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

ICS - Pathology, Immunity and Pharmacology Flashcards

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
Q

What is the difference between resolution and repair?

A

Resolution is when the initiating factor is removed and the tissue is able to regenerate. In repair, the initiating factor is still present and the tissue is unable to regenerate.

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26
Q

Name 5 types of cells capable of regeneration.

A
  1. Hepatocytes.
  2. Osteocytes.
  3. Pneumocytes.
  4. Blood cells.
  5. Gut and skin epithelial cells.
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27
Q

Name 2 types of cells that cannot regenerate.

A

Myocardial cells
Neurons

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28
Q

Define abscess.

A

Acute inflammation with a fibrotic wall.

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29
Q

Define thrombosis.

A

Formation of a solid mass from blood constituents in an intact vessel in the living.

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30
Q

Give 2 reasons why thrombosis formation is uncommon.

A

Laminar flow of blood
Endothelium is non-sticky

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31
Q

What are the 3 factors that can lead to thrombosis formation (virchow’s Triad)

A
  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)
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32
Q

Define embolus.

A

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.

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33
Q

Define ischaemia.

A

Decreased blood flow to tissues w/o other complications

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34
Q

Define infarction.

A

Decreased blood flow to a tissue that results in subsequent cell death.

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35
Q

Define Acute inflammation

A

Initial Response to tissue injury
Inflammation that is:
sudden onset,
lasts for a short duration and usually resolves
Involves Neutrophils and Monocytes

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36
Q

How do bacteria and viruses cause harm?

A

Bacteria - release exo/endotoxins that initiate the inflammatory pathways

Viruses - Intracellular replication causes cell death

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37
Q

What processes do the endogenous chemical mediators lead to?

A

Vasodilation
chemotaxis
increased vascular permeability
itching and pain

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38
Q

What are the main cell types in acute inflammation?

A

Neutrophil polymorphs
Macrophages
Fibroblasts
Endothelial cells
Lymphocytes

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39
Q

What are the main cell types in chronic inflammation?

A

Macrophages
Lymphocytes
Plasma cells

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40
Q

What is a multinucleated giant cell?

A

The cell that forms when several macrophages try to ingest the same pathogen and end up fusing together.

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41
Q

What are some differences between acute and chronic inflammation?

A

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

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42
Q

What is resolution?

A

Tissue restored to normal pre injury state tissue architecture is undamaged
tissue initiating factor is removed

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43
Q

What is lobar pneumonia

A

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

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44
Q

What is healing by first intention?

A
  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.
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45
Q

What is healing by second intention?

A

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.

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46
Q

What are the constituents of a thrombus?

A

Platelets. Red blood cells, fibrin.

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47
Q

What are the stages of thrombosis?

A

Vasospasm
Platelet aggregation - VWF binds exposed collagen and platletes bind to this via GP1b. Then platelets aggregate by binding to each other through GP2a/3b
Clotting cascade.

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48
Q

What clotting facotrs make up the intrinsic, extrinsic and common coagulation cascade?

A

Intrinsic - 12, 11, 9, 8
Extrinsic - 3, 7

Common - 10 , 5, 2, 1

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49
Q

What is the Role of platelets?

A

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

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50
Q

What stimulates platelet aggregation?

A

Endothelial damage changes localised blood flow from laminar to turbulent.
Platelets come into contact with the endothelium and stick.

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51
Q

What are the different types of thrombosis and what causes them?

A

Arterial thrombosis - atherogenesis
Venous thrombosis - venous stasis

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52
Q

How would you treat an arterial and venous thrombosis?

A

Arterial thrombosis - Antiplatelets
Venous Thrombosis - Anticoagulants

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53
Q

What are the clinical features of an arterial and venous thrombus?

A

Arterial thrombi:
Loss of pulse distal to thrombus
Area becomes cold, pale and painful
Possible gangrene

Venous thrombi:
Tender
Area becomes reddened and swollen

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54
Q

What are the fates of a thrombosis?

A

Resolution - thrombus degrades and returns to normal
Organisation - Leaves scar tissue behind
Embolism - fragments of thrombi break off and get lodged in the circulation

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55
Q

Define embolism.

A

A solid mass in the blood vessel which causes a blockage to the vasculature.

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56
Q

What happens to an embolus if it enters the venous system?

A
  • 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
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57
Q

What happens to an embolus if it enters the arterial system?

A

It will travel anywhere downstream of its entry point

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58
Q

Where may an infarct have a reduced impact?

A

on areas with a dual blood supply
Brain,
Liver
Lungs

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59
Q

what is an atheroma?

A

Focal thickening of the tunica intima arteries produced through the movement of ldls from the lumen.

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60
Q

How is an atheroma formed?

A

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.

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61
Q

What is atherosclerosis?

A

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

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62
Q

What is a foam cell?

A

Where a macrophage has phagocytosed LDL

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63
Q

What is an atherosclerotic plaque made up of?

A

Fibrous tissue
Lipid component - Cholesterol
Lymphocytes
FOAM cells

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64
Q

What are the stages of atherosclerotic plaque formation?

A
  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
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65
Q

How does Atherosclerosis compare in a high and low-pressure vessel?

A

Atherosclerosis is never present in low pressure systems (pulmonary circulation) -but will form in high pressure vessels such as the systemic circulation

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66
Q

Name some system specific complications of atherosclerosis.

A
  • 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
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67
Q

why does aspirin help a patient if they have atherosclerosis?

A

Aspirin inhibits platelet aggregation, therefore reducing plaque formation.

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68
Q

What are the risk factors for atherosclerosis?

A

Age
gender
FHx
smoking
sedentary lifestyle
High cholesterol
Hyperlipidaemia
Hypertension
Diabetes

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69
Q

Define apoptosis

A

Non inflammatory programmed cell controlled death.

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70
Q

What are the steps of apoptosis?

A

Pyknosis - nucleus condenses
Blebs form - cell membrane becomes irregular
Apoptotic bodies form
cell membrane breaks off into fragments for easy phagocytosis

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71
Q

What are the mediators of apoptosis?

A

Caspases

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72
Q

What regulates the activity of caspases?

A

Intrinsic:
Bcl2 family of enzymes:
Bcl2 - inhibits apoptosis
Bax - promotes apoptosis

Extrinsic:
Fas
Binding of Fas ligand to the fas receptor induces apoptosis

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73
Q

What is necrosis?

A

Inflammatory unprogrammed traumatic cell death that induces inflammation and repair.

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74
Q

What are the different types of necrosis?

A

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)

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75
Q

Give 3 differences between apoptosis and necrosis.

A

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.

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76
Q

Define genetic disease.

A

A genetic disease is one that occurs primarily from a genetic abnormality.

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77
Q

Define congenital disease.

A

A disease which is present at birth.

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78
Q

Define inherited disease.

A

Caused by inherited genetic abnormality, it may not manifest itself until later life.

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79
Q

Define an acquired disease.

A

Caused by non genetic environmental factors that usually occurs after birth.

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80
Q

Define atrophy.

A

Decrease in tissue size caused by the decreased in number of constituent cells or a decrease in their size.

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81
Q

Define hypertrophy.

A

Increase in tissue size caused by an increase in the size of the constituent cells.

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82
Q

Define hyperplasia.

A

Increase in tissue size caused by an increase in the number of the constituent cells.

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83
Q

Define metaplasia.

A

Change in differentiation of a cell from one fully differentiated type to a different fully differentiated type.

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84
Q

Define dysplaysia.

A

Morphological changes seen in cells in the progression to becoming cancer.

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85
Q

Define carcinogenesis

A

The transformation of normal cells to neoplastic cells through permanent genetic alterations or mutations
This is a multistep process

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86
Q

What is a carcinogen?

A

A mutagenic agent known to cause cancer

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87
Q

Define carcinogenic?

A

Cancer causing

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88
Q

Define Oncogenic?

A

Tumour causing

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89
Q

Define oncogenesis?

A

The process by which normal cells transform into neoplastic cells

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90
Q

What is a neoplasm?

A

An autonomous abnormal persistent new growth that continues to grow after the initial growth stimulus has been removed.

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91
Q

What can neoplasms arise from?

A

They can only arise from nucleated cells
(eg. not RBCs but could arise from their precursors)

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92
Q

What is a tumour?

A

Any abnormal swelling

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93
Q

What percentage of cancer risk is environmental?

A

85%

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94
Q

What host risk factors will increase the risk of cancer?

A

Race
Diet
Sex
Age
Inherited predisposition
premalignant conditions
Transplacental exposure

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95
Q

Give examples of how race can affect cancer risk?

A

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.

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96
Q

Give some examples of inherited predispositions that will increase cancer risk?

A

Familial polyposis coli - increase risk of bowel cancer

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97
Q

Give some examples of premalignant conditions that will increase the risk of cancer?

A

Colonic polyps
Ulcerative colitis
Undescended Testis

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98
Q

Give an example of how transplacental exposure increased the risk of cancer

A

The daughters of moths who took diethylstilboestrol for morning sickness had and increased risk of developing vaginal cancer

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99
Q

Name 5 different categories of carcinogens?

A

Viral
Chemical
Ionising and non-ionising radiation
Hormones, parasites and mycotoxins
Miscellaneous

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100
Q

Give some examples of viruses that cause cancer?

