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ICSS lecture notes Flashcards

1
Q

When does acute inflammation occur?

  • to the benefit of the individual
  • when can it become harmful
A

Beneficial: in response to infection, in immunity
Harmful: autoimmunity, overreaction to the stimulus

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2
Q

What are the cells involved in acute inflammation?

A

Neutrophil polymorphs,(PRIMARY CELL involved). Also macrophages, lymphocytes

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3
Q

Describe neutrophil polymorphs

  • life span
  • role in acute inflammation
A
  • short lived
  • first on scene in acute inflammation. Contain cytoplasmic granules of enzymes that kill bacteria.
    Usually die at the scene.
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4
Q

Describe macrophages

  • life span
  • role in acute inflammation
A
  • long lived (months)

- Phagocytic, ingest bacteria and debris. May carry debris away. May present antigen to lymphocytes

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5
Q

Describe lymphocytes

  • life span
  • role in acute inflammation
A
  • long lived (years)

- produce chemicals which attract other inflammatory cells. Immunological memory for past infections and antigens.

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6
Q

Describe the role of endothelial cells in acute inflammation

A
  • line capillary blood vessels and become sticky in areas of inflammation for adherence
  • become porous to allow cells involved in acute inflammation to enter
  • cytokines may open structures in capillaries
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7
Q

examples of acute inflammation?

A

Acute appendicitis

Lobar pneumonia

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8
Q

examples of chronic inflammation?

A
  • If acute appendicitis is not caught, appendix can rupture and lead to chronic inflammation
  • Tuberculosis
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9
Q

Why is tuberculosis an example of chronic inflammation?

A
  • no initial acute inflammation

- macrophages fail to kill ingested mycobacterium. Lymphocytes and macrophages appear.

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10
Q

What are prostaglandins?

A

Chemical mediators of inflammation

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11
Q

How (basic) do NSAIDs work?

A

Inhibit synthesis of prostaglandins

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12
Q

How (basic) do corticosteroids work?

A

Bind to DNA

Upregulate inhibitors of inflammation, downregulate chemical mediators of inflammation

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13
Q

What is the difference between resolution and repair folllowing tissue damage?

A

Resolution: initiating factor removed, tissue undamaged and able to regenerate
Repair: initiating factor still present, tissue damaged and unable to regenerate - replaced by fibrous tissue (collagen produced by fibroblasts).

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14
Q

Eg of cells which can regenerate - resolution

A 
hepatocytes
pneumocytes
osteocytes
skin epithelium
gut epithelium
all blood cells
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15
Q

What happens when liver cells are damaged?

What about when damage is prolonged?

A
  • normally, liver is able to regenerate (resolution)
  • prolonged damage, such as alcohol abuse, leads to cirrhosis: (repair, not resolution) and tissue is replaced by fibrous tissue
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16
Q

Describe the process of regeneration following abrasion of the skin (superficial skin wounds)

A

Scab forms over superficial damage, cells left to grow and regenerate.
Epidermis regrows.

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17
Q

What is healing by 1st intention in the skin?

A

When suture is possible .
Incision –> weak fibrin join by blood –> epidermal regrowth, collagen synthesis beneath –> strong collagen join (scar)

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18
Q

What is healing by 2nd intention in the skin?

A

Skin edges cannot be brought together by suture.

Capillaries and fibroblasts form granulation tissue. Eventually epidermal cells can grow in and a bigger scar is formed.

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19
Q

e.g of repair following damage in the body?

A
  • heart after myocardial infarction
  • brain after myocardial infarction
  • spinal cord post-trauma
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20
Q

what is a fibrosis in the brain known as?

A

brain gliosis

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21
Q

What is laminar flow?

A

the flow of red blood cells through blood vessels

platelets are carried along. Endothelial cells act as teflon - anti-stick!

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22
Q

How does injury of endothelial cells lining capillaries lead to thrombus formation?

A
  1. ENDOTHELIAL DAMAGE - endothelial cell injury disturbs laminar flow
    - collagen beneath is exposed: platelets stick and aggregate, releasing chemicals to attract other platelets in positive feedback.
    - RBC also aggregate
  2. THROMBUS FORMATION - fibrinogen polymerised to form fibrin. Fibrin deposition forms meshwork, thrombus added to and fills blood vessel.
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23
Q

Define thrombosis

A

Solid mass of blood constituents formed within intact vascular system during life.

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24
Q

What 3 factors cause thrombus?

A

change in vessel wall
change in blood flow
change in blood constituents

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25
Q

why are veins more prone to thrombosis during periods of stasis?

A

Flow is slower, blood is touching vein walls as no central laminar flow - usually this is fine, as endothelial cells are non-stick - however if the wall is damaged they will stick and clump forming a thrombus, though at a slower rate than in an artery.

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26
Q

How does aspirin prevent thrombus formation

A

inhibits platelet aggregation

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27
Q

Define an embolus

A

Mass of material in the vascular system becomes lodged within vessel wall, blocking it.
Commonly caused when a thrombus breaks off and circulates to block a small vessel

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28
Q

Classic hospital strategy for prevention of embolus?

A

Low dose heparin

Stockings

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29
Q

Define ischaemia

A

Reduction in blood flow so cells further from vessel don’t receive enough oxygen. This is especially dangerous if cells are metabolically active.

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30
Q

What is infarction and how does it relate to ischaemia?

A

Subset of ischaemia (which can be defined as reduced blood flow) wherein cells die due to lack of blood flow.

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31
Q

How might embolism affect an organ which has an end artery supply, such as the kidney, compared with an alternative supply such as the lungs/some parts of the brain/the liver?

A

Kidney: if supply is blocked by embolism, infarction occurs

Alternative supply: infarction rare as cells still receive oxygen

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32
Q

Presence of which cells indicate acute inflammation?

A

Neutrophils

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33
Q

Presence of which cells indicates chronic inflammation?

A

Lymphocytes and macrophages

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34
Q

Describe a granuloma

A

Rounded mass/gathering of macrophages.
Type of chronic inflammatory response.
Associated with type IV hypersensitivity.

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35
Q

Describe the normal districution of atheromas in atherosclerosis

A

Found in high pressure, left side arteries: aorta/systemic arteries.
Not in pulmonary

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36
Q

What is an atherosclerotic plaque composed of?

