?
Lung function tests CT scans Chest X rays
300
What is involved in the treatment of drug hypersensitivity reactions?
Withdraw offending drug Give steroids for severe respiratory failure
301
What is autoimmunity?
Pathological response verses self antigens. Caused by faulty immune tolerance or molecular mimickry
302
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
303
Give some non organ specific autoimmune diseases
Systemic Lupus Erythematosus Autoimmune Haemolytic Anaemia Immune Thrombocytopenic purpura Rheumatoid Arthritis
304
Name different types of drug interactions
Synergism Antagonism Summation Potentiation
305
Define synergism?
Interaction of 2 compounds leads to a greater combined effect (1+1>2)
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Define Antagonism
Interaction of 2 compounds where one may block another from working so the overall net effect is 0 (1+1=0)
307
Define Summation
Interaction of 2 compounds with similar pharmacodynamics combine to give an increased expected effect (1+1=2)
308
Define Potentiation
Where one compound may increase the potency of another drug without affecting its own state (1+1=1+1.5)
309
What are some host risk factors for drug interactions?
Old age Polypharmacy Genetics Hepatic Disease Renal Disease
310
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
311
Name some mechanisms through which drug interactions can take place?
Pharmacokinetic mechanism Pharmacodynamic mechanism
312
What are the 2 major routes of drug administration?
Enteral - Gut involved (eg. oral) Parenteral - Bypasses the gut (eg. IV, IM, SC)
313
Define Pharmacokinetics
What happens to the drug within the body
314
What are the different pharmacokinetic mechanisms?
ADME Absorption Distribution Metabolism Excretion
315
What factors affect a drugs absoprtion?
Gut motility Acidity Solubility Complex formation Direct action on enterocytes
316
What factors affect drug distribution?
Protein binding Chemical properties (water soluble/lipid soluble) Blood flow to area
317
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
318
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)
319
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
320
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
321
Give an example of compounds that will inhibit CPY450/enzymes?
Metronidazole - inhibits Alcohol Dehydrogenase - prevents ethanol metabolism - increases drunkenness
322
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
323
Define Pharmacodynamics
The effect that a drug has on the body
324
What do drugs usually target? Give examples of different types?
PROTEINS!! Receptors Enzymes Transporters Ion Channels
325
What are the different effects of a ligand?
Agonists Partial Agonist Antagonist - Competitive or non-competitive
326
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
327
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
328
Define Bioavailability?
Amount of drug taken up into systemic circulation unaltered as a proportion of the amount administered
329
How can we avoid drug interactions?
Prescribe rationally BNF/NICE guidelines Ward pharmacists Patient information leafles
330
What are some important drug side effects to know?
Simvastatin - Rhabdomyolysis Warfarin - bleeding SSRIs - Serotonin syndrome NSAID + ACEi + Furosemide - renal failure
331
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
332
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
333
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
334
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
335
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
336
What are the 3 types of GPCR?
Gs - stimulatory - activates Adenylate cyclase Gi - Inhibitory - Inhibits Adenylate Cyclase Gq - Activates PLC - increases IP3 and DAG
337
Give examples of different GPCRs
Muscarinic 3 receptor - Gq GPCR B2 Adrenoceptor - Gs GPCR
338
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
339
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
340
What is an agonist?
A compound that binds to a receptor to activate it It has both affinity and efficacy
341
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
342
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
343
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)
344
What is the Emax?
The maximum response that can be achieved (The Efficacy)
345
What is the EC50?
The concentration of a drug that gives half the maximal response It tells us about potency
346
What does the EC50 tell us about?
How potent a drug is
347
Would a drug with a lower EC50 have a lower or greater potency?
Greater Potency
348
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.
349
Define efficacy?
How well a ligand activates a receptor how well it induces a conformational change
350
Define Affinity
How well a ligand can bind to a receptor
351
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
352
What is the effect of fewer receptors on drug potency?
Fewer receptors will shift the dose-response curve to the right → potency reduced
353
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
354
What is the effect of less signal amplificiation on drug response?
Less signal amplification gives a reduced drug response
355
Describe allosteric modulation?