A

Hepatitis B anda C - HCC
HHV8 (human herpes virus 8) - kaposi sarcoma
HPV - Squamous cell carcinoma
EBV - Burkitts Lymphoma
HIV - cerebral lymphoma

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101
Q

How can hormones cause cancer?

A

increase in oestrogen can cause endometrial cancer

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102
Q

What parasite can cause cancer?

A

Shistosoma causes bladder cancer

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103
Q

What miscellaneous materials can cause cancer?

A

Asbestos
Metals - arsenic

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104
Q

What type of cancer do polyaromatic hydrocarbons cause and what exposes people to these?

A

Lung and skin cancer

Smoking and mineral oils

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105
Q

What cancer do aromatic amines cause?

A

bladder cancer

People who work with dye or rubber

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106
Q

What cancer do nitrosamine cause?

A

Gut cancer

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107
Q

What type of cancer do alkylating agents cause?

A

Leukaemias

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108
Q

Define Neoplasia?

A

A lesion resulting from new and abnormal tissue growth which persists independent of its initiating stimulus.

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109
Q

What are the two types of neoplasia?

A

Benign and malignant

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110
Q

How can neoplasias be classified?

A

By behaviour
By histogenesis

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111
Q

What is a benign tumour?

A

Slow growing - low mitotic activity
Well circimuscribed - no invasion to surrounding tissue
Resemble cell origin - rarely necrose or ulcerate
Exophytic - grow outwards

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112
Q

what are some long-term effects of benign tumours?

A

Pressure on adjacent tissues
Obstruction of ducts/hollow organs
produce hormones
Can be pre-malignant
Anxiety

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113
Q

What are the features of a malignant tumour?

A

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.

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114
Q

What are some complications of malignant tumours?

A

Pressure on adjacent structures
form secondary tumours
Obstructory
very painful
blood loss

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115
Q

What is the structure of a neoplasm?

A

Neoplastic cell
Stroma

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116
Q

What are neoplastic cells?

A

Always derived from nucleatedcells
Usually monoclonal
Growth pattern related to parent cell
Synthetic activity related to parent cell - eg. hormone producing.

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117
Q

What is the stroma of a neoplasm?

A

Supported by connective tissue framework that provides mechanical and nutritional support. usually blood vessels.

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118
Q

What factors promote angiogenesis?

A

VEGF
Fibrobalst growth factor

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119
Q

What is the behavioural classification of neoplasms?

A

Benign
Borderline - defy precise classification
Malignant

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120
Q

What are the main histological classifications of tumours?

A

epithelial
Connective tissue
Lymphoid
Haematopoietic

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121
Q

What cancer does not have a stroma?

A

Leukaemia

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122
Q

What is a benign non-glandular eplithelial neoplasm called?

A

Papilloma

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123
Q

What is a benign glandular epithelial neoplasm called?

A

Adenoma

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124
Q

What is a malignant epithelial neoplasm?

A

Carcinoma

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125
Q

What is a carcinoma?

A

A malignant epithelial neoplasm

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126
Q

What is the suffix for malignant connective tissue neoplasms?

A

Sarcoma

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127
Q

What is a benign neoplasm of adipocytes?

A

Lipoma

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128
Q

What is a benign neoplasm of adipocytes?

A

Lipoma

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129
Q

What is a benign neoplasm of Cartilage?

A

Chondroma

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130
Q

What is a benign neoplasm of bone

A

Osteoma

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131
Q

What is a benign neoplasm of vasculature?

A

Angioma

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132
Q

What is a benign neoplasm of striated muscle

A

Rhabdomyoma

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133
Q

What is a benign neoplasm of smooth muscle

A

Leiomyoma

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134
Q

What is a benign neoplasm of nerves

A

Neuroma

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135
Q

What is a well-differentiated tumour?

A

A tumour that closely resembles normal tissue.
These have a lower grade and tend to have a better prognosis.

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136
Q

If a neoplasm doesnt resemble normal tissue what is it said to be?

A

Poorly differentiated
higher grade and would carry a worse prognosis

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137
Q

What does the term anaplastic mean?

A

When the cell type of origin is unknown the tumour is anaplastic

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138
Q

What is a melanoma?

A

A malignant neoplasm of melanocytes

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139
Q

What is a mesothelioma?

A

A malignant neoplasm of mesothelial cells

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140
Q

What is a lymphoma?

A

A malignant neoplasm of lymphoid cells

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141
Q

What is burkitts lymphoma?

A

A B cell malignancy caused by EBV

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142
Q

What is kaposi sarcoma?

A

A vascular endothelial malignancy caused by Human herpes virus 8 and related to HIV

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143
Q

What is ewings sarcoma?

A

A bone malignancy

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144
Q

is a teratoma?

A

A cancer of all 3 embryonic germ layers

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145
Q

What is a blastoma?

A

A tumour of an embryo

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146
Q

What is the pathway of metastasis?

A
  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
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147
Q

What are the different methods of spread of a metastasis?

A

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

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148
Q

What are the characteristics of a neoplastic cell?

A

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.

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149
Q

What cancers commonly spread to bone?

A

BLT KP
Bladder
Lung
Thyroid
Kidney
Prostate

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150
Q

What is a neoplasm in situ?

A

When a neoplasm has proliferated but has not broken through the basement membrane to other tissues

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151
Q

When is a cancer considered to be invasive?

A

When it has breached its own tissue type into another area

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152
Q

What is a micro-invasive carcinoma?

A

A carcinoma that has only just broken through the basement membrane

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153
Q

What is invasion of a cancer dependent on?

A

Decreased cellular adhesion
abnormal increased cellular motility
Production of lytic enzymes to breakdown surrounding tissue

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154
Q

Define metastasis

A

The process by which a malignant neoplasm spreads from its primary site to produce secondary neoplasms at distant sites.

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155
Q

How do tumours invade surrounding tissues?

A

Proteases break down tissue surrounding neoplasm

tumour cell derived motility factors allow it to invade

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156
Q

How do tumours enter and exit blood vessels
(intravasion)

A

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

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157
Q

How do neoplasms evade host defenses?

A

Aggregation with platelets
Shedding of surface antigens
Adhesion to other tumour cells

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158
Q

Why do malignant tumours often have a necrotic centre?

A

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.

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159
Q

What are some angiogenesis inhibitors?

A

Angiostatin
Endostatin
Vasculostatin

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160
Q

Describe the process for metastasis to the lung?

A
  • 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
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161
Q

Describe the process for metastasis to the liver?

A
  • 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.
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162
Q

What cancers are screened for in the UK?

A

Cervical
Breast
Colorectal

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163
Q

Eosinophillic granulomas would be an indication of what?

A

Parasitic infection

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164
Q

What cells are polymorphonuclear leukocytes?

A

Neutrophils
Eosinophils
Basophils

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165
Q

What cells are the mononuclear leukocytes?

A

Monocytes
T cells
B cells

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166
Q

Where is complement secreted from?

A

The liver

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167
Q

What are the 3 modes of action for complement?

A

Direct lysis - MAC
Chemotaxis - attract more leukocytes
Opsonisation - coat invading organisms

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168
Q

How can antibodies circulate in the blood

A

Bound to B cells
Free in plasma

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169
Q

Which part of the strucutre of an antibody is responsible for antigen binding?

A

FAB regions
Variable in sequence
Bind to specific antigens

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170
Q

What part of the structure of an antibody is responsible for antigen elimination?

A

Fc region
Constant sequence
binds to complement, Fc receptors on phagocytes or NK cells

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171
Q

What are the 5 classes of antibodies?

A

IgG
IgM
IgA
IgE
IgD

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172
Q

What is the structure, where it is found and its function for the IgG class of antibody?

A

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

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173
Q

What is the structure, where it is found and its function for the IgM class of antibody?

A

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

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174
Q

What is the structure, where it is found and its function for the IgA class of antibody?

A

Dimer
Found at mucosal surfaces (secretory Ig)
also found in serum

First line of defence

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175
Q

What is the structure, where it is found and its function for the IgE class of antibody?

A

50% found in blood. the rest bound to mast cells or basophils

Responsible for hypersenitivity reactions and anaphylaxis.
Important in parasitic infections

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176
Q

What is the structure, where it is found and its function for the IgD class of antibody?

A

Found on mature B cells
No effector functions identified

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177
Q

What are the different mechanisms of action of antibodies?

A

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

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178
Q

What are cytokines?

A

Proteins secreted by immune and non-immune cells

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179
Q

What do interferons do?

A

Induce a stateof viral resistance in uninfected cells and limit the spread of viral infection

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180
Q

What are the 3 types of interferons and which cells secrete them?

A

IFN alpha and beta
produced by virus-infected cells

IFN gamma
Produced by activated Th1 cells and this activates Macrophages

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181
Q

What do interleukins do?

A

Can be proinflammatory or anti-inflammatory

Cause cells to divide, differentiate and secrete factors

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182
Q

What do colony stimulating factors do?

A

Direct the division and differentiation of bone marrow stem cells

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183
Q

what do tumour necrosis factors do?

A

TNF alpha and beta
Mediate inflammation and cytotoxic reactions

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184
Q

What are chemokines?

A

proteins that direct the movement of cells from the blood stream to the tissues.