A

Fibrous tissue
Lipids: cholesterol
Lymphocytes

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37
Q

What are some risk factors for atherosclerosis?

A

Smoking, hypertension, age, diabetes mellitus, hyperlipidaemia. Maps very closely with social deprivation and CHD.

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38
Q

Describe the endothelial damage theory which is the currently accepted theory for the mechanism of formation of atherosclerotic plaques

A

endothelial cell damage –> platelet aggregation –> thrombus formation: could be the start of an atherosclerotic plaque.
Steady small incremental damages to endothelial cells over a long period of time leads to plaque build up and atherosclerosis.
Endothelial cells usually produce NO preventing sticking.
Damage can be by:
- free radicals/nicotine/CO in cigarettes
- shearing forces from hypertension
- superoxide anions from poorly controlled diabetes
- hyperlipidaemia causing direct damage

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39
Q

Complications of atherosclerosis

A

Infarction of various tissues/organs depending on site of plaque

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40
Q

what is apoptosis compared to necrosis?

A

apoptosis is programmed cell death

necrosis is traumatic cell death

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41
Q

How is the decision to apoptose a fully differentiated resting cell triggered?

A

By DNA damage

Capases and protein p53 within cells detecting damage may switch on apoptosis

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42
Q

eg Roles of apoptosis in:

  • development:
  • body:
  • disease:
A
  • development: to form separate fingers
  • body: turnover of cells in skin/gut
  • disease: lack of apoptosis in cancer due to mutation in p53 protein, so DNA damage is not recognised and apoptosis is not switched off. Too much apoptosis occurs in HIV.
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43
Q

What are the 3 different types of necrosis?

A

Coagulative (sticky), liquid, and caseous (looks like cream cheese)

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44
Q

What could caseous necrosis be a sign of?

A

TB

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45
Q

Examples of necrosis (traumatic cell death)

A 
Infarction
Frostbite
Toxic spider venom
Avascular necrosis of bone, e.g. due to fracture of the scaphoid that goes unnoticed and so not kept immobile
Pancreatitis
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46
Q

what is hypertrophy?

A

Increase in size of tissue due to increase in size of cells within the tissue

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47
Q

What is hyperplasia?

A

Increase in tissue size due to increased number of cells in tissue

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48
Q

Give an example of hypertrophy of a tissue

A

skeletal muscles of body builders

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49
Q

Give an example of hyperplasia of a tissue

A

enlarged prostate is due to hyperplasia of muscle cells

neuronal hyperplasia, endothelial hyperplasia occur in pregnancy

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50
Q

What is atrophy?

eg

A

Decrease in size of a tissue due to decrease in size OR number of constituent cells.
eg brain atrophy in dementia

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51
Q

What is metaplasia?

eg

A

Change in differentiation of a cell from one cell type to a different cell type.
e.g. squamous metaplasia of ciliated columnar cells to form squamous epithelium in the bronchi of a smoker.

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52
Q

What is dysplasia?

A

Imprecise term; used to refer to the morphological changes seen in cells in the progression to becoming cancer.
(also sometimes used to refer to developmental abnormality)

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53
Q

Describe ageing in terms of telomere length

A

Dividing cells have a limit to replication - telomere shortens with each replication and eventually can no longer divide.
People in less affluent areas have shorter telomere length!

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54
Q

What is the condition progeria?

A

accelerated ageing due to congenital abnormality. Due to protein deficiency

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55
Q

Common conditions associated with ageing

A

dermal elastasia (wrinkles), osteoporosis, cataracts, senile dementia, sarcopenia, deafness

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56
Q

Treating cancer based on pathology

Basal cell carcinoma

A

Only invades locally and will not spread to body. Therefore cured by complete local excision.

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57
Q

Treating cancer based on pathology

Leukamia

A

Tumour of WBCs (bone marrow)
Will usually have spread around the body before detection.
Tumour will circulate, so cannot be excised, so chemo must be used.

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58
Q 
Treating cancer based on pathology
Breast cancer
- type 
- spread
- treatment
A

Carcinoma will spread to the lymph drainage area of that site.
In BC, spreads to axillary nodes.
Treatment:
- small needle biopsy to confirm BC
- check if has spread to axilla:
YES: axillary node clearance to drain
NO: check rest of body, cancer is staged according to how far it has spread.
If it has spread, chemo is necessary. If it has not, excision without axillary node clearance to treat.
Adjuvant therapy (radiotherapy) after surgical excision (lumpectomy) to eliminate micrometasteses that are too small to be picked up. OR adjuvant anti-oestrogen therapy for oestrogen receptive tumours.

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59
Q

In which cancers can carcinoma spread to bone?

A

Breast, prostate, lung, thyroid, kidney

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60
Q

what is carcinogenesis?

A

the transformation of normal cells to neoplastic cells through permanent genetic alterations/mutations.
A multi-step process
Applies to malignant neoplasms (oncogenesis = benign and malignant tumours)

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61
Q

What are carcinogens?

problems with identification of causative carcinogens in the environment?

A

Agents known or suspected to cause tumours.
85% of cancer risk is environmental.
Problems: latent interval between exposure and diagnosis may be decades
complexity of environment
ethical constraints
Identification relies on epidemiological evidence

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62
Q

5 classes of carcinogens

A
  1. Chemical
  2. Viral
  3. Ionising/non-ionising radiation
  4. Biological agents: hormones, parasites, mycotoxins
  5. miscellaneous
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63
Q

Examples of chronic inflammation that show granulatomous inflammation

A

TB, sarcoidosis, leprosy, Crohn’s disease

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64
Q

Is cholecystitis (viral infection of the gall bladder) an example of acute or chronic inflammation?

A

Starts acute, develops into chronic

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65
Q

What is a neoplasm vs a tumour?

A

Tumour: any abnormal swelling. e.g. neoplasm, inflammation, hypertrophy, hyperplasia.
Neoplasm: a lesion (localised abnormality) from autonomous abnormal growth of cells which persists after the initiating stimulus has been removed. A new growth.

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66
Q

Define neoplasia

A

Neoplasm: a lesion (localised abnormality) from autonomous abnormal growth of cells which persists after the initiating stimulus has been removed. A new growth.

Key points:
neoplasia is:
- autonomous
- abnormal
- persistent
- a new growth
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67
Q

Strcuture of neoplasm

What is it made up of?