An allosteric modulator binds to a different site (the allosteric site) on a receptor and influences the role of an agonist.
356
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.
357
Define tolerance?
A reduction in the effect of a drug overtime Due to continuous use, repeated use or use at high concentrations
358
Describe the difference between tolerance and desensitisation
- Tolerance - reduction in drug effect over time (continuously repeated high conc) - Desensitisation - receptors become degraded / uncoupled / internalised
359
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
360
What is the drug target for statins?
HMG-CoA reductase
361
What is the action of statins?
Block the rate limiting step in the cholesterol pathway
362
what is the end effect of statin use?
Lipid lowering Prevent CVD Reduce CVD and mortality of those at risk
363
What is the Renin-angiotensin aldosterone system responsible for?
Blood pressure control
364
What is the function of ACE inhibitors?
Reduces the production of angiotensin II Reduces blood pressure
365
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
366
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)
367
What is the mechanism of action of tolcapone and entacapone?
Catechol-O-methyl transferase (COMT) inhibitor prevents breakdown of L-DOPA and dopamine
368
Can tolcapone cross the BBB?
Yes
369
What is the mechanism of action of selegiline and rasagiline?
Monoamine oxidase - B (MOA) inhibitors Prevent the breakdown of dopamine
370
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
371
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
372
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
373
What class of drug is amlodipine?
Angioselective calcium channel blocker
374
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
375
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
376
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
377
Give 3 examples of potassium channel blockers used to treat T2DM?
Repaglinide Nateglinide Sufonylureal
378
What do barbiturates do and give an example of a drug in this class?
Phenobarbitone GABA receptor agonists GABA is an inhibitory ionotropic receptor
379
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
380
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
381
What does the rate of metabolism determine?
Duration and intensity of a drugs pharmacological action
382
What is Cytochrome P450?
Major microsomal enzyme in the liver Most drugs are inactivated by CYP however some require CYP to be activated
383
What are the different categories of opioids?
Naturally occurring Simple chemical modifications Synthetic opioids Synthetic partial agonists
384
What are the naturally occurring opioids?
Morphine (from the opium poppy) Codeine
385
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)
386
What are the modern synthetic opioids?
Fentanyl Alfentanil Remifentanil
387
give an example of a synthetic partial agonist opioid?
Buprenorphine
388
What drug is the antagonist to opioids and is important to treat overdose with?
Naloxone - acts on the u receptor
389
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!
390
What are the main routes of administration of opioids?
Parenteral: IM SC IV (fastest) Epidural Transdermal patches - fentanyl
391
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.
392
What is the difference between potency and efficacy?
Potency: the amount of drug needed to produce a given effect Efficacy: is it possible to get a maximal response with the drug or not?
393
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
394
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.
395
What is the main opioid receptor?
u, Mu or MOP
396
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
397
How would you treat opioid induced respiratory depression?
With Naloxone
398
What enzyme metabolises codeine and what is it metabolised to?
CYP2D6 metabolises codeine to morphine (codeine is a prodrug)
399
What is morphine metabolised to?
Morphine-6-glucoronide (more potent than morphine)
400
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!
401
What is tramadol?
A weak opioid agonist (slightly stronger than codeine) Also acts as a SSRi and noradrenaline reuptake inhibitor.
402
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
403
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)
404
What nerves are the PNS made up of?
- Oculomotor (CN III) - Facial (CN VII) - Glossopharyngeal (CN IX) - Vagus (CN X) - Further outflow via *sacral nerve* innervations of the pelvis
405
What neurotransmitter and receptor are associated with the Parasympathetic nervous system?
Acetylcholine acting on muscarinic receptors
406
What neurotransmitter is released by the preganglionic nerve fibres within the ANS?
Acetylcholine acting on N2 receptors
407
What neurotransmitter is released by the post ganglionic nerve fibres within the sympathetic NS?
Noradrenaline acting on alpha/beta adrenoceptors
408
What neurotransmitter is released in the somatic NS at the effector cells?
Acetylcholine acting on N1 receptors
409
give examples of non-adrenergic/cholinergic autonomic transmitters?