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185
Q

What is innate immunity

A

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

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186
Q

What physical and chemical barriers are involved in the innate immune response

A

Physical barriers - skin, mucus, cilia
Chemical barriers - lysozymes in tears, stomach acid

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187
Q

What are pattern recognition receptors?

A

Receptors on immune cells that detect the presence of PAMPs

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188
Q

PAMPS and DAMPS?

A

Pattern-associated molecular patterns
Damage associated molecular patterns

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189
Q

What are Toll-like receptors?

A

A type of PRR that recognise structurally conserved molecules derived from microbes.

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190
Q

What is the TLR responsible for detecting Gram +tve Bacteria and Lipoteichoic acid/peptidoglycan?

A

TLR 2

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191
Q

What is the TLR Responsible for detecting Gram Negative Bacteria and Lipopolysaccharide (LPS)

A

TLR-4

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192
Q

What components make up the innate immunity?

A

Physical and chemical barriers
Phagocytic cells -neutrophils, macrophages
Blood proteins - complement, acute phase proteins.

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193
Q

How can physical barriers be breached for allowing pathogens to entre the body?

A

Tissue trauma
Infection

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194
Q

What are the steps to the whole inflammatory response?

A
  • 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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195
Q

What are 3 features of inflammation?

A

Increased blood supply
Increased Vascular permeability
Increased leukocyte extravasation

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196
Q

What cells detect presence of antigens in the blood?

A

Monocytes
neutrophils

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197
Q

What cells detect the presence of antigens in the tissues?

A

Macrophages
DCs

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198
Q

What are the 3 activation pathways for the complement system?

A

Classical - antibody binds to microbe

Alternative - C’ binds to microbe

Lectin - activated by mannose-binding lectin bound to a microbe.

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199
Q

What are the 3 mechanisms of action of complement?

A

Direct lysis - Membrane attack complex (MAC)

Chemotaxis - C3a and C5a

Opsonisation - coat microbes to make them easier to phagocytose (C3b)

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200
Q

Describe the process of Extravasation of neutrophils in acute inflammation

A
  1. E-selectin (an adhesion molecule on the capillary endothelium), is activated by IL-1 and TNF-α from damaged cells and binds to the glycoprotein CD15 on neutrophils in blood.
  2. This causes neutrophils in the blood to slow down and roll along the endothelium lining.
  3. ICAM-1 on endothelium (induced by LPS, IL-1, TNF-α) binds to integrin on neutrophil; the neutrophil stops.
  4. Diapedesis: neutrophil squeezes through endothelium (holes caused by C3a, C5a, chemokines, histamines, prostaglandins, leukotrienes (causing smooth muscle contractions in the bronchioles))
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201
Q

What are 3 ways phagocytosis can be initiated?

A

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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202
Q

What are the main steps in phagocytosis?

A

Binding
Engulfment (phagosome)
Phagolysosome
bacterial killing
clear debris

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203
Q

What are the 2 pathways that neutrophils and macrophages use to kill microbes?

A

Oxygen dependent

Oxygen independent

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204
Q

What is oxygen dependent killing of microbes?

A

Uses ROI (reactive oxygen intermediates)
Superoxide ions are converted to H2O2 and then to a hydroxide free radical

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205
Q

What is the oxygen independent mechanism of killing microbes?

A

Enzymes - lysozymes
proteins - defensins
pH
TNF

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206
Q

What are the 3 outcomes of phagocytosis?

A

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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207
Q

What cells are APCs (antigen presenting cells)?

A

Dendritic cells
Macrophages
B cells

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208
Q

What is the function of a neutrophil?

A

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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209
Q

What is the function of macrophages?

A

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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210
Q

What is the function of eosinophils?

A

Contain MBP
Often in response to a parasitic infection.

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211
Q

What is the function of Basophils and mast cells?

A

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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212
Q

What is the function of a natural killer cell?

A

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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213
Q

What is the function of a dendritic cell?

A

These cells act as APCs and provide an interface between the innate and adaptive immune system.

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214
Q

What are the 3 conditions that must be met to enable antigen presenting to function?

A

Primary receptor binding
co-stimulation molecules
Cytokine release

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215
Q

What does TLR 1 detect?

A

Gram positive bacteria

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216
Q

What does TLR 2 detect?

A

Gram positive bacteria such as lipopeptides, lipoteichoic acid

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217
Q

What does TLR 3 detect?

A

Endogenous viral infection and tissue necrosis
Responds to ds RNA

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218
Q

What does TLR 4 detect?

A

Gram Netagive Bacteria
detects endotoxin such as LPS

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219
Q

What does TLR 5 detect?

A

Flagellin

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220
Q

What does TLR 7 detect?

A

Single stranded RNA

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221
Q

What does TLR 8 detect?

A

Viral and bacterial pathogens
Important for detecting pyogenic bacteria

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222
Q

What does TLR 9 detect?

A

Non-methylated DNA

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223
Q

What is the adaptive immune response?

A

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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224
Q

Why do we need an adaptive immune response?

A

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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225
Q

Which part of the immune system deals with intracellular and extracellular microbe

A

B cell (humoral - antibody) - extracellular

T cell (cell-mediated) - Intracellular

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226
Q

To recognise self from non-self what is required?

A

MHC proteins

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227
Q

What do T lymphocytes respond to?

A

Intracellular presented antigens

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228
Q

Where do T cells mature?

A

In the thymus

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229
Q

Where do B cells mature?

A

In the bone marrow

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230
Q

What is Thymic central tolerance?

A

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

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231
Q

What is the common T cell marker?
What is the Marker of T cell activation?

A

CD3
CD25

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232
Q

Where is MHC I found?

A

On all nucleated cells

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233
Q

Where is MHC II found?

A

On APCs Only

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234
Q

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?

A
  • MHC Class I
  • All cells express MHC Class I (except for red blood cells) (everyone expresses MHC Class one
  • Tcytotoxic (CD8) cells
  • Kill infected cell with intracellular pathogen directly
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235
Q

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?

A
  • 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
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236
Q

What is required for full T cell activation?

A

Co-stimulatory molecules CD28 on the T cell binds to CD80/CD86 on the APC to fully activate the T cell

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237
Q

What is secreted from an activated T cell?

A

IL2
binds to the T cell receptor (autocrine)

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238
Q

What does T cell activation lead to?

A

Division
Differentiation (to CD4 or CD8)
Effector functions
Memory

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239
Q

What determines whether a T cell will differentiate into a Th1 or Th2 CD4 T cell?

A

Levels of IL-12
High IL-12 = Th1
Low IL-12 = Th2

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240
Q

What is the function of a Th1 CD4 T cell?

A

Travel to secondary lymphoid tissue
Secrete IFN gamma to help kill intracellular antigens

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241
Q

What is the function of a Th2 CD4 T-cell?

A

Binds to a B cell presenting an antigen and stimulates B cell divide (clonal expansion) and differentiation
Secretes IL-4 to stimulate differentiation

242
Q

What is the function of a Cytotoxic CD8 T cell?

A

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

243
Q

Which membrane bound antibodies do B cells Express?

A

IgM or IgD monomers

244
Q

How many types of antibodies can an individual B cell make?

A

1 Antibody specific to 1 antigen.

245
Q

What happens if a B cell recognises self?

A

The B cell is killed in the bone marrow

246
Q

How do B cells act as APCs?

A

Phagocytose the pathogen
Present the epitope on MHC II
Tcell binds to MHC II
lots of costimulatory molecules required such as CD80 and CD86

247
Q

How is a B cell activated?

A

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

248
Q

What is the Mature B cell marker?

A

CD20

249
Q

What is B cell somatic hypermutation?

A

A cellular mechanism where the immune system adapts to new foreign elements that confront it

250
Q

What is B cell class switching?

A

Where an activated B cell changes its Ab production from IgM to either IgE, IgA or IgG depending on the functional requirements

251
Q

What causes Somatic hypermutation?

A

AID
Activation induced Cysteine deaminase

252
Q

What interleukin promotes class switching from IgM to IgA and IgE?

A

IL-4

253
Q

What chromosome is the MHC protein found on?

A

Chromosome 6

254
Q

What is the role of Tregs?

A

Regulatory T cells
These are important in immune tolerance and ensuring T cells are not autoreactive

255
Q

What interleukin stimulates a naive T cell to become a Treg?

A

TGF-b and IL-2
Tregs secrete IL-10 which is anti-inflammatory

256
Q

What Interleukin stimulates a naive T cell to become a Th17?

A

IL-17

257
Q

What is passive immunisation?

A

The transfer of pre-formed antibodies

258
Q

What are the two types of passive immunisation?

A

Natural - Transfer of preformed maternal antibodies across the placenta or through breast milk

Artificial - Treatment with pooled normal human IgG (immunoserum)

259
Q

What would artificial immunisation be effective against?

A

Individuals with immunocompromisation
No time for active immunisation - against pathogens with a short incubation time
Anti-toxins or anti-venoms

260
Q

What are the disadvantages of passive immunisation?

A

Does not provide immunological memory - no long term protection
IgG is cleared form the circulation

261
Q

How do toxins act on a nerve cell to produce toxic effects?

A

Toxin prevents fusion of vesicles at the synapse so the neurotransmitters cannot get into the synapse

262
Q

How does tetanus toxin act on the synapse?

