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Phase 2a > My ICS > Flashcards

My ICS Flashcards

1
Q

Deaths are referred to the coroner when:

A

Presumed natural, but unknown - not seen by doctor in last 14 days or longer
Presumed iatrogenic (from care during surgery and shortly after)
Presumed unnatural, from accidents, industry, suicide, unlawful killing etc

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2
Q

Which autopsies are performed by a histopathologist?

A
  • Accidental deaths or suicide
  • Natural deaths
  • Drowning
  • Suicide
  • Accidents
  • Road traffic deaths
  • Fire deaths
  • Industrial deaths
  • Peri/postoperative death
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3
Q

Which autopsies are performed by a forensic pathologist?

A
  • Deaths which may be deliberate/ criminal
  • Homicide
  • Death in custody
  • Neglect
  • Any from histopathologist list that may be due to the action of a third party
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4
Q

Stages of autopsy

A
  • History/ scene investigation
  • External examination; photography, microbiology
  • Digital autopsy; CT scanning
  • Maybe (50% ish) conventional dissection of parts including genetics and histology
  • Rarely full body dissection
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5
Q

Describe external examination in autopsy

A
  • Identification: sex, age, jewellery, body modification, clothing
  • Evidence of disease and its treatment
  • Evidence of injuries
  • if suspicious, referred to forensic pathologist
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6
Q

Describe evisceration in autopsy

A
  • Y-shaped incision (from behind ears down to clavicle the down to midline)
  • Open all body cavities
  • Examine organs in situ, then remove organs and examine them
  • remove brain
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7
Q

Which organ system is typically avoided in autopsy and why?

A

Avoid the lower GI tract if possible - presents infection risk

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8
Q

Hypertrophy

A

Increase in the size of a tissue caused by increase in the size of constituent cells

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9
Q

Hyperplasia

A

Increase in size of tissue caused by increase in number of constituent cells

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10
Q

Atrophy

A

A decrease in size of tissue due to decrease in number of constituent cells, or decrease in size of cells.

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11
Q

Causes of atrophy

A

Disease state or in limb injury, in unused muscles.

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12
Q

Metaplasia

A

Change in differentiation of the cell from one fully-differentiated type to another.

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13
Q

Give an example of metaplasia

A

Damaged ciliated columnar epithelium can differentiate to squamous epithelium to resist further damage. This is due to basal reserve cells differentiating into squamous cells rather than ciliated cells as intended.

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14
Q

Dysplasia

A

(Imprecise term) Morphological changes seen in cells in the progression to becoming cancer.

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15
Q

Apoptosis

A

Programmed cell death

  • Orderly event taking place in single cells
  • Important process in normal cells turnover in the body, preventing cells with accumulated genetic damage from dividing and producing cells which could develop into cancer cells.
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16
Q

Protein involved in apoptosis

A

Protein p53 checking for DNA damage. If there is DNA damage the cell will trigger a series of proteins, leading to a release of enzymes within the cell which eventually autodigest the cell. Many of these enzymes are caspases, involved in a cascade of activated enzymes.

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17
Q

Necrosis

A

Traumatic cell death
Destruction of large numbers of cells by an external factor

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18
Q

Causes of necrosis

A
  • Infarction due to loss of blood supply
  • Frostbite
  • Toxic venom from reptiles/ insects
  • Pancreatitis - necrosis of pancreas can occur if the duct is blocked, and pancreatic enzymes can digest themselves
  • Avascular necrosis of bone - eg scaphoid after falling on hand can lose blood supply and die.
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19
Q

What occurs following necrosis if tissue cannot regenerate?

A

After necrosis, macrophages phagocytose dead cells and typically the necrotic tissue is replaced by fibrous scar tissue. This is only if the tissue cannot regenerate.

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20
Q

Resolution

A

Initiating factor removed, and the tissue is undamaged or able to regenerate

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21
Q

Repair

A

Healing by fibrosis (scar formation) when there is substantial damage to the connective tissue framework and/or the tissue lacks the ability to regenerate specialised cells

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22
Q

Cells able to regenerate

A
  • in the liver, hepatocytes can regenerate
  • in the lungs, pneumocytes can regenerate, but alveolar walls cannot regenerate
  • all blood cells can regenerate
  • Osteocytes
  • the gut epithelium and skin epithelium can regenerate
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23
Q

Inflammation

A

The body’s response to injury or infection using different types of cells and molecules.

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24
Q

Process of repair

A
  • Dead tissues and acute inflammatory exudate are first removed from the damaged areas by macrophages
  • the defect then becomes filled by the ingrowth of a specialised vascular connective tissue - granulation tissue
  • the granulation tissue then gradually produces collagen to form a fibrous (collagenous) scar constituting the process of repair
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25
Q

Why can’t dividing cells divide forever?