A

Stroma: connective framework - supporting cells. Nutritional and mechanical.
Neoplastic cells: derive from nucleated cells. Usually monoclonal. Growth pattern and synthetic activity related to parent cell: collagen, mucin, keratin, hormones etc produced.

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68
Q

Describe the process of malignant tumour angiogenesis

A

The process by which a transformed cell becomes an avascular tumour nodule —> prgresses to a vascularised tumour –> vascularised tumour with central necrosis as it outgrows its blood supply

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69
Q

Why do benign tumours usually not have necrosis at the centre compared with malignant tumours?

A

Benign grows slower so does not outgrow its blood supply.

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70
Q

WHY is classification of neoplasms important?

HOW are neoplasms classified?

A

WHY: to determine appropriate treatment and obtain prognostic information
HOW: behavioural - is it benign/malignant?
histogenetic - what are the cells of origin?

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71
Q

Main ways benign and malignant neoplasms differ

A
  1. Differentiation
  2. Rate of growth
  3. Local invasion
  4. Metastasis
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72
Q

how do benign and malignant tumours differ in terms of differentiation?

A 
benign:
well differentiated
looks like tissue of origin
circumscribed/encapsulated
malignant:
poorly differentiated 
variable resemblance to normal tissue (less = more aggressive tumour)
poorly defined/irregular border
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73
Q

how do benign and malignant tumours differ in terms of growth rate?

A

benign = slower

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74
Q

how do benign and malignant tumours differ in terms of local invasion?

A 
benign:
localised, non-invasive, may push surrounding tissue away
may be surrounded by a fibrous capsule
malignant:
invasive
poorly defined border
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75
Q

how do benign and malignant tumours differ in terms of metastases?

A

benign:
may push surrounding tissue away
malignant:
can metastasise

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76
Q

compare benign and malignant tumours in terms of these features:

  • necrosis
  • ulceration
  • exo/endophytic
A

Benign:
necrosis rare, ulceration rare, exophytic
Malignant:
necrosis common, ulceration common, endophytic (grow inward into tissue)

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77
Q

what are the concerns for an individual with a benign neoplasm?

A
  • pressure exerted on adjacent structures causing pressure necrosis
  • obstruct/interfere with blood flow
  • production of hormones
  • transformation into a malignant neoplasm
  • anxiety for patient
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78
Q

what are the concerns for an individual with a malignant neoplasm?

A
  • encroach on and destroy surrounding tissue
  • metastasis
  • blood loss from ulcers
  • obstruct flow
  • hormone production
  • paraneoplastic effects
  • anxiety and pain (pain tends to be a late feature)
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79
Q

describe histogenetic classification of neoplasms

A

Histopathological examination to find cells of origin of the neoplasm.
May arise from epithelial cells, connective tissue, lymphoid/haematopoeitic tissue

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80
Q

Nomenclature of neoplasms:

How is the suffix and prefix determined?

A

Suffix = oma for all neoplasms

Prefix depends on behavioural classification and cells of origin (histogenetic)

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81
Q

EPITHELIAL neoplasms:
describe the types of benign epithelial neoplasms

describe malignant epithelial neoplasms

A

Papilloma = benign tumour of non-glandular, non-secretory epithelium
Adenoma = benign tumour of glandular/secretory epithelium
Prefix with cell of origin
Carcinoma = malignant epithelial neoplasm
Prefix with name of epithelial cell type

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82
Q

Define “carcinoma”

A

malignant epithelial neoplasm

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83
Q

describe the nomenclature of benign connective tissue neoplasms
egs?

A 
Named according to cell of origin, with suffix -oma
Lipoma = adipocytes
Chondroma = cartilage
Osteoma = bone
Angioma = vascular
Rhabdomyoma = striated muscle (rare)
Leiomyoma = smooth muscle (more common)
Neuroma
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84
Q

Describe the nomenclature of malignant connective tissue neoplasms
egs?

A

‘sarcoma’ prefixed by cell type of origin
e.g.
liposarcoma = malignancy of adipose tissue
leiomyosarcoma = smooth muscle
chrondrosarcoma = cartilage
osteosarcoma = bone

85
Q

Malignant neoplams:
How are carcinomas (malignant epithelial neoplasms) and sarcomas (malignant connective tissue neoplasms) further classified?

A

According to degree of differentiation: how much do they resemble normal tissue?
Scaled as low grade –> high grade

86
Q

What is meant by anaplastic when applied to a neoplasm?

A

Poorly differentiated to the point that the cell type of origin is unknown

87
Q

exceptions to rules of neoplasm nomenclature:

- what are examples of medical terms suffixed with -oma that are not neoplasms?

A

granuloma (chronic inflammation)
mycetoma (type fungus)
tuberculoma (a mass in TB)

88
Q

when might a malignant tumour not be named with ‘sarcoma’/’carcinoma’?
eg?

A

When the benign version doesn’t exist/is very rare.
Melanoma = malignant neoplasm of melanocytes (no such thing as benign)
Mesothelioma = malignant neoplasm of mesothlial cells (benign version very rare)
Lymphoma = malignant neoplasm of lymphocytes (all malignant)

89
Q

What are some examples of eponymously named tumours?

A

Burkitt’s lymphoma
Ewing’s sarcoma (bone)
Grawitz tumour (renal)
Kaposi’s sarcoma (angio, caused by herpes virus)

90
Q

A cancer cell is lining a breast duct. What are the 3 stages it could invade?

A
  1. Ductal carcinoma in situ: not an invasion, can be excised locally
  2. Micro-invasive carcinoma: begins to invade past the duct
  3. Invasive ductal carcinoma: no longer contained in duct. First step of metastasis.
91
Q

How does the cancer cell invade the basement membrane?

A
  1. Proteases chew through

2. Motility of cell: produce chemicals

92
Q

Describe the process of metastasis

A
  1. INVASION of basement membrane from tissue
  2. INTRAVASION - enter blood vessel/lymph (must avoid body’s immune response e.g. by aggregation with platelets, shedding surface antigens, adhesion to other tumour cells)
  3. EXTRAVASION - enters different tissue site, determined using receptors
  4. Growth at site: autocrine growth factors, positive feedback
  5. angiogenesis to ensure enough O2 reaches growing cells
93
Q

Describe the general routes of metastasis

A

Tumour cells usually invade lymph/benous channels and not arteries.
From lymph –> congregate at thoracic duct –> vena cava –>lungs
From venous channels –> vena cava –> lungs
The lungs are a key site of metastasis.
From the lungs, cancer can spread to the arterial side.