A

Tetanus toxin inhibits the release of inhibitory neurotransmitters GABA and Glycine which prevents muscle relation
It causes muscle contraction and spasticity

263
Q

How does Botulinum toxin act on the synapse?

A

Botulinum vesicles contain ACh which prevents muscle contraction
It causes muscle relaxation and flaccidity

264
Q

What is active immunisation?

A

Manipulation of the immune system to generate a persistent protective response against pathogens by mimicking natural infection

265
Q

What is the difference between innoculation and active immunisation?

A

Inoculation refers to the introduction of viable microorganisms into the individual to evoke an immune response

266
Q

What are the advantages of active immunisation?

A
  • Mobilises immune system to generate immunological memory - B and/or T cell memory
  • Learned immunological behaviour → faster response
267
Q

What are the stages of active immunisation?

A

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

268
Q

What are the primary and secondary responses of active immunisation?

A

Initial response:
Relies on innate system
IgM predominates
Low affinity

Secondary response:
Rapid and large
High affinity IgG
Somatic hypermutation

269
Q

Give an example of an artificial active immunity

A

Vaccinations

270
Q

What are the different antigen options used in vaccines?

A

Whole organism - live attenuated or killed/inactived
Subunit - toxoids, antigenic extracts, recombinant protein
Peptides
DNA/RNA
Engineered virus

271
Q

Give examples of a whole organism vaccination

A

Live attenuated - TB, Typhoid
Killed/inactivated - Influenza, Hep A

272
Q

What are the advantages and disadvantages of Live attenuated vaccinations?

A

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

273
Q

What are the advantages and disadvantages of dead/inactivated Vaccinations?

A

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

274
Q

What is an adjuvant

A

Any substance added to a vaccine to stimulate an enhanced immune response

275
Q

Give an example of an adjuvant and explain how it functions

A

Aluminium salts:
Activate macrophages and lymphocytes
help APCs absorb antigen
extend the presence of antigen in the blood
potentiate opsonised phagocytosis

276
Q

What cells are involved in the cell mediated immune repsonse?

A

Neutrophils and monocytes
Lymphocytes (T and B cells)

277
Q

What is involved in the non-cellular humoral immune response?

A

Immunoglobulins (antibodies)
complement
Surfactant proteins

278
Q

What immunoglobulin is made at the beggining of an infection?

A

IgM

279
Q

What immunoglobulin is in high abundance upon second exposures?

A

IgG specific antibodies

280
Q

What immunoglobulin is often involved with an allergic reaction?

A

IgE

281
Q

What are the common features of anaphylaxis?

A

Rapid onset
Blotchy rash
Swelling of face and lips
Hypotension
Wheeze
Cardiac arrest if severe

282
Q

What drugs can commonly cause hypersensitivity reactions?

A

Amiodarone
Bleomycin
Methotrexate
NSAIDs
Nitrofurantoin
Novel Ig treatments

283
Q

Describe a Type 1 hypersensitivity Reaction

A

> 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.

284
Q

Give example of type 1 hypersensitivity reactions

A

Allergic Rhinitis (hayfever)
asthma
Nut,food and drug allergies

285
Q

What is Atopy?

A

An inherited tendency to produce an exaggerated IgE response to an antigen
(hayfever, eczema, Asthma)

286
Q

How are type one hypersensitivity reactions diagnosed?

A

Skin prick tests
Radioallergosorbent Tests (RASTs)

287
Q

What is the treatment for hayfever?

A

Prevent exposure
Anti-histamines
steroids - reduce local inflammation
Desensitisation therapy - controlled, gradually increased exposure to the antigen

288
Q

What is the treatment for acute anaphylaxis

A

Adrenaline 500mg IM (intramuscularly)

if necessary:
Antihistamines - Chlorphenamine
Cortisol - hydrocortisone

289
Q

Describe a Type 2 hypersensitivity reaction

A

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.

290
Q

What can cause Type 2 hypersensitivity reactions?

A

Transplant rejection
Autoimmune diseases

291
Q

Describe a Type 3 Hypersensitivity reaction?

A

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

292
Q

Give examples of Type 3 hypersensitivity reactions?

A

Systemic Lupus Erythematosus (SLE)

Post strep glomerulonephritits

Rheumatoid Arthritis

293
Q

Describe a Type 4 hypersensitivity reaction?

A

> 1️⃣ CD4 and T-helper cells recognise antigens in complex with MHC class II on the surface of APCs.

> 2️⃣ The APC (commonly macrophages or monocytes) secrete IL-12 which stimulates the proliferation of CD4+TH-1 cells and their release of IL-2 and INF-y

> 3️⃣ IL2 and INF induce further TH-1 cytokine release.

> 4️⃣ Immune response leads to the activation of; CD8 T-cells - destroy target cells on contact; macrophages - produce hydrolytic enzymes and transform into multinucleated giant cells on presentation with certain intracellular pathogens

294
Q

Give examples of Type 4 hypersensitivity reactions?

A

TB
Contact dermatitis
Sarcoidosis

295
Q

What is involved in the diagnosis of drug hypersensitivity reactions?

A

Lung function tests
CT scans
Chest X rays

296
Q

What is involved in the treatment of drug hypersensitivity reactions?

A

Withdraw offending drug
Give steroids for severe respiratory failure

297
Q

What is autoimmunity?

A

Pathological response verses self antigens.
Caused by faulty immune tolerance or molecular mimickry

298
Q

Give examples of organ specific Autoimmune disease?

A

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

299
Q

Give some non organ specific autoimmune diseases

A

Systemic Lupus Erythematosus
Autoimmune Haemolytic Anaemia
Immune Thrombocytopenic purpura
Rheumatoid Arthritis

300
Q

Name different types of drug interactions

A

Synergism
Antagonism
Summation
Potentiation

301
Q

Define synergism?

A

Interaction of 2 compounds leads to a greater combined effect
(1+1>2)

302
Q

Define Antagonism

A

Interaction of 2 compounds where one may block another from working so the overall net effect is 0
(1+1=0)

303
Q

Define Summation

A

Interaction of 2 compounds with similar pharmacodynamics combine to give an increased expected effect
(1+1=2)

304
Q

Define Potentiation

A

Where one compound may increase the potency of another drug without affecting its own state
(1+1=1+1.5)

305
Q

What are some host risk factors for drug interactions?

A

Old age
Polypharmacy
Genetics
Hepatic Disease
Renal Disease

306
Q

What are some drug risk factors for drug interactions?

A

Drugs with a narrow therapeutic index
Drugs with a steep dose response curve
Drugs with a saturable metabolism

307
Q

Name some mechanisms through which drug interactions can take place?

A

Pharmacokinetic mechanism
Pharmacodynamic mechanism

308
Q

What are the 2 major routes of drug administration?

A

Enteral - Gut involved (eg. oral)
Parenteral - Bypasses the gut (eg. IV, IM, SC)

309
Q

Define Pharmacokinetics

A

What happens to the drug within the body

310
Q

What are the different pharmacokinetic mechanisms?

A

ADME
Absorption
Distribution
Metabolism
Excretion

311
Q

What factors affect a drugs absoprtion?

A

Gut motility
Acidity
Solubility
Complex formation
Direct action on enterocytes

312
Q

What factors affect drug distribution?

A

Protein binding
Chemical properties (water soluble/lipid soluble)
Blood flow to area

313
Q

What factors affect a drugs metabolism?

A

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

314
Q

What factors affect a drugs excretion?

A

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)

315
Q

How are drugs metabolised?

A

By the liver mostly
Phase 1 - microsomal enzymes increase reactivity by adding groups
Phase 2 - non-microsomal enzymes conjugate compounds to increase hydrophilicity

316
Q

What is CYP450 induction/inhibition and what can affect this?

A

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

317
Q

Give an example of compounds that will inhibit CPY450/enzymes?

A

Metronidazole - inhibits Alcohol Dehydrogenase - prevents ethanol metabolism - increases drunkenness

318
Q

How do Avocado and grapefruit affect drug pharmacokinetics?

A

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

319
Q

Define Pharmacodynamics

A

The effect that a drug has on the body

320
Q

What do drugs usually target?
Give examples of different types?

A

PROTEINS!!

Receptors
Enzymes
Transporters
Ion Channels

321
Q

What are the different effects of a ligand?

A

Agonists
Partial Agonist
Antagonist - Competitive or non-competitive

322
Q

Give examples of receptor based drug interactions

A

Agonists - Alcohol + benzodiazepine at a GABA A receptor causes a summative effect

Antagonists - Beta Blockers and asthma - make asthma worse

323
Q

Give examples of how signal transduction can lead to drug interactions?

A

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

324
Q

Define Bioavailability?

A

Amount of drug taken up into systemic circulation unaltered as a proportion of the amount administered

325
Q

How can we avoid drug interactions?

A

Prescribe rationally
BNF/NICE guidelines
Ward pharmacists
Patient information leafles

326
Q

What are some important drug side effects to know?

A

Simvastatin - Rhabdomyolysis
Warfarin - bleeding
SSRIs - Serotonin syndrome
NSAID + ACEi + Furosemide - renal failure

327
Q

Define a receptor?

A

A component of a cell that interacts with a specific ligand and initiates a change in biochemical events leading to ligand-observed effects

328
Q

What is the difference between a target cell and non-target cell?