Sympathetic - ATP, Neuropeptide y Parasympathetic - NO, VIP
410
What nervous system pathway does cholinergic pharmacology deal with?
Manipulation of the parasympathetic pathway
411
What does nicotine stimulate?
Stimulates all automimic ganglia via preganglionic nicotinic receptors Activates both the SNS and PNS
412
What does muscarine stimulate?
Activates the muscarinic receptors specific to the PNS
413
What type of receptor are muscarinic and nicotinic receptors?
Muscarinic - GPCR - M1-5 Nicotine - Ligand gated ion channels
414
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
415
What is the effect of muscarinic agonists at the M2 receptors?
Slows the heart rate
416
What is the effect of muscarinic agonists at the M3 receptors?
Causes bronchoconstriction of smooth muscle Will increase sweating, saliva and GI motility.
417
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)
418
What is pilocarpine?
A muscarinic agonist Stimulates salivation - treats Sjogrens syndrome Contracts iris smooth muscle - treats glaucoma by draining aqueous humour
419
What is a side effect of pilocarpine?
Slows the heart (non-selective muscarinic agonist)
420
What is atropine?
A muscarinic antagonist Prevents bradycardia - used to treat bradycardia in cardiac arrest Dry secretions perioperatively
421
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
422
What other roles can anticholinergics play?
Solifenacin - treat overactive bladder Mebeverine - Treat IBS
423
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
424
How is ACh synthesised?
Acetyl CoA combined with Choline; mediated by Choline Acetyl Transferase
425
What enzyme is responsible for ACh breakdown in the synaptic cleft?
Acetylcholinesterase
426
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
427
What is the purpose of competitive antagonists at the NMJ?
Competitive antagonists block Ach receptors → muscle relaxants, adjuncts to general anaesthesia (pancuronium)
428
What is the action of depolarising agonists?
Act as blockers as they cause receptor desensitisation
429
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
430
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
431
What are some side effects of anticholinergics?
- Worsening memory/ confusion - Constipation - Dry mouth - Blurred vision
432
What are organophosphates?
Used in insecticides and nerve gases They are irreversible AChE inhibitors Cause muscle tremors, twitching, salivation and confusion.
433
Give some examples of AChE inhibitors?
Neostigmine Pyridostigmine Rivastigmine
434
What is Curare and Pancuronium?
An nACh-R antagonist
435
What does overstimulation of Ach at the NMJ lead to?
Cholinergic Crisis (SLUDGE) Salivation Lacrimation Urination Defecation GI distress Emesis
436
What nervous system pathway does adrenergic pharmacology deal with?
Sympathetic nervous system
437
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
438
What is the synthetic pathway of catecholamines?
Tyrosine DOPA Dopamine Noradrenaline Adrenaline
439
What is the primary function of α1 adrenoceptors?
Vasoconstriction (contraction of BV) Bladder contraction Dilation of pupils
440
What is the primary function of α2 adrenoceptors?
Responsible for pre-synaptic inhibition - prevents NAd release Used in analgesia
441
What neurotransmitter predominates in α1 and α2 interactions?
α1 - Noradrenaline α2 - Adrenaline = noradrenaline
442
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
443
What neurotransmitter predominates in β1, β2 and β3 interactions?
β1 - Noradrenaline = adrenaline β2 - Adrenaline β3 - Noradrenaline
444
What is the primary function of β2 adrenoceptors?
Decrease SM tone - Bronchodilation Vasodilation (partly)
445
What are the primary functions of β3 adrenoceptors?
Increased Lipolysis Bladder - detrusor muscle relaxation
446
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)
447
What is the role of adenylate cyclase?
Converts ATP to cyclic AMP (cAMP) to activate PKA
448
What do α1 adrenergic agonists do?
Vasoconstriction; used for treatment of septic shock
449
What do α1 adrenergic antagonists (alpha blockers) do?
Vasodilation; lowers blood pressure (doxazosin)
450
What disease could an α1 adrenergic antagonist be used in the treatment of?
Benign prostatic hyperplasia; tamsulosin blocks α1 receptors in the prostate
451
What drugs act on Alpha 2 receptors and what could they be used for?