94
Q

What are the most common tumours that spread to the lungs?

A 
breast.
colorectal.
kidney.
head and neck (such as laryngeal)
testicular.
bone (such as osteosarcoma)
soft tissue sarcoma.
melanoma.
95
Q

What route can colorectal cancer spread by?

A

Colorectal cancer –> portal vein –> liver (/stomach/pancreas)
(Liver = key site of metastasis)

96
Q

What kind of tumours is conventional chemotherapy effective at treating?
What treatment is necessary for other tumours?

A

Fast dividing tumours such as acute leukaemias, lymphomas, embryonal paediatric tumours.
For most, slower-growing tumours, targetted chemotherapy is necessary and aims to exploit differences between normal cells and cancer cells.

97
Q

what is the basis of the TNM grading scale for cancers?

A 
T = size of original tumour 
N = the extent of spread to the lymph nodes 
M = presence of metastasis
98
Q

what cells, found in the bone marrow, do all WBCs and RBCs originate from?

A

multopotent haematopoeitic stem cells

mature in the bone marrow then enter the blood

99
Q

what are 3 polymorphonuclear leukocytes in order of abundance?
describe nucleus

A
  1. Neutrophil, 70%: most abundant. Multi-lobed nucleus.
  2. Eosinophil, bilobed nucleus
  3. Basophil, bilobed
100
Q

what are the mononuclear leukocytes? abundance?

describe nucleus

A

Monocyte: kidney-shaped nucleus, 10-15% cells. Differentiates into macrophagewhen enters blood/tissue.
T cells and B cells = 80% cells.

101
Q

what are the soluble factors present in the blood?

A 
Complement
Antibodies (Ab)
Immunoglobulins (Ig)
Cytokines
Chemokines
102
Q

what are complement factors?

A

series of 20ish serum proteins secreted by the liver
Activated in a cascade during the immune response.
Modes of action:
- direct lysis
- attract more leukocytes to site of infection
- coat invading pathogens

103
Q

innate immunity components:

  • egs of physical and chemical barriers
  • phagocytic cells
  • serum proteins
A
  1. Cilia, sebum of skin, mucus, lysosomes in tears/other secretions, stomach acid, flushing of the urinary tract…
  2. neutrophils and macrophages
  3. complement, acute phase
104
Q

when does the inflammatory response occur?

A

when barriers are breached, by trauma/infection.

Can be acute or chronic

105
Q

Principles of the inflammatory response - what are the components and aim?

A
  • coagulation
  • acute inflammation involving leukocytes
  • aim to kill pathogens, neutralise toxins, limit spread
  • phagocytosis
  • proliferation of cells to repair damage
  • remove clot, remodel extracellular matrix
  • re-establish normal structure/function tissue
    Can be acute (results in elimination of pathogen, resolution and full regeneration) or chronic (persists unresolved)
106
Q

What are hallmarks of the inflammatory response?

A
  • increased blood supply
  • increased vascular permeability
  • increased extravasion
107
Q

cells of the innate immune system
cells of the adaptive immune system
What do cells of the former respond to compared with cells of the latter?

A

innate: macrophages, dendritic, mast cells, neutrophils
adaptive: b cells, t cells
Former respond to PAMPs (Pathogen Associated Molecular Patterns), as they have Pathogen Recognition Receptors, whereas the latter respond to antigens

108
Q

What is passive immunisation?

2 types

A

the transfer of preformed antibodies. Can be natural or artificial

109
Q

egs of natural passive immunisation

A
  • transfer of maternal antibodies across the placenta to the foetus
  • in breast milk
110
Q

how does artificial passive immunisation work?

when is it currently used?

A

Treatment with polled normal human IgG/immunoserum against pathogens/toxins.
Uses: antitoxins; prophylactically after exposure (hep, measles, rabies); anti-venins

111
Q

What is active immunisation?

A

vaccination

  • safe mimicking of natural infection to generate persistent protective response against pathogens
  • aims to mobilise immunity and create B and/or T cell immunological memory
112
Q

what are the 4 types of drug interaction involved in pharmacodynamics?

A
  1. summation: 1 + 1 = 2
  2. synergism: 1 + 1 > 2 both drugs make the other more powerful
  3. 1 + 1 = 0, drugs have antagonistic effects
  4. Potentiation: 1 + 1 = 1 + 1.5 , drug A makes drub B more powerful but not vice versa
113
Q

What are the 4 principles of pharmacokinetics?

A
  1. Absorption
  2. Distribution
  3. Metabolism
  4. Excretion
114
Q

What factors affect absorption?

A

Motility - peristalsis slows down when in pain, drugs given to speed up motility
Acidity - ionised particles cannot cross membranes, unionised can. If the acidity of the environment is changed, the particles absorbed in the gut are affected.
Physiochemical

115
Q

Pharmacokinetics: distribution of the drug - what are the options of how the drug may be distributed once in the blood stream?

A
  • bound to protein: if 2 drugs that are highly protein bound are administered, effects will be increased
  • to other tissues: if distribution is high, other tissues form an effectively infinite store
  • to effect/target site: where you want the drug to act
116
Q

Pharmacokinetics: drug metabolism - as an example, what is the pathway by which morphine is metabolised?

What are examples of drug interactions that interfere with morphine metabolism by:

a) enzyme induction
b) enzyme inhibition

A

Morphine enters the CYP450 pathway to form morphine-6-glucoronide, which is very potent and is renally excreted.
Therefore, care must be taken administering morphine to individuals with renal failure.
a) phenytoin(anti-seizure)/alcohol increases metabolism, so lots of morphine-6-glucoronide. This means there is potential for respiratory arrest as effects are increased.
b) metronidazole (antibiotic) slows down the CYP450 pathway

117
Q

Pharmacodynamics: in the event of aspirin overdose, what action is taken to counteract effects?

A

Aspirin is an acidic drug.