A

> 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

329
Q

What are the different types of receptors targeted by drugs?

A

Ligand gated ion channels
G-protein coupled receptors (GPCRs)
Kinase-linked receptors
Cytosolic/nuclear receptors

330
Q

How do ligand gated ion channels work and give an example?

A

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

331
Q

How do GPCRs work?

A

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

332
Q

What are the 3 types of GPCR?

A

Gs - stimulatory - activates Adenylate cyclase
Gi - Inhibitory - Inhibits Adenylate Cyclase
Gq - Activates PLC - increases IP3 and DAG

333
Q

Give examples of different GPCRs

A

Muscarinic 3 receptor - Gq GPCR
B2 Adrenoceptor - Gs GPCR

334
Q

How do kinase linked receptors work and give an example?

A

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

335
Q

How do cytosolic/nuclear receptors work and give an example?

A

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

336
Q

What is an agonist?

A

A compound that binds to a receptor to activate it
It has both affinity and efficacy

337
Q

What is an antagonist?

A

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

338
Q

What is a partial agonist?

A

A agonist which, no matter how much it is exposed to the receptor, a maximal response is never reached
Does not have full efficacy

339
Q

What are the 2 types of antagonist?

A

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)

340
Q

What is the Emax?

A

The maximum response that can be achieved
(The Efficacy)

341
Q

What is the EC50?

A

The concentration of a drug that gives half the maximal response
It tells us about potency

342
Q

What does the EC50 tell us about?

A

How potent a drug is

343
Q

Would a drug with a lower EC50 have a lower or greater potency?

A

Greater Potency

344
Q

Which is more efficacious, a full agonist or partial agonist?

A

A full agonist is more efficacious as a full agonist has the capability of inducing a 100% response.

345
Q

Define efficacy?

A

How well a ligand activates a receptor
how well it induces a conformational change

346
Q

Define Affinity

A

How well a ligand can bind to a receptor

347
Q

What are the two subtypes of Cholinergic receptors and what are their respective agonists and antagonists?

A
  • Muscarinic (mAchR) - GPCRAgonist → muscarine
    Antagonist → atropine
  • Nicotinic (nAchR) - Ion channelAgonist → nicotine
    Antagonist → curare
348
Q

What is the effect of fewer receptors on drug potency?

A

Fewer receptors will shift the dose-response curve to the right → potency reduced

349
Q

What is a receptor reserve?

A

Where an agonist needs to activate only a small fraction of the existing receptors to produce the maximal system response

350
Q

What is the effect of less signal amplificiation on drug response?

A

Less signal amplification gives a reduced drug response

351
Q

Describe allosteric modulation?

A

An allosteric modulator binds to a different site (the allosteric site) on a receptor and influences the role of an agonist.

352
Q

What is inverse agonism?

A

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.

353
Q

Define tolerance?

A

A reduction in the effect of a drug overtime
Due to continuous use, repeated use or use at high concentrations

354
Q

Describe the difference between tolerance and desensitisation

A
  • Tolerance - reduction in drug effect over time (continuously repeated high conc)
  • Desensitisation - receptors become degraded / uncoupled / internalised
355
Q

What 3 ways can a receptor become desensitised?

A

Uncoupled - agonist unable to interact with the GPCR
Internalised - The receptor is taken into the cell via endocytosis
Degraded

356
Q

What is the drug target for statins?

A

HMG-CoA reductase

357
Q

What is the action of statins?

A

Block the rate limiting step in the cholesterol pathway

358
Q

what is the end effect of statin use?

A

Lipid lowering
Prevent CVD
Reduce CVD and mortality of those at risk

359
Q

What is the Renin-angiotensin aldosterone system responsible for?

A

Blood pressure control

360
Q

What is the function of ACE inhibitors?

A

Reduces the production of angiotensin II
Reduces blood pressure

361
Q

What is the function of L-DOPA in parkinsons?

A

It is a dopamine precursor
It can freely cross the BBB and thus be given as part of a treatment for parkinsons

362
Q

What are the mechanisms of action of Co-Careldopa (carbidopa)?

A

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)

363
Q

What is the mechanism of action of tolcapone and entacapone?

A

Catechol-O-methyl transferase (COMT) inhibitor
prevents breakdown of L-DOPA and dopamine

364
Q

Can tolcapone cross the BBB?

A

Yes

365
Q

What is the mechanism of action of selegiline and rasagiline?

A

Monoamine oxidase - B (MOA) inhibitors
Prevent the breakdown of dopamine

366
Q

What are the 3 types of protein ports?

A

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

367
Q

What does amiloride act on and what is its function?

A

Epithelial sodium channel (ENaC)
Stops reabsorption of water in the kidney
Used as an antihypertensive

368
Q

What does thiazide act on and what is it function?

A

NaCl cotransporter
Stops reabsorption of water in the DCT of the nephron
Used as an antihypertensive

369
Q

What class of drug is amlodipine?

A

Angioselective calcium channel blocker

370
Q

What is the mechanism of action of amlodipine?

A

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

371
Q

What is the mechanism of action of lidocane and what class of drug is it?

A

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

372
Q

How do potassium channel blockers help in T2DM?

A

Block of potassium cause membrane depolarisation in pancreatic beta cells
opens calcium channels which cause exocytosis of insulin

373
Q

Give 3 examples of potassium channel blockers used to treat T2DM?

A

Repaglinide
Nateglinide
Sufonylureal

374
Q

What do barbiturates do and give an example of a drug in this class?

A

Phenobarbitone

GABA receptor agonists
GABA is an inhibitory ionotropic receptor

375
Q

What is the mechanism of action of digoxin?

A

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

376
Q

What do proton pump inhibitors do an give an example?

A

Omeprazole

Act on the stomach by decreasing gastric acid production by irreversible inhibition.
Decrease the pH of gastric acid

377
Q

What does the rate of metabolism determine?

A

Duration and intensity of a drugs pharmacological action

378
Q

What is Cytochrome P450?

A

Major microsomal enzyme in the liver
Most drugs are inactivated by CYP however some require CYP to be activated

379
Q

What are the different categories of opioids?

A

Naturally occurring
Simple chemical modifications
Synthetic opioids
Synthetic partial agonists

380
Q

What are the naturally occurring opioids?

A

Morphine (from the opium poppy)
Codeine

381
Q

What are the simple chemical modifications class of opioids?

A

Diamorphine (2x stronger than morphine)
Oxycodone (1.5x more potent than morphine)
Dihydrocodeine (1.5x more potent that codeine)

382
Q

What are the modern synthetic opioids?

A

Fentanyl
Alfentanil
Remifentanil

383
Q

give an example of a synthetic partial agonist opioid?

A

Buprenorphine

384
Q

What drug is the antagonist to opioids and is important to treat overdose with?

A

Naloxone - acts on the u receptor

385
Q

What percentage of oral morphine is metabolised in first pass metabolism?

A

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!

386
Q

What are the main routes of administration of opioids?

A

Parenteral:
IM
SC
IV (fastest)
Epidural
Transdermal patches - fentanyl

387
Q

What is important about IV PCA?

A

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.

388
Q

What is the difference between potency and efficacy?

A

Potency: Strength of binding affinity of the drug for the receptor
Efficacy: is it possible to get a maximal response with the drug or not?

389
Q

What is the difference between tolerance and dependence?

A

Tolerance: ↓ regulation of receptors with prolonged drug use

Dependence: what happens when you stop: physical and psychological effects

390
Q

What is the mechanism of action of opioids?

A

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.

391
Q

What is the main opioid receptor?

A

u, Mu or MOP

392
Q

What are the main side effects of opioids?

A
  1. Respiratory distress
  2. Sedation
  3. Nausea and Vomiting
  4. Constipation
  5. Itching
  6. Immune suppression
  7. Endocrine effects
393
Q

How would you treat opioid induced respiratory depression?

A

With Naloxone

394
Q

What enzyme metabolises codeine and what is it metabolised to?

A

CYP2D6 metabolises codeine to morphine
(codeine is a prodrug)

395
Q

What is morphine metabolised to?

A

Morphine-6-glucoronide (more potent than morphine)

396
Q

Describe the dose response curve to morphine

A

As dose increases response increases. This association is initially rapidly and then the graph plateaus. It is not sigmoidal!

397
Q

What is tramadol?

A

A weak opioid agonist (slightly stronger than codeine)

Also acts as a SSRi and noradrenaline reuptake inhibitor.

398
Q

What systemic effects can be controlled by manipulating cholinergic and adrenergic pathways?

A

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

399
Q

How does the structure of the Somatic NS and the Autonomic NS differ?

A
  • 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)
400
Q

What nerves are the PNS made up of?

A
  • Oculomotor (CN III)
  • Facial (CN VII)
  • Glossopharyngeal (CN IX)
  • Vagus (CN X)
  • Further outflow via sacral nerve innervations of the pelvis
401
Q

What neurotransmitter and receptor are associated with the Parasympathetic nervous system?

A

Acetylcholine acting on muscarinic receptors

402
Q

What neurotransmitter is released by the preganglionic nerve fibres within the ANS?

A

Acetylcholine acting on N2 receptors

403
Q

What neurotransmitter is released by the post ganglionic nerve fibres within the sympathetic NS?