Conidine/ alpha-methyldopa CNS acting vasodilators
452
What do β1 adrenergic agonists do?
Increase heart rate and chronotropic effects; used for treating conditions like septic shock (dobutamine)
453
What do β1 adrenergic antagonist do?
Reduce CO and reduce renin secretion; lower blood pressure (Bisoprolol, Atenolol, Metoprolol)
454
What diseases could an β1 adrenergic antagonist be used in the treatment of?
Hypertension, angina and arrhythmia.
455
What do β2 agonists do?
Muscle relaxation; life-saving treatment for asthma and delay onset of premature labour
456
What do β3 agonists do?
Smooth muscle relaxation; relaxation of detrusor muscle to reduce over-active bladder symptoms
457
Give examples of cardioselective beta blockers and non-selective beta blockers?
Cardioselective (against B1) - Atenolol, Metoprolol Non-selective - Propanolol
458
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
459
Where are DA (dopamine receptors) most found?
Nucleus accumbens in the brain
460
What is the main excitatory and main inhibitory neurotransmitter in the CNS?
Excitatory - glutamate Inhibitor - GABA
461
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
462
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)
463
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
464
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).
465
What are the patient risk factors for ADRs?
- Gender (F>M) - Elderly - Neonates - Polypharmacy - Genetic predisposition - Hypersensitivity/ allergies - Hepatic/ renal impairment - Adherence problems
466
What are the drug risk factors for ADRs?
- Steep dose-response curve - Low therapeutic index
467
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
468
What drugs commonly cause ADRs?
- Antibiotics (penicillin) - Anti-neoplastics - Cardiovascular drugs - Hypoglycaemics - NSAIDs - CNS drugs
469
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
470
Give examples of common ADR presentations
- Confusion - Nausea - Balance problems - Diarrhoea - Constipation - Hypotension
471
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)
472
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
473
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
474
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
475
Describe a Type C ADR?
*Chronic.* - Occurs after long term therapy (eg. Nephropathy caused by long term NSAID use)
476
Describe a Type D ADR?
Delayed Occurs many years after treatment (eg. teratogenesis caused by thalidomide)
477
Describe a Type E ADR?
End of use Complications of stopping medication (withdrawal) eg. opioids
478
Describe a Type F ADR?
Failure of therapy (eg. Failure of the oral contraceptive pill in the presence of enzyme inducer drugs)
479
What does the acroyn DoTS mean?
Dose relatedness - Toxic, collateral or hypersusceptibility Timing - fast rxns, or late Rxns Susceptibility - Patient factors
480
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
481
Define Drug hypersenstivity?
Reproducible symptoms or signs that are initiated by the exposure to a drug at a dose tolerated by normal subjects
482
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
483
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.
484
How is anaphylaxis managed?
- Commence basic life support (ABCDE) - Stop the drug if currently being infused - Adrenaline (IM) 500mcg - second dose after five minutes 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)
485
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
486
Define Absorption (pharmacokinetics)
The process of transfer from the site of administration into the general or systemic circulation
487
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
488
How do drugs cross membranes to reach their target sites?
Passive diffusion Facilitated diffusion Active transport non-ionic diffusion Pinocytosis
489
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
490
What is the strength of drug ionisation dependent on?
The strength of the ionisable group pH of the solution
491
What are other terms used to describe ionised drugs vs. unionised drugs?
Water soluble vs. lipid soluble respectively
492
What is the pKa of a drug?
The pH at which half of the substance is ionised and half is unionised
493
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.)
494
Drugs that are weak bases are best absorbed where?
The intestines
495
What is the effect of an increase in pH on a weak acid?
The weak acid will become more ionised
496
What is the effect of an increase in pH on a weak base?
The weak base will become less ionised.
497
What is the effect of a decrease in pH on a weak acid?
The weak acid will become less ionised
498
What is the effect of a decrease in pH on a weak base?
The weak base will become more ionised
499
What route of drug administration has a bioavailability of 1?
IV - all the drug administered will go into the plasma
500
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.
501
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
502
What equation can be used to determine the degree of ionisation at a specific pH?