Na2CO3 is administered to make blood more alkaline, therefore more of the acidic substance is excreted by the kidneys

118
Q

Warfarin: important drug/diet interactions

A

Substances that increase protein binding will act as enzyme inducers (e.g. grapefruit juice) increasing the effects of warfarin.
(? not much online about this)

119
Q

What are 4 drugs that should be avoided/questioned in individuals with acute kidney injury?

which of these drugs interact, and in what way pharmacodynamically?

A

a. Gentamicin
b. Furosemide
c. NSAIDs
d. ACE inhibitors

a with b, and c with d, have synergistic effects

120
Q

define pharmacodynamics vs pharmacokinetics?

A

pharacodynamics: how the drug affects the body
pharmacokinetics: the disposition of a compound within an organism (ADME)/action of drug in body

121
Q

define receptor

what is meant by exogenous vs endogenous

A 
A component of a cell that interacts with a specific ligand and initiates a change of biochemical events leading to the ligand's observed effects.
Can be exogenous (drugs)
or endogenous (hormones, neurotransmitters)
122
Q

Basic concepts of pharmacology: what effects can receptor ligands have?

A

Agonist : compound + receptor –> activation
Antagonist: compound reduces effect of agonist
Inverse agonist: produces downregulated
Affinity
Efficacy - how well ligand activates the receptor

123
Q

Oral administration of drugs
what are the positives?
what are the obstacles in terms of absorption?

A

Positive: easiest, most convenient, least invasive, splanchnic circulation and large surface area of small intestine means rapid and complete absorption of substances is possible.
Obstacles:
1. Drug structure: must be lipid soluble to be absorbed from gut. Some drugs are unstable at low pH of gut lumen
2. Drug formulation: capsule/tablet must disentegrate and dissolve rapidly
3. Gastric emptying: how soon oral drug reaches small intestine. Slowed down by food/trauma, quicker if had gastric surgery
4. First pass metabolism: major metabolic barriers drugs must pass to reach circulation

124
Q

First pass metabolism: what are the 4 major metabolic barriers drugs may have to pass to reach circulation?

A
  • intestinal lumen: contains digestive enzyme
  • intestinal wall: rich in cellular enzymes. Efflux transporters may limit absorption by passing drugs back the wrong way. Extensive bowel surgery decreases SA.
  • liver: blood passes from gut to splanchnic circulation to liver, major site of dru metabolism
  • lungs
125
Q

When is transcutaneous administration of drugs useful?

A

For slow, limited absorption - e.g fentanyl patches last for 3 days.
The human epidermis acts as a barrier to water soluble compounds, and the rate and absorption of lipid soluble compounds is also limited.

126
Q

Limitations/uses of intradermal/subcutaneous drug administration

A
  • avoids barrier of stratum corneum, small volume can be given, useful for local effects (eg local anaesthetic) or to deliberately limit absorption rate (contraceptive patch)
  • limited by blood flow
127
Q

Effect of blood flow and solubility on effects of intramuscularly administered drugs

A

increase in either enhances drug removal

128
Q

positives and negatives of iinhalation mode of drug administration

A
  • good SA and blood flow of lungs

- but risk of toxicity to alveoli, and limited to volatiles

129
Q

what are the 2 phases of drug metabolism

A

phase 1: unmasking/adding functional group. CYP450

phase 2: conjugation. Products excreted by kidney

130
Q

how may drugs be excreted?

A

In:
fluids (urine, bile, sweat, tears, breast milk)
solids (faecal, hair, bile)
gases (volatiles)

131
Q

how is total urine secretion calculated?

A

total excretion = glomerular filtration + tubular secretion - renal absorption

132
Q

why is maths important in pharmacokinetics?

A
  • oral and IV drugs require different doses
  • calculation of dosages and dose intervals in chronic drug treatment
  • loading dose (initial high dose before maintenance dose)
  • dose adjustments in liver and kidney disease
  • drug doses in vulnerable patients - trials are usually done in fit, healthy volunteers, so adjustments must be made
133
Q

define bioavailability of a drug

A

the fraction of administered drug that reaches the circulation unaltered

134
Q

what does the distribution rate depend on for:

  • water soluble drugs
  • lipid soluble drugs
A

water: depends on passage across membrane
lipid: depends on blood flow to tissues that accumulate drug

135
Q

what factors make a patient more susceptible to adverse drug reactions?

A 
- gender (f)
elderly
neonates
polypharmacy
genetics
hypersensitivity/allergy
hepatic/renal impairment
adherance
136
Q

what are some common causes of adverse drug reactions?

A 
pharmaceutical variation
receptor abnormality
abnormal biological system unmasked by drug
abnormalities in drug metabolism
immunological
drug-drug interactions
multifactorial
137
Q

describe symptoms and causes of anaphylaxis

A
  • occurs within minutes, lasts 1-2 hrs
  • uticaria (rash)
  • vasodilation = red face
  • increased vascular permeability = swelling
  • bronchoconstriction = wheezing
  • angio-oedema = facial swelling
138
Q

what is the management of anaphylaxis?

A
  • commmence basic life support ABC
  • if infusion, stop the drug
  • ADRENALINE IM 500micrograms !!!! most important
  • high flow O2
  • IV fluids, anti-histamine, hydrocortisone
    If anaphylactic shock, may need IV adrenaline
139
Q 
MICROBIOLOGY
what is meant  by the following terms:
commensal
opportunist pathogen
virulence
asymptomatic carriage
A

commensal - colonises host but no disease
opportunist pathogen - causes disease only if host defences are compromised
virulence - degree of pathogenicity
asymptomatic carriage - pathogen carried harmlessly at tissue site, no disease

140
Q

what are surfaces of the body that are sterile and therefore not open to bacterial colonisation?

A

lungs, gall bladder, kidneys, bladder. upper urethra.

Mucosal surfaces, however, are open to bacterial colonisation.

141
Q

bacterial morphology:

how can coccus (circles) and bacillus (rods) be further subdivided?

A

gram positive and gram negative

142
Q

how do gram positive and gram negative bacteria differ?