A

Noradrenaline acting on alpha/beta adrenoceptors

404
Q

What neurotransmitter is released in the somatic NS at the effector cells?

A

Acetylcholine acting on N1 receptors

405
Q

give examples of non-adrenergic/cholinergic autonomic transmitters?

A

Sympathetic - ATP, Neuropeptide y

Parasympathetic - NO, VIP

406
Q

What nervous system pathway does cholinergic pharmacology deal with?

A

Manipulation of the parasympathetic pathway

407
Q

What does nicotine stimulate?

A

Stimulates all automimic ganglia via preganglionic nicotinic receptors
Activates both the SNS and PNS

408
Q

What does muscarine stimulate?

A

Activates the muscarinic receptors specific to the PNS

409
Q

What type of receptor are muscarinic and nicotinic receptors?

A

Muscarinic - GPCR - M1-5
Nicotine - Ligand gated ion channels

410
Q

Where are the different subtypes of muscarinic receptors found?

A

M1 - Brain
M2 - Heart
M3 - Glandular and smooth muscle (lungs and GI tract)
M4 - Mainly CNS
M5 - Mainly CNS

411
Q

What is the effect of muscarinic agonists at the M2 receptors?

A

Slows the heart rate

412
Q

What is the effect of muscarinic agonists at the M3 receptors?

A

Causes bronchoconstriction of smooth muscle
Will increase sweating, saliva and GI motility.

413
Q

What is the difference between a selective and non-selective drug?

A

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)

414
Q

What is pilocarpine?

A

A muscarinic agonist
Stimulates salivation - treats Sjogrens syndrome
Contracts iris smooth muscle - treats glaucoma by draining aqueous humour

415
Q

What is a side effect of pilocarpine?

A

Slows the heart
(non-selective muscarinic agonist)

416
Q

What is atropine?

A

A muscarinic antagonist
Prevents bradycardia - used to treat bradycardia in cardiac arrest

Dry secretions perioperatively

417
Q

What drugs are used in the treatment of bronchoconstriction?

A

Drugs that block the M3 receptors - anticholinergics/anti-muscarinics

Short acting (SAMA) - Ipratropium bromide
Long acting (LAMA) - Tiotropium

418
Q

What other roles can anticholinergics play?

A

Solifenacin - treat overactive bladder
Mebeverine - Treat IBS

419
Q

Give 2 examples of ACh action in the CNS?

A

Motion sickness - ACh stimulates vomiting centre in the brain
Worsen Parkinsons symtpoms - ACh increases dopamine re-uptake

420
Q

How is ACh synthesised?

A

Acetyl CoA combined with Choline; mediated by Choline Acetyl Transferase

421
Q

What enzyme is responsible for ACh breakdown in the synaptic cleft?

A

Acetylcholinesterase

422
Q

What is the action of the botulinum toxin at the NMJ?

A

Botulinum inhibits Ach release at the NMJ → Cause paralysis/decrease muscle contractions - cosmetic and antispasmodic uses

423
Q

What is the purpose of competitive antagonists at the NMJ?

A

Competitive antagonists block Ach receptors → muscle relaxants, adjuncts to general anaesthesia (pancuronium)

424
Q

What is the action of depolarising agonists?

A

Act as blockers as they cause receptor desensitisation

425
Q

What are AChE inhibitors used for?

A

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

426
Q

What is Myasthenia Gravis and how is it treated?

A

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

427
Q

What are some side effects of anticholinergics?

A
  • Worsening memory/ confusion
  • Constipation
  • Dry mouth
  • Blurred vision
428
Q

What are organophosphates?

A

Used in insecticides and nerve gases
They are irreversible AChE inhibitors
Cause muscle tremors, twitching, salivation and confusion.

429
Q

Give some examples of AChE inhibitors?

A

Neostigmine
Pyridostigmine
Rivastigmine

430
Q

What is Curare and Pancuronium?

A

An nACh-R antagonist

431
Q

What does overstimulation of Ach at the NMJ lead to?

A

Cholinergic Crisis (SLUDGE)
Salivation
Lacrimation
Urination
Defecation
GI distress
Emesis

432
Q

What nervous system pathway does adrenergic pharmacology deal with?

A

Sympathetic nervous system

433
Q

What are the principle catecholamines involved in the sympathetic nervous system?

A
  • 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
434
Q

What is the synthetic pathway of catecholamines?

A

Tyrosine
DOPA
Dopamine
Noradrenaline
Adrenaline

435
Q

What is the primary function of α1 adrenoceptors?

A

Vasoconstriction (contraction of BV)
Bladder contraction
Dilation of pupils

436
Q

What is the primary function of α2 adrenoceptors?

A

Responsible for pre-synaptic inhibition - prevents NAd release
Used in analgesia

437
Q

What neurotransmitter predominates in α1 and α2 interactions?

A

α1 - Noradrenaline

α2 - Adrenaline = noradrenaline

438
Q

What is the primary function of β1 adrenoceptors?

A

Increased cardiac effects to increase SV and CO
Increase ionotropy (force of contraction)
Increase chronotropy (heart rate)
Increase Dromotropy (electrical conduction)

Increase renin secretion

439
Q

What neurotransmitter predominates in β1, β2 and β3 interactions?

A

β1 - Noradrenaline = adrenaline
β2 - Adrenaline
β3 - Noradrenaline

440
Q

What is the primary function of β2 adrenoceptors?

A

Decrease SM tone - Bronchodilation
Vasodilation (partly)

441
Q

What are the primary functions of β3 adrenoceptors?

A

Increased Lipolysis
Bladder - detrusor muscle relaxation

442
Q

Where are the various adrenoceptors located?

A

α1 - Vascular smooth muscle, pupil
α2 - Presynaptic neurone (CNS Acting)

β1 - Heart
β2 - Lungs
β3 - Bladder detrusor muscle (and increase lipolysis)

443
Q

What is the role of adenylate cyclase?

A

Converts ATP to cyclic AMP (cAMP) to activate PKA

444
Q

What do α1 adrenergic agonists do?

A

Vasoconstriction; used for treatment of septic shock

445
Q

What do α1 adrenergic antagonists (alpha blockers) do?

A

Vasodilation; lowers blood pressure (doxazosin)

446
Q

What disease could an α1 adrenergic antagonist be used in the treatment of?

A

Benign prostatic hyperplasia; tamsulosin blocks α1 receptors in the prostate

447
Q

What drugs act on Alpha 2 receptors and what could they be used for?

A

Conidine/ alpha-methyldopa
CNS acting vasodilators

448
Q

What do β1 adrenergic agonists do?

A

Increase heart rate and chronotropic effects; used for treating conditions like septic shock
(dobutamine)

449
Q

What do β1 adrenergic antagonist do?

A

Reduce CO and reduce renin secretion; lower blood pressure
(Bisoprolol, Atenolol, Metoprolol)

450
Q

What diseases could an β1 adrenergic antagonist be used in the treatment of?

A

Hypertension, angina and arrhythmia.

451
Q

What do β2 agonists do?

A

Muscle relaxation; life-saving treatment for asthma and delay onset of premature labour

452
Q

What do β3 agonists do?

A

Smooth muscle relaxation; relaxation of detrusor muscle to reduce over-active bladder symptoms

453
Q

Give examples of cardioselective beta blockers and non-selective beta blockers?

A

Cardioselective (against B1) - Atenolol, Metoprolol

Non-selective - Propanolol

454
Q

What is the suffix for:
Murine Antibodies
Chimeric Antibodies
Humanised Antibodies
Human Antibodies

A

Murine Antibodies - omab
Chimeric Antibodies - ximab
Humanised Antibodies - zumab
Human Antibodies - umab

455
Q

Where are DA (dopamine receptors) most found?

A

Nucleus accumbens in the brain

456
Q

What is the main excitatory and main inhibitory neurotransmitter in the CNS?

A

Excitatory - glutamate
Inhibitor - GABA

457
Q

Give an example of a GABA agonist and what it may be used to treat?

A

Benzodiazepines (eg. Diazepam, Lorazepam)

Treats:
Anxiety
Sleep disorders
Alcohol withdrawal

458
Q

Give an example of a Histamine (H1 and H2) receptor antagonist and what they would be used to treat?

A

H1 Antagonist - Loratidine - treats allergy (T1 hypersensitivity)

H2 antagonist - cimetidine, Ranitidine - Treats GORD/reflux (Reduces gastric acid)

459
Q

What is an adverse drug reaction (ADR)?

A

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

460
Q

Are side effects and ADRs the same?

A

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).

461
Q

What are the patient risk factors for ADRs?

A
  • Gender (F>M)
  • Elderly
  • Neonates
  • Polypharmacy
  • Genetic predisposition
  • Hypersensitivity/ allergies
  • Hepatic/ renal impairment
  • Adherence problems
462
Q

What are the drug risk factors for ADRs?

A
  • Steep dose-response curve
  • Low therapeutic index
463
Q

What are some potential causes for ADRs?

A
  • Pharmaceutical variation
  • Receptor abnormalities
  • Abnormal biological system unmasked by drug
  • Abnormalities in drug metabolism
  • Immunological
  • Drug-drug interactions
  • Multifactorial
464
Q

What drugs commonly cause ADRs?