Henderson Hasselbach. pH = log[A-]/[HA] + pKa.
503
What can enhance non ionic diffusion?
Non ionic diffusion can be enhanced if adjacent compartments have pH difference.
504
Give an example of a proton pump inhibitor.
Omeprazole
505
Give an example of a statin
Simvastatin Atorvostatin
506
Give an example of an ACE inhibitor?
Enalapril
507
Give an example of a COX inhibitor?
Aspirin Ibuprofen
508
Give an example of a beta 2 adrenoceptor agonist?
Salbutamol
509
Give an example of a beta 1 adrenoceptor antagonist?
Atenolol
510
Give an example of a Calcium channel blocker?
Amlodipine
511
Give an example of a broad spectrum antibiotic?
Amoxicillin
512
Give an example of a phosphodiesterase inhibitor?
Sildenafil / Dipyridamole - stimulates prostacyclin and inhibits thromboxane A2
513
Give an example of an opiate analgesic?
Tramadol
514
Give an Example of a Direct Factor Xa inhibitor?
DOACs Apixaban Rivaroxaban
515
Give an Example of an indirect thrombin and factor Xa inhibitor?
Heparin - activates anti-thrombin to inhibit thrombin and Factor Xa
516
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)
517
What pharmaceutical properties can affect the rate of drug absorption?
Pharmaceutical form - syrup/pill Ability to disintegrate Ability to dissolve
518
What physiochemical properties of a drug affects the rate of drug absorption?
Solubility pH Molecular weight
519
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
520
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
521
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.
522
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.
523
What is the most common protein that drugs bind to?
Albumin
524
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
525
How are water soluble and lipid soluble drugs eliminated?
Water soluble: directly by the kidney Lipid soluble: must be metabolised to water soluble products
526
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.
527
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
528
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.
529
Define half-life
The time taken for a concentration of a drug to reduce by half.
530
What would be the bioavailability of an oral drug?
F<1 as they are incompletely absorbed and undergo incomplete first pass metabolism.
531
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
532
What is the volume of distribution and how is it calculated?
A measure of how widely a drug is distributed between various body fluids and tissues. Amount of drug in the body / Measured plasma concentration
533
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
534
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
535
Give the equation for renal clearance?
Renal clearance = Rate of appearance in urine / plasma concentration.
536
Define hepatic extraction ratio (HER).
The proportion of a drug removed by one passage through the liver.
537
What is the limiting factor when a drug has a high HER?
Hepatic blood flow, perfusion limited
538
What is the limiting factor when a drug has a low HER?
Diffusion limited. A low HER is slow and not efficient.
539
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.
540
What is steady state?
A balance between drug input and elimination
541
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.
542
What are APUDomas?
Neuroendocrine tumours
543
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.
544
What cytokines are released from Th1 cells and Th2 cells
Th1 - IL2 and INFy Th2 - IL-4, IL-5, IL-6, IL-10
545
Give 3 functions of antibodies.
1. Neutralise toxins. 2. Opsonisation. 3. Activate classical complement system.
546
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.
547
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.
548
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.
549
What is the function of these complement proteins: MAC C3a and C5a C3b
MAC - Lyse microbes directly C3a /C5a - Chemotaxis C3b - Opsonisation
550
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.
551
Which complement plasma proteins are pro-inflammatory and cause chemotaxis and activation of neutrophils and monocytes etc?
C3a and C5a.
552
Which complement plasma proteins have opsonic properties when bound to a pathogen?
C3b and C4b.
553
Name 3 receptors that make up the PRR family.
1. Toll-like receptors (TLR). 2. Nod-like receptors (NLR). 3. Rig-like receptors (RLR).
554
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.
555
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.
556
What disease could be caused by a non-functioning mutation in NOD2?
Crohn's disease.
557
What is the main function of RLR's?
RLR's detect intracellular double stranded RNA. This triggers interferon production and so an antiviral response.
558
TLR's are adapted to recognise damaged molecules. What characteristic do these damaged molecules often have in common?
They are often hydrophobic.
559
What kind of TLR's can be used in vaccine adjuvants?
TLR4 agonists.
560
What is extravasation?