A

Gram positive cell walls have a capsule and inner membrane, between which is a thick peptidoglycan layer. Gram positive bacteria will stain purple because of their thick peptidoglycan cell wall.
Gram negative stain blue, as their cell wall is composed of endotoxin (lipopolysaccharide)

143
Q

compare endotoxin (component of outer membrane of gram -ve bacteria) and exotoxin (produced by both gram +ve and gram -ve) in terms of:

  • composition
  • action
  • heat
  • antigenicity
  • type bacteria produced by
  • converted to toxoid?
A 
EXOTOXIN
- composition = protein
- action = specific
- heat = labile
- antigenicity = strong
- type bacteria produced by = gram +ve and gram -ve
- converted to toxoid? = yes
ENDOTOXIN
- composition = lipopolysaccharide
- action = non-specific
- heat = stable
- antigenicity = weak
- type bacteria produced by = -ve
- converted to toxoid? = no
144
Q 
describe s. aureus
species?
coag +ve/-ve?
spread?
Virulence factors?
A

Type of gram positive bacteria, species staphylococcus.
Coagulase +ve (enzyme produced by bacteria that clots blood plasma)
Spread by aerosol and touch, people can be carriers and shedders.
Virulence: pore-forming toxins, proteases, TSS toxin, protein A…

145
Q

what is MRSA

A

MRSA is a type of s. aureus which is resistant to common antibiotics.

146
Q 
describe s. epidermis
species?
coag +ve/-ve?
spread? causes...
Virulence factors?
A

species staphylococcus
coag negative
spread? causes infections in debilitated prostheses, catheters… opportunistic
Virulence factor: ability to form persistent biofilm

147
Q 
describe s, saprophyticus
species?
coag +ve/-ve?
causes...
Virulence factors?
A

staphyloccocus
coag -ve
Acute cystitis
Virulence: haemaglutinin for adhesion, urease causes kidney stress

148
Q

what does s. pyogenes cause?

Virulence:
surface factors
exported factors
toxin eg

A
  • wound infections: cellulitis
  • tonsilitis and pharyngitis
  • impetigo
  • scarlet fever
    Surface: capsule - hyaluronic acid. Has M protein on surface which encourages complement degradation.
    Exported: enzymes(hyaluronidase for spreading, streptokinase breaks down cloys, C5a peptidase reduces chemotaxis)
    Toxin SPeA exaggerates host inflammatory response
149
Q

how is strep classified?

A

By haemolysis: alpha, beta, gamma.

By lancefield grouping (A-H, K-V), biochemically

150
Q

examples of bacteria in the strep species

A

strep pneumoniae

viridans strep

151
Q

which immunoglobulin is usually involved in allergy and hypersensitivity?
Describe its role in allergic response

A

IgE:
inflexible as no hinge region so therefore matches with very high affinity.IgE high affinity receptors are on mast cells in tissues, whereas eosinophils and basophils are circulatory.
When allergen enters, receptors cluster together and produce amplified response very quickly= allergic response.
has a shorter half life than IgG
does not fix complement (not directly involved in inflammation)

152
Q

what is meant by allergy? Atopy?

A

allergy - abnormal response to harmless foreign materials

atopy - tendency to develop allergies

153
Q

what cells are involved in allergy and hypersensitivity

A

mast (important)
eosinophil = effector cell
lymphocytes = Th2 cytokines
dendritic cells= antigen presentation
epithelial cells = compromised barrier function
smooth muscle, fibroblasts - mucus production, constriction

154
Q

describe the role of mast cells in allergic response and immunity
what do the granules contain?

A

Main effector cells in IgE-mediated immunity.
Primary role in innate and acquired immunity.
Heterogenous: diff roles in diff tissues.
Granulated:
protease, histamine, chemotactic factors (causing accumulation of immune cells), proteoglycans such as heparin

155
Q

What are ways in which mast cells are indirectly activated?
Direct?
Other?

A

Indirect: via IgE. By allergens (prior exposure necessary), bacterial/viral antigens.
Direct: direct activators (no prior exposure) such as cold/mechanical deformation (asthma), aspirin, latex, NO2.
Other: phagocytosis of enterobacteria.

156
Q

describe anaphylaxis in terms of mast cells

A

Immediate activation of mast cell/basophil.
Ig`E/direct activation (idiopathic)
Or by serum tryptase/elevated histamine.

157
Q

example of chronic allergic disease

A

asthma

158
Q

What are ways that allergens can be treated?

A
  • avoid allergens
  • desensitisation to allergens by immunotherapy
  • poss prevention of IgE production by supression of Th2 response
  • prevent interaction of IgE with receptor: expensive anti-IgE therapy
  • prevent mast cell activation by using stabilisers such as beta-2-agonists, glucocorticoids, signalling inhibitors
  • inhibit products produced by mast cells: anti-histamine, tryptase inhibitors
159
Q

long-term treatment of asthma?

A

immune suppression with inhaled corticosteroids

160
Q

what makes an allergen?

A
  • weak PAMP –> immune activation
  • particulate delivery of antigens (e.g. pollen)
  • nasal/skin delivery - oral would desensitise
  • low doses: high dose desensitises
161
Q

T cell differentiation occurs in response to threat detected - adaptive response.
how does the Th2 response produced by mast cells in allergic reaction shut down other immune response?

A

T cells produce IgE, which binds to mast cells causing them to produce Th2 cytokines, which further activate T cells.
A positive feedback loop.

162
Q

describe the microbiology of mycobacteria

examples of common mycobacteria?

A

Family of actinobacteria
Rod, gram positive.
Aerobic, non-spore forming, non-motile bacillus.
Cell wall of lipids = wax coating, enables them to survive low pH environments such as lysosomes.
Slow-growing.
M. tuberculosis - tuberculosis
M. avium complex - chronic lung infection
M. leprae - leprosy

163
Q

Describe the body’s immune response to mycobacteria?

Role of granuloma…

A

Waxy lipid cell wall means macrophage’s lysosome cannot kill mycobacteria.
Macrophage signals T-cell mediated immunity, which signals to macrophages and primes them to kill specific mycobacteria.
Granuloma formed as an immune mechanism, from fusion of macrophages, infiltrated by T cells and with fibroblasts laid inside. Centre may necrose. This starves mycobacteria of nutrients, so it remains dormant.

164
Q

Why are the immuno-compromised susceptible to mycobacterium?

A

Granuloma may stop working due to CD4 depletion/TnF4 depletion, and reactivation occurs long after exposure.

165
Q

Tuberculosis - what factors increase risk?

A

Risk increases with age, malnutrition, immunosuppression, high exposure.

166
Q

What is the basis of the Mantoux test for TB?