A

Dividing cells eventually stop dividing due to the shortening of telomeres each time DNA divides. Eventually the telomeres are too short, and the cell is unable to divide.

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26
Q

Why do non-dividing cells die?

A

Non-dividing cells will die once they have accumulated a certain amount of damage to their cellular systems:
- DNA mutations
- Cross-linking of proteins
- Loss of calcium influx controls
- Accumulation of toxic by-products of metabolism
- Damage to mitochondrial DNA
- Loss of DNA repair mechanism
- Free-radical generation
- Activation of ageing and death genes

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27
Q

Congenital

A

Present at birth
Does not necessarily mean genetic, can be developmental eg foetal alcohol syndrome

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28
Q

Acquired

A

Caused by non-genetic environmental factors, can be congenital (eg foetal alcohol syndrome)

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29
Q

Mendelian inheritance types

A

Autosomal inheritance: on an autosome (non-sex)
- Autosomal dominant: only one copy of the gene needed to cause disease (DD or Dr)
- Autosomal recessive: both copies of the gene are required to cause the disease (rr)
- Autosomal co-dominant: eg blood type, combination of both inherited alleles (Dr)

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30
Q

Polygenic inheritance

A
  • Many genes that each increase risk a small amount all together in one person can greatly increase risk.
  • This can cause a family history without a single causative mutated gene.
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31
Q

Features of Inflammation

A

Redness (rubor): An acutely inflamed tissue appears red due to the dilation of small blood vessels within the damage area
Heat (calor): Increase in temperature is seen only in peripheral parts of the body, such as the skin. Due to increased blood flow (hyperaemia) through the region, resulting in vascular dilation and the delivery of warm blood to the area. Systemic fever, which results from some of the chemical mediators of inflammation, also contributes to the local temperature
Swelling (tumor): Swelling results from oedema - the accumulation of fluid in the extravascular space as part of the fluid exudate. Swelling also results from the physical mass of the inflammatory cells migrating into the area. As the inflammation response progresses, formation of new connective tissue contributes to the swelling
Pain (dolor): Results from the stretching and distortion of tissues due to inflammatory oedema and from pus under pressure in an abscess cavity. Some of the chemical mediators of acute inflammation, including bradykinin, the prostaglandins and serotonin, are known to induce pain.
Loss of function: Movement of an inflamed area is consciously and reflexively inhibited by pain. Severe swelling may physically immobilise the tissues.

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32
Q

Acute Inflammation

A
  • Sudden onset
  • Short duration - few hours to a few days
  • Usually resolves - Resolution of damage, disappearance of leukocytes, full regeneration of tissue
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33
Q

Causes of acute inflammation

A
  • Infection
  • Corrosive chemicals
  • Physical agents
  • Hypersensitivity
  • Bacterial toxins
  • Tissue necrosis
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34
Q

Blood vessel changes in acute inflammation

A
  • Blood vessels around the site dilate and leak a protein-rich fluid exudate
  • Endothelial cells become sticky in areas of inflammation so that inflammatory cells adhere to them, and become porous to allow them to pass into tissue.
  • The smooth muscle of arteriolar walls form precapillary sphincters which regulate blood flow into the capillary bed. in acute inflammation, these sphincters relax to increase the blood flow through the capillaries (adds redness and heat)
  • When sphincters are Open, more fluid goes out into tissue (causes swelling), even at venous end of capillaries.
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35
Q

Which lymphocytes are involved in acute inflammation?

A

Neutrophil polymorphs and macrophages

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36
Q

What do neutrophils do in acute inflammation?

A
  • The first cells that arrive at the site
  • Adhere to the injured vascular endothelium - pavementing, due to interaction between paired adhesion molecules on leukocyte and Endothelial surfaces.
  • Emigrate in through the walls of venules and small veins
  • Phagocytose debris and bacteria, and contain lysosomes which kill and digest the bacteria.
  • Form abscesses - large bundles
  • Release chemicals to attract other inflammatory cells ie macrophages.
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37
Q

What do macrophages do in acute inflammation?

A

Macrophages arrive after neutrophils and phagocytose bacteria, debris, and dead neutrophils.
May present antigen to lymphocytes to induce a secondary immune reaction

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38
Q

Chronic Inflammation

A
  • Slow onset
  • Long duration
  • May never resolve
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39
Q

Causes of chronic inflammation

A
  • May be due to persistent causal agent of acute inflammation
  • Alternatively, may represent a primary disease process:
  • Resistance of an infective agent to phagocytosis/ intracellular killing
  • Endogenous materials
  • Exogenous materials
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40
Q

Sequence of Chronic Inflammation

A
  • No or very few neutrophils
  • Macrophages and lymphocytes, then usually fibroblasts
  • Granulomas appear in some types of chronic inflammation - collection of macrophages attempting to kill bacteria, surrounded by lymphocytes. This may be seen around foreign material in tissue.
  • Chronic inflammatory cells (especially macrophages) generate high levels of reactive oxygen and nitrogen species to fight Infection.
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41
Q

Describe the immune system

A

Made up of organs, tissues, cells including leukocytes, molecules and soluble factors.
Protects from microorganisms, removes toxins, promotes inflammation, destroys tumour cells.