Leukocyte (WBC) migration across the endothelium.
561
What do macrophages at the tissues secrete to initiate extravasation?
TNF alpha.
562
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.
563
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.
564
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
565
Which common condition often diagnosed in childhood is a contraindication of beta-blockers and why?
Asthma Beta blockers cuase bronchoconstriction
566
What is the role of p53 protein?
p53 protein looks for DNA damage, if damage is present p53 switches on apoptosis.
567
Define chronic inflammation.
Subsequent and prolonged tissue reactions to injury.
568
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.
569
What kind of drugs can be used in targeted chemotherapy?
Monoclonal antibodies (MAB) and small molecular inhibitors (SMI).
570
What enzymatic cascade systems does plasma contain?
1. The complement system. 2. The kinin system. 3. The coagulation system. 4. The fibrinolytic system.
571
Give examples of 3 extracellular PRR.
1. Mannose receptors. 2. Scavenger receptors. 3. TLR's.
572
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.
573
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.
574
What is cancer immunosurveillance?
When the immune system recognises and destroys transformed cells, this is an important host protection process.
575
What are the 3 E's of cancer immunoediting?
1. Elimination. 2. Equilibrium. 3. Escape.
576
Which infection is most often seen in patients with hypogammaglobulinemia?
Streptococcus penumonia sinusitis.
577
Give 5 examples of PAMPs.
1. Lipopolysaccharides. 2. Endotoxins. 3. Bacterial flagellin. 4. Peptidoglycans. 5. dsRNA.
578
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.
579
Give a side effect of using TNF blockers.
Increased susceptibility to TB.
580
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.
581
Name an IL-6 blocker.
Tocilizumab.
582
When are IL-6 blockers used?
They're used in the treatment of rheumatoid arthritis when TNF blockers fail.
583
What factors govern drug action?
Receptor related: Affinity Efficacy Tissue Related: Receptor number Signal amplification
584
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.
585
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.
586
Give examples of adverse muscarinic agonist effects.
DUMBELS: 1. Diarrhoea. 2. Urination. 3. Miosis. 4. Brachycardia. 5. Emesis (vomiting). 6. Lacrimation. 7. Salivation.
587
Which enzymes inactivate catecholamines?
MAO and COMPT.
588
Define pain.
An unpleasant sensory and emotional experience associated with actual or potential tissue damage.
589
Give 3 advantages of pain.
1. Gives a warning for tissue damage. 2. Immobilisation for healing. 3. Memory establishment.
590
Define acute pain.
Pain caused by nociceptor activation. It is of short duration,
591
Define chronic pain.
Pain that is on-going or persistent, it lasts for >3-6 months.
592
Define neuropathic pain.
Pain caused by a primary lesion or dysfunction of the nervous system.
593
Define nociceptive pain.
Pain caused by actual or potential damage to non neural tissue, it is due to nociceptor activation.
594
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.
595
Give 4 risk factors for hypersensitivity.
1. Protein based macromolecules. 2. Female > male. 3. Immunosuppression. 4. Genetic factors.
596
Why are drug interactions such a big problem today?
1. Ageing population. 2. Polypharmacy. 3. Increased use of over the counter drugs.
597
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.
598
What are the 3 actions of NSAIDS?
1. Anti-inflammatory. 2. Analgesic. 3. Anti-pyrexic. (AAA).
599
Give examples of Non-selective NSAIDs?
Diclofenac Ibuprofen Naproxen High Dose Aspirin Inhibit both COX1/COX2 to reduce conversion of Arachidonic acid to prostaglandins
600
Give Examples of Selective NSAIDs?
Celecoxib Specifically Targets COX2 Low dose Aspirin - Targets COX1
601
What are the effects of a competitive antagonist?
Decreases potency of a drug but does not affect the efficacy
602
What are the effects of a non-competitive antagonist?
Decreases both the potency and efficacy.
603
Give examples of alpha 1 blockers and what they can be used to treat
Doxazosin - Decrease BP Phenoxybenzamine - Treats phaeochromocytoma
604
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
605
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
606
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
607

Medicine Phase 2a (20 decks)

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