A

The huge immune response to TB often results in Type 4 hypersensitivity, whereby memory T cells cause hyperinflammatory response on reexposure.
If you have a latent TB infection, your skin will be sensitive to PPD tuberculin and a small, hard red bump will develop at the site of the injection.

167
Q

Describe Primary Tuberculosis, which is revealed by the Mantoux test but usually resolves and does not present clinical disease.
What occurs in the 5% of cases that do not resolve?

A

Primary TB: Latent infection, whereby mycobacterium tuberculosis is breathed into the lungs. The bacilli travel in lymphatics to hilar lymph nodes, resulting in cell mediated immune response from T cells.
In 5%…
Pulmonary TB:
Granuloma forms around bacilli that had settles in the apex. Caseating necrosis, fluid-filled absess, material coughed up and mycobacterial disease spreads and disseminates beyond lungs.
Granuloma + lymphatics + lymph nodes = known as Primary Complex

168
Q

Basic properties of viruses

A
  1. Grow only inside living cells
  2. One type of nucleic acid: DNA/RNA
  3. Outer protein coat/lipid envelope, not cell wall
  4. Inert outside host cell, but enzymes function inside
  5. Protein receptors on virus surface allow attachment to host cell.
169
Q

Priniciples of virus replication within a host

A
  1. Attachment - by specific receptors
  2. Cell entry - viral core of nucleic acid and proteins enter host cell, shed coat
  3. Interaction with host cells - use of materials inside host cell for replication, subvert defence mechanism
  4. Replication
  5. Assembly - occurs in nucleus/ytoplasm/cell membrane
  6. Release - by lysis/leaking/move cell to cell over time
170
Q

Viruses cause disease by damaging host cells in a variety of ways.
How does poliovirus cause damage?

A

Direct destruction of host cells - lysis.

171
Q

Viruses cause disease by damaging host cells in a variety of ways.
How does rotavirus cause damage?

A

Shortening and atrophy of villi.

This causes decreased surface area, leading to malabsorption and diarrhoea.

172
Q

Viruses cause disease by damaging host cells in a variety of ways.
How does hep B cause damage?
Describe the chronic carrier state
When might presentation with jaundice NOT occur?

A

Indirect damage due to over-reactivity of the host as a response to infection: immunopathological.
Hep B infects liver cells, which are killed as part of immune response by T cells. This causes liver damage.
Chronic carrier state is reached when virus replication and host defences reach a steady state. This may lead to cirrhosis/cancer.
Jaundice not present if individual has HIV/immunosuppression (lack T cells)

173
Q

Viruses cause disease by damaging host cells in a variety of ways.
How does HPV cause damage?

A

Damage through cell proliferation and cell immortilisation.
Some types cause development of cervical cancer…
Viral proteins interfere with host proteins responsible for cell death, causing them to become immortalised. Integrates with cell DNA and inserts oncogenic genes.

174
Q

Viruses cause disease by damaging host cells in a variety of ways.
How (basic) does HIV cause damage?

A

By evasion of host defences, direct destruction, modification of cell structure/function, immuno-pathological damage.
Escapes by cell to cell transmission, does not travel in the blood.

175
Q

What is meant by the pathogen attributes of:
Infectivity
Virulence
Invasiveness

A

Infectivity - ability to become established in host. Adherence, immune escape.
Virulence - ability, once established, to cause disease
Invasiveness - capacity to penetrate mucosal surfaces and reach normally sterile sites

176
Q

How does influenza virus evade host?

A

Changes coat antigen

177
Q

What is the humoral response to viral infection?

Cell mediated?

A

Humoral:
Various antibodies block binding, cause opsonisation of infected cell (eg makes it more palatable to macrophages), agglutinates particle, causes lysis.
Cell-mediated:
Interferons, cytotoxic lymphocytes, macrophages

178
Q

What are the 4 major groups of protazoa

A
  1. Flagellates
  2. Amoebae
  3. Sporozoa
  4. Ciliated
179
Q

Key symptoms of malaria

A

MAIN: fever +recent travel
Can also have tachycardia, pyrexia leading to dehydration, abdominal discomfort (due to infected liver cells bursting, infecting RBCs), presence of blood and leukocytes in urine, chills, headache, myalgia, fatique, diarrhoea, vomiting

180
Q

Transmission of malaria

A

Bite of female anopheles mosquito

181
Q

Haemolysis leads to which signs of malaria?

A

anaemia, jaundice, hepatosplenomegaly, black water fever (whereby haemoglobin discolours urine)

182
Q

Which form of malaria has the highest mortality? WHy?

A

Plasmodium falciparum
Has sticky proteins on cell surface membrane of RBCs, causing endothelial cytoadherance, leading to vascular occlusion in various sites

183
Q

Complications of severe complicated falciparum malaria.

Treatment?

A

Cerebral
Acute lung injury and acute respiratory distress syndrome (ARDS)
Renal Failure
Sepsis
Bleeding/anaemia
Treatment IV artesunate, plus supportive measures such as O2 for ARDS

184
Q

What are hypnozoites in malaria and how are they treated?

A

P ovale and p vivax forms of malaria can form hypnozoites in the liver which lie dormant. Primiquine must be given to eliminate these.

185
Q

Definition of antibiotics

A

Molecules that work by binding a target site on a bacteria

186
Q

How do β lactams, the most ubiquitous and important class of antibiotics, act?
What bacteria are they particularly useful for?
eg…

A

Bind covalently and disrupt peptidoglycan production, reuslting in cell wall disruption and lysis.
Useful for gram +ve (gram -ve have additional lipopolysaccharide membrane)
eg: penicillins, cepphaalosportins, carbapenems, monobactams

187
Q

How (basic) do antibiotics work?

A

Can kill/disable bacteria.

Give time and support for the immune system to deal with an infection.

188
Q

In what ways do bacteria cause accidental damage to the organism they enter?

A
  • Direct: destroy phagocytes/cells
  • Release toxins (exo/endotoxins)
  • Indirect: trigger inflammation/immuno-pathology
  • Cause diarrhoea in an attempt to flush out gut bacteria
189
Q

Compare how bacteriostatic and bactericidal antibiotics work

%killed in 18-24hrs?