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42
Q

Phagocytes

A
  • Form a phagosome around pathogens
  • Destroy some pathogens with cytoplasmic granules where granules fuse with phagosome and drop pH to kill the pathogen, or digest with lysosomes
  • Oxidative burst: produce highly reactive oxygen eg H2O2 to Destroy pathogens
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43
Q

Antigen-presenting cells

A

Present antigens to T-cells following phagocytosis (MH class 2) or infection (MH class 1)

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44
Q

Granulocytes

A
  • contain granules in cytoplasm
  • all other than mast cells are polymorphonuclear
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45
Q

Which leukocytes are phagocytes?

A

Neutrophils
Eosinophils
Monocytes
Dendritic cells
Macrophages

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46
Q

Which leukocytes are granulocytes?

A

Basophils
Mast cells
Neutrophils
Eosinophils

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47
Q

Which leukocytes are antigen-presenting cells?

A

Monocytes
Dendritic cells
Macrophages
Lymphocytes

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48
Q

Basophils

A
  • Bi-lobed nucleus obscured by the staining of cytoplasmic granules - stain purple
  • Granules contain histamine, involved in the inflammatory response, and to prevent coagulation and agglutination
  • Aid in fighting parasites - involved in inflammatory response
  • Circulating form of mast cells, mature into mast cells
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49
Q

Mast cells

A
  • Granulocytes, non-phagocytic - involved in the inflammatory response
  • Contain histamine in granules - degranulate to release histamine
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50
Q

Neutrophils

A
  • Most abundant white blood cell - 70%
  • Last around one day so constantly produced
  • Granulocytes, phagocytic
  • Have a multi-lobed nucleus and a granular cytoplasm
  • Release cytokines to reduce inflammation
  • Circulate in blood and invade tissue spaces
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51
Q

Eosinophils

A
  • Granulocytes, phagocytic
  • Bi-lobed nucleus
  • Stain with eosin- cytoplasm goes bright orange
  • Distinctive large red cytoplasmic granules with crystalline inclusions
  • Antagonistic in action to basophils and mast cells
  • Neutralise histamine to restrict inflammation
  • Contain lozenge-shaped granules with crystalline cores
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52
Q

Monocytes

A
  • Immature cells which reside in the circulation
  • Phagocytic
  • Reniform (kidney bean shaped) mononuclear nucleus
  • Differentiate into one of several cell types, found in many places
  • Can differentiate into macrophages
  • Some differentiate into antigen-presenting cells
  • Have small cytoplasmic granules
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53
Q

Dendritic cells

A
  • Phagocytes
  • Typically ‘on patrol’ in epithelial tissues for non-cell
  • Long tentacle arms (dendrites) to detect non-cell in tissues
  • Antigen-presenting cells - present antigens to T cells
  • Release cytokines to recruit other cells
  • Consume large proteins
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54
Q

Macrophages

A
  • Phagocytes, antigen-presenting cells
  • Large and granular, lots of cytoplasm
  • Release cytokines to recruit other cells
  • Stay in connective tissue and lymphoid organs, not in the blood
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55
Q

Lymphocytes

A

B-cells: develop into plasma cells and secrete antibodies
T-cells: involved in immunity, many categories (T-regulator, T-helper, cytotoxic, natural killer cell)
Natural killer cells are involved in anti-tumour response
- Very few cytoplasmic inclusions resulting in a clear cytoplasm
- Both look the same with H+E
- Mononuclear
- Very little cytoplasm

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56
Q

Innate vs adaptive immunity

A

Innate Immunity is nonspecific and acts as the first line of defence. Adaptive Immunity is specific and has a response specific to the antigens present.

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57
Q

Innate immunity

A
  • Fast response with no memory (remains unchanged)
  • Starts with barriers, then inflammation, then microbial killing mechanisms
  • Nonspecific cells: phagocytic cells, natural killer cells
  • blood proteins eg complement system
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58
Q

How does the immune system detect microbes?

A

The innate immune system can recognise structures expressed by large groups of pathogens (pathogen-associated molecular patterns), and the common biologic consequences of infection (damage-associated molecular patterns). The cells recognise general patterns rather than very specific sequences of amino acids.

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59
Q

Which lymphocytes detect