A
  • Antibiotics (penicillin)
  • Anti-neoplastics
  • Cardiovascular drugs
  • Hypoglycaemics
  • NSAIDs
  • CNS drugs
465
Q

What body systems are commonly affected by ADRs?

A
  • Gastrointestinal
  • Renal
  • Haemorrhagic (i.e. NSAIDs in patients on warfarin can cause gastric ulcer causing a catastrophic bleed)
  • Metabolic
  • Endocrine
  • Dermatologic
466
Q

Give examples of common ADR presentations

A
  • Confusion
  • Nausea
  • Balance problems
  • Diarrhoea
  • Constipation
  • Hypotension
467
Q

How are ADRs categorised?

A
  • Toxic effects - above therapeutic range
  • Collateral effects - at normal therapeutic range
  • Hypersusceptibility effects - below therapeutic range (e.g. tiny does of penicillin causing anaphylaxis)
468
Q

What is the Rawlins Thompson System of ADRs?

A

Type A - Augmented
Type B - Bizarre
Type C - Chronic
Type D - Delayed
Type E - End of use
Type F - Failure

469
Q

Describe a Type A ADR

A

Augmented (or pharmacological).

  • Common and predictable from physiological effects of the drug; often dose related.
    (eg. Anticoagulants causing haemorrhage)
    Treatment is reduce drug dose
470
Q

Describe a Type B ADR

A

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
471
Q

Describe a Type C ADR?

A

Chronic.
- Occurs after long term therapy
(eg. Nephropathy caused by long term NSAID use)

472
Q

Describe a Type D ADR?

A

Delayed
Occurs many years after treatment
(eg. teratogenesis caused by thalidomide)

473
Q

Describe a Type E ADR?

A

End of use
Complications of stopping medication (withdrawal)
eg. opioids

474
Q

Describe a Type F ADR?

A

Failure of therapy
(eg. Failure of the oral contraceptive pill in the presence of enzyme inducer drugs)

475
Q

What does the acroyn DoTS mean?

A

Dose relatedness - Toxic, collateral or hypersusceptibility
Timing - fast rxns, or late Rxns
Susceptibility - Patient factors

476
Q

When should you suspect an ADR?

A
  • Symptoms after a new drug is started
  • Symptoms after dosage increase
  • Symptoms disappear when drug is stopped
  • Symptoms reappear when drug is restarted
477
Q

Define Drug hypersenstivity?

A

Reproducible symptoms or signs that are initiated by the exposure to a drug at a dose tolerated by normal subjects

478
Q

Give explanations for the main features of anaphylaxis?

A
  • 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
479
Q

What is non-immune anaphylaxis?

A
  • 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.
480
Q

How is anaphylaxis managed?

A
  • Commence basic life support (ABCDE)
  • Stop the drug if currently being infused
  • Adrenaline (IM) 500mg - second dose after five miuntes if patient is not initially responding.
  • High flow oxygen
  • IV fluids - fluid shifts peripherally; IV fluids maintain intravascular volume
  • IV Antihistamine (Chlorphenamine 10mg)
  • IV Hydrocortisone (100 to 200mg)
481
Q

What does adrenaline do during anaphylaxis Treatment?

A
  • 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
482
Q

Define Absorption (pharmacokinetics)

A

The process of transfer from the site of administration into the general or systemic circulation

483
Q

What are the routes of drug administration?

A

po - oral

iv - intravenous

pr - rectal

sc - subcutaneous

im - intramuscular

in - intra-nasal

top - topical

sl - sublingual

inh - inhaled

neb - nebulised

et - endotracheal

484
Q

How do drugs cross membranes to reach their target sites?

A

Passive diffusion
Facilitated diffusion
Active transport
non-ionic diffusion
Pinocytosis

485
Q

What is drug ionisation?

A

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

486
Q

What is the strength of drug ionisation dependent on?

A

The strength of the ionisable group
pH of the solution

487
Q

What are other terms used to describe ionised drugs vs. unionised drugs?

A

Water soluble vs. lipid soluble respectively

488
Q

What is the pKa of a drug?

A

The pH at which half of the substance is ionised and half is unionised

489
Q

Drugs that are weak acids are best absorbed where?

A

The stomach
(eg. Aspirin is a weak acid and so becomes less ionised in the stomach due to the low gastric pH.)

490
Q

Drugs that are weak bases are best absorbed where?

A

The intestines

491
Q

What is the effect of an increase in pH on a weak acid?

A

The weak acid will become more ionised

492
Q

What is the effect of an increase in pH on a weak base?

A

The weak base will become less ionised.

493
Q

What is the effect of a decrease in pH on a weak acid?

A

The weak acid will become less ionised

494
Q

What is the effect of a decrease in pH on a weak base?

A

The weak base will become more ionised

495
Q

What route of drug administration has a bioavailability of 1?

A

IV - all the drug administered will go into the plasma

496
Q

Explain what would happen to the bioavailability of aspirin if gastric pH increased.

A

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.

497
Q

How many litres of water are there in the following body compartments:

a) Plasma.
b) Interstitial space.
c) Intracellular space.

A

a) 3L.
b) 11L.
c) 28L

498
Q

What equation can be used to determine the degree of ionisation at a specific pH?

A

Henderson Hasselbach.

pH = log[A-]/[HA] + pKa.

499
Q

What can enhance non ionic diffusion?

A

Non ionic diffusion can be enhanced if adjacent compartments have pH difference.

500
Q

Give an example of a proton pump inhibitor.

A

Omeprazole

501
Q

Give an example of a statin

A

Simvastatin
Atorvostatin

502
Q

Give an example of an ACE inhibitor?

A

Enalapril

503
Q

Give an example of a COX inhibitor?

A

Aspirin
Ibuprofen

504
Q

Give an example of a beta 2 adrenoceptor agonist?

A

Salbutamol

505
Q

Give an example of a beta 1 adrenoceptor antagonist?

A

Atenolol

506
Q

Give an example of a Calcium channel blocker?

A

Amlodipine

507
Q

Give an example of a broad spectrum antibiotic?

A

Amoxicillin

508
Q

Give an example of a phosphodiesterase inhibitor?

A

Dipyridamole - stimulates prostacyclin and inhibits thromboxane A2

509
Q

Give an example of an opiate analgesic?

A

Tramadol

510
Q

Give an Example of a Direct Factor Xa inhibitor?

A

DOACs
Apixaban
Rivaroxaban

511
Q

Give an Example of an indirect Anti-thrombin inhibitor?

A

Heparin - activates anti-thrombin to inhibit thrombin and Factor Xa

512
Q

Give an example of a Vitamin K antagonist?

A

Warfarin Decreases Factor II (prothrombin) and is an antagonist to Vitamin K
Therefore reduces Vit K dependent clotting factors (2, 7, 9, 10)

513
Q

What pharmaceutical properties can affect the rate of drug absorption?

A

Pharmaceutical form - syrup/pill
Ability to disintegrate
Ability to dissolve

514
Q

What physiochemical properties of a drug affects the rate of drug absorption?

A

Solubility
pH
Molecular weight

515
Q

What physiological variables can affect the rate of drug absorption?

A

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

516
Q

What is first pass metabolism?

A

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

517
Q

Define distribution (pharmacokinetics)

A

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.

518
Q

What is important about drugs binding to proteins in the plasma?

A

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.

519
Q

What is the most common protein that drugs bind to?

A

Albumin

520
Q

What type of drugs pass easily into the brain?

A

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

521
Q

How are water soluble and lipid soluble drugs eliminated?

A

Water soluble: directly by the kidney

Lipid soluble: must be metabolised to water soluble products

522
Q

What are the phases of metabolism?

A

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.

523
Q

What is first order kinetics?

A

Rate of metabolism is directly proportional to Drug concentration
Where a constant fraction of drug is eliminated per unit time

524
Q

What is zero order kinetics?

A

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.

525
Q

Define half-life

A

The time taken for a concentration of a drug to reduce by half.

526
Q

What would be the bioavailability of an oral drug?

A

F<1 as they are incompletely absorbed and undergo incomplete first pass metabolism.

527
Q

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?

A

10x the oral dose

528
Q

What is the volume of distribution and how is it calculated?

A

A measure of how widely a drug is distributed between various body fluids and tissues.

Amount of drug in the body / Measured plasma concentration

529
Q

Do water soluble or lipid soluble drugs have a higher volume of distribution?

A

Lipid soluble - these will move into the tissues more readily

Water soluble - highly protein bound and will be confined to the blood

530
Q

Define Clearance?

A

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

531
Q

Give the equation for renal clearnace?

A

Renal clearance = Rate of appearance in urine / plasma concentration.

532
Q

Define hepatic extraction ratio (HER).

A

The proportion of a drug removed by one passage through the liver.

533
Q

What is the limiting factor when a drug has a high HER?

A

Hepatic blood flow, perfusion limited

534
Q

What is the limiting factor when a drug has a low HER?

A

Diffusion limited. A low HER is slow and not efficient.

535
Q

What happens to high and low HER drugs when enzyme induction is increased?

A

The clearance of low HER drugs increases. There is minimal effect on high HER drugs.

536
Q

What is steady state?

A

A balance between drug input and elimination

537
Q

What is the role of the lymphatic system in acute inflammation?

A

Lymphatic channels dilate and drain away oedematous fluid therefore reducing swelling. Antigens are also carried to lymph nodes for recognition by lymphocytes.