A

Bacteriostatic: prevent growth of bacteria (by inhibition protein synthesis, DNA replication, metabolism), reduce toxin production.
This kills >90% in 18-24hrs.
Bactericidal: agent kills the bacteria. By inhibition of cell wall synthesis. Useful if poor penetration (eg endocarditis) or hard to treat or need quick action (eg meningitis)
Kill >99.9% in 18-24hrs

190
Q

How is the amount of antibiotic needed calculated?

Why is this not the only measure that must be taken into account?

A

MIC: minimum inhibitory concentration
However, lowest MIC may not relate to best antibiotic: drug must attach to binding target, occupy adequate no. binding sites, anf remain for a prolonged period. Therefore, pharmacokiinetics must be used to determine which antibiotic is suitable based on:
- which antibiotics will penetrate siite
- pH of site
- lipid solubility
- dosage interval/duration to keep antibiotic at binding site of pathogen for long enough

191
Q

By what mechanisms may bacteria develop antimicrobial resistance?

A
  1. change antibiotic target site (by changing its molecular config. or blocking it)
  2. destroy antibiotic
  3. prevent antibiotic access eg by hydrolysis by bacterial enzymes
  4. remove antibiotic from target site (conc/time dependent) eg proteins act as efflux pumps
192
Q

how is MRSA resistant to flucloxacillin?

A

Changes molecular config. of binding site/ blocks it

193
Q 
How do bacteria resist beta lactams?
eg?
What class of antibiotics are useful against this?
A

Beta lactams all have beta lactam ring in common. Beta lactamase produced by bacteria able to hydrolyse beta lactams.
eg… Staphylococcus produces penicillinase, which inactivates penicillin. Flucoxacilllin must be used.
Carbapenems are highly resistant to bata lactamase hydrolysis

194
Q

WHY?HOW do bacteria develop antimicrobial resistance?

A
  1. Intrinsic: naturally resistant, all sub-populations of a species equally resistant
  2. Acquired:
    a) spontaneous gene mutation - new bp = change in aa sequence
    b) horizontal gene transfer, by conjugation (sex pilus – transfer of DNA as plasmid) or transduction (virus affects how bacteria passes its DNA) or transformation (bacteria takes up free DNA left in environment)
195
Q

WHat is C. Diff and its relation to antibiotics?

A

A hospital acquired gut infection caused by the disruption, due to antibiotic use, of normal gut flora. Results in diarrhoea

196
Q

What is MRSA

A

any beta lactam resistant staph aureus

M = methicillin, which is not used anymore

197
Q

Why are CPEs so dangerous?

A

they have acquired resistance to carbapenemsm the broadest spectrum beta lactams available which were previously a last resort.

198
Q

What makes HIV such a successful virus?

A
  • sexually transmitted
  • dormant
  • affects the immune system = infections and malignancy
  • Mutability: replicates with mutations 50% of the time, so escapes recognition by the immune system/designed drug
199
Q 
HIV replication
describe the process of HIV replication in CD4 T cells:
1. Attachment/entry
2. Uncoating
3. Reverse transcription
4. Genome integration
5. Transcription of viral DNA
6. Splicing mRNA and translation into protein
7. Assembly
8. Budding
A
  1. Attachment/entry: HIV in plasma recognises CD4 receptor and fuses
  2. Uncoating: viral coat is shedded
  3. Reverse transcription: protein capsid enters cell and viral RNA converted to viral DNA by reverse transcriptase
  4. Genome integration: viral DNA integrated into CD4 nucleus
  5. Transcription of viral DNA: production of new viral contents
  6. Splicing mRNA and translation into proteins - used cells material to make new chains of HIV proteins
  7. Assembly of new virions: leaves nucleus and is repackaged
  8. Budding: buds from CD4 cell with some of CD4 membrane to form new HIV
200
Q

Describe the passage of HIV on entering the vaginal mucosa.

How is able to infect the T cells?

A

First cell it meets is macrophage, aimed to destroy it.
The macrophage ingests antigens, processes them and presents them to the T cell in the lymph nodes.
HIV is thus able to infect the T cell.
This process represents the time lag between exposure and the point at which individual is infectious.
The body then produces its immune response, after which comes the clinical latency period.

201
Q

What are the characteristics of HIV in its progression to AIDs, in terms of T cells?

A

Progressive decline in number and function of CD4 T-lymphocytes leading to susceptibility to infection.

202
Q

Why is HIV so hard to remove from the body even with effective supression with treatment?

A

Reservoirs of HIV replication remain, acting as sanctuary sites housing HIV.

203
Q

Describe the progression of HIV to AIDs. (4 stages)

What symptoms may each stage present with?

A
  1. Acute HIV syndrome(seroconversion). From no antibody to antibody production. Symptoms similar to flu/glandular fever. (fever, sore throat, myalgia, rash… some V+D, weight loss, headache…)
  2. Clinical latency - no symptoms (some have persistant generalised lymphadenopathy)
  3. Early symptomatic HIV: susceptibility to common bacterial, viral, fungal, auroimmune and constitutional problems
  4. Acquired Immune Deficiency Syndrome: a CD4 count of less than 200, OR AIDs defining illness present
204
Q

Give examples of AIDs defining illnesses?

A

Pneumocystitis pneumonia (PCP)
TB
CNS problems - mass lesions, meningitis, mass lesions
Cancers - HIV increases risk of any cancer associated with a virus (HPV, herpes, hep b/c, epstein barr)

205
Q

What drugs are currently used in HIV management

A

HAART - 3+ anti retroviral drugs

Act on diff points in HIV replication cycle to suppress the virus

206
Q

Describe Pneumocystitis pneumonia (PCP), a common opportunistic infection associated with AIDs

A

Fungal opportunistic infection, leads to global inflammation.
Presents with exertional drop in O2 sats.
Fevers, SOB, x-ray shows white (fluid)
INduced sputum sample needed to flag up PCP.

207
Q

HIV mutates 1 in every 2 new viruses produced. Triple therapy is effective against this - but what factors can lead to drug resistance?

A
  1. Non-adherance

2. Drug-drug interactions

208
Q

what are the 4 possible outcomes of acute inflammation?

A

Resolution
Suporation (pus)
Organisation (into scar tissue/fibrosis)
Progression to chronic inflammation

209
Q

Causes of acute inflammation:

give an example of each

A
  1. Bacterial -
  2. Toxins
  3. Chemical
  4. Physical
  5. Hypersensitivity
  6. Tissue necrosis

Phase 2 (16 decks)

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