538
Q

What are APUDomas?

A

Neuroendocrine tumours

539
Q

Describe T cell Activation

A

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.

540
Q

What cytokines are released from Th1 cells and Th2 cells

A

Th1 - IL2 and INFy
Th2 - IL-4, IL-5, IL-6, IL-10

541
Q

Give 3 functions of antibodies.

A
  1. Neutralise toxins.
  2. Opsonisation.
  3. Activate classical complement system.
542
Q

Give 3 examples of O2 dependent mechanisms of killing.

A
  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.
543
Q

What is the role of NO in killing pathogens?

A

NO leads to vasodilation and increased extravasation. This means more neutrophils etc pass into the tissues to destroy pathogens.

544
Q

Why can superoxides be used to destroy pathogens?

A

Superoxides can be converted to H2O2 and then to hydroxyl free radicals. Hydroxyl free radicals are highly reactive and can destroy pathogens.

545
Q

What is the function of these complement proteins:
MAC
C3a and C5a
C3b

A

MAC - Lyse microbes directly
C3a /C5a - Chemotaxis
C3b - Opsonisation

546
Q

What is the function of MAC in a pathogens’ membrane?

A

MAC is a leaky pore like channel. Ions and water pass through the channel and disrupt the intracellular microbe environment -> microbe lysis.

547
Q

Which complement plasma proteins are pro-inflammatory and cause chemotaxis and activation of neutrophils and monocytes etc?

A

C3a and C5a.

548
Q

Which complement plasma proteins have opsonic properties when bound to a pathogen?

A

C3b and C4b.

549
Q

Name 3 receptors that make up the PRR family.

A
  1. Toll-like receptors (TLR).
  2. Nod-like receptors (NLR).
  3. Rig-like receptors (RLR).
550
Q

What is the main function of TLR’s?

A

TLR’s send signals to the nucleus to secrete cytokines and interferons. These signals initiate tissue repair. Enhanced TLR signalling = improved immune response.

551
Q

What is the main function of NLR’s?

A

NLR’s detect intracellular microbial pathogens. They release cytokines and can cause apoptosis if the cell is infected.

552
Q

What disease could be caused by a non-functioning mutation in NOD2?

A

Crohn’s disease.

553
Q

What is the main function of RLR’s?

A

RLR’s detect intracellular double stranded RNA. This triggers interferon production and so an antiviral response.

554
Q

TLR’s are adapted to recognise damaged molecules. What characteristic do these damaged molecules often have in common?

A

They are often hydrophobic.

555
Q

What kind of TLR’s can be used in vaccine adjuvants?

A

TLR4 agonists.

556
Q

What is extravasation?

A

Leukocyte (WBC) migration across the endothelium.

557
Q

What do macrophages at the tissues secrete to initiate extravasation?

A

TNF alpha.

558
Q

Describe the process of extravasation.

A
  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.
559
Q

Define Adsorption and give an example

A

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.

560
Q

How would you treat paracetamol overdose?

A

If less than 1hour since ingestion:
Give Activated charcoal with N-acetylcysteine

If longer than an hour since ingestion:
give N-acetylcysteine

561
Q

Which common condition often diagnosed in childhood is a contraindication of beta-blockers and why?

A

Asthma
Beta blockers cuase bronchoconstriction

562
Q

What is the role of p53 protein?

A

p53 protein looks for DNA damage, if damage is present p53 switches on apoptosis.

563
Q

Define chronic inflammation.

A

Subsequent and prolonged tissue reactions to injury.

564
Q

Why is adjuvant therapy often used in the treatment of carcinomas?

A

Micrometastes are possible even if a tumour is excised and so adjuvant therapy is given to suppress secondary tumour formation.

565
Q

What kind of drugs can be used in targeted chemotherapy?

A

Monoclonal antibodies (MAB) and small molecular inhibitors (SMI).

566
Q

What enzymatic cascade systems does plasma contain?

A
  1. The complement system.
  2. The kinin system.
  3. The coagulation system.
  4. The fibrinolytic system.
567
Q

Give examples of 3 extracellular PRR.

A
  1. Mannose receptors.
  2. Scavenger receptors.
  3. TLR’s.
568
Q

What are the 7 hallmarks for cancer?

A
  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.
569
Q

What are the two types of tumour antigens and where are they found?

A
  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.
570
Q

What is cancer immunosurveillance?

A

When the immune system recognises and destroys transformed cells, this is an important host protection process.

571
Q

What are the 3 E’s of cancer immunoediting?

A
  1. Elimination.
  2. Equilibrium.
  3. Escape.
572
Q

Which infection is most often seen in patients with hypogammaglobulinemia?

A

Streptococcus penumonia sinusitis.

573
Q

Give 5 examples of PAMPs.

A
  1. Lipopolysaccharides.
  2. Endotoxins.
  3. Bacterial flagellin.
  4. Peptidoglycans.
  5. dsRNA.
574
Q

What class of biological agent is often used in the treatment of rheumatoid arthritis when DMARDs fail?

A

TNF blockers - they bind to TNF to prevent it interacting with its receptors.

575
Q

Give a side effect of using TNF blockers.

A

Increased susceptibility to TB.

576
Q

How do IL-6 blockers work?

A

IL-6 is an inflammatory cytokine. The biological agent binds to IL-6 so as to prevent it interacting with its receptor.

577
Q

Name an IL-6 blocker.

A

Tocilizumab.

578
Q

When are IL-6 blockers used?

A

They’re used in the treatment of rheumatoid arthritis when TNF blockers fail.

579
Q

What factors govern drug action?

A

Receptor related:
Affinity
Efficacy

Tissue Related:
Receptor number
Signal amplification

580
Q

Give 4 properties of the ‘ideal drug’.

A
  1. Small Vd (high bioavailability)
  2. Drug broken down effectively by enzymes.
  3. Predictable dose:response relationship.
  4. Low risk of toxicity.
581
Q

Give an advantage of a drug having a low Vd.

A

It is easy to reach steady state and plasma concentration is ‘responsive’ to dose rate.

582
Q

Give examples of adverse muscarinic agonist effects.

A

DUMBELS:
1. Diarrhoea.
2. Urination.
3. Miosis.
4. Brachycardia.
5. Emesis (vomiting).
6. Lacrimation.
7. Salivation.

583
Q

Which enzymes inactivate catecholamines?

A

MAO and COMPT.

584
Q

Define pain.

A

An unpleasant sensory and emotional experience associated with actual or potential tissue damage.

585
Q

Give 3 advantages of pain.

A
  1. Gives a warning for tissue damage.
  2. Immobilisation for healing.
  3. Memory establishment.
586
Q

Define acute pain.

A

Pain caused by nociceptor activation. It is of short duration,

587
Q

Define chronic pain.

A

Pain that is on-going or persistent, it lasts for >3-6 months.

588
Q

Define neuropathic pain.

A

Pain caused by a primary lesion or dysfunction of the nervous system.

589
Q

Define nociceptive pain.

A

Pain caused by actual or potential damage to non neural tissue, it is due to nociceptor activation.

590
Q

Describe the gate control theory.

A

Non-noxious stimuli trigger larger A beta fibres, these override smaller pain fibres and ‘close the gate’ to pain transmissions to the CNS.

591
Q

Give 4 risk factors for hypersensitivity.

A
  1. Protein based macromolecules.
  2. Female > male.
  3. Immunosuppression.
  4. Genetic factors.
592
Q

Why are drug interactions such a big problem today?

A
  1. Ageing population.
  2. Polypharmacy.
  3. Increased use of over the counter drugs.
593
Q

What is dobutamine used in the treatment of and at what receptor is it an agonist?

A

Dobutamine is a beta 1 agonist. It is used in the treatment of heart failure.

594
Q

What are the 3 actions of NSAIDS?

A
  1. Anti-inflammatory.
  2. Analgesic.
  3. Anti-pyrexic.
    (AAA).
595
Q

Give examples of Non-selective NSAIDs?

A

Diclofenac
Ibuprofen
Naproxen
High Dose Aspirin

Inhibit both COX1/COX2 to reduce conversion of Arachidonic acid to prostaglandins

596
Q

Give Examples of Selective NSAIDs?

A

Celecoxib
Specifically Targets COX2

Low dose Aspirin - Targets COX1

597
Q

What are the effects of a competitive antagonist?

A

Decreases potency of a drug but does not affect the efficacy

598
Q

What are the effects of a non-competitive antagonist?

A

Decreases both the potency and efficacy.

599
Q

Give examples of alpha 1 blockers and what they can be used to treat

A

Doxazosin - Decrease BP
Phenoxybenzamine - Treats phaeochromocytoma

600
Q

What drugs are CYP450 Inducers and what does that do to drug effects?

A

Drug effects reduced

PCBRAS:
Phenytoin
Carbamazepine
Barbiturates
Rifampicin
Alcohol (chronic use)
Sulfonylureas

601
Q

What drugs are CYP450 Inhibitors and what does that do to drug effects?

A

Drug effects increased

ODEVICES:
Omeprazole
Disulfiram
Erythromycin
Valproate
Isoniazid
Ciprofloxacin
Ethanol (acute)
Sulphonamides

602
Q

What is the Role of platelets?

A

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

Phase 2a (24 decks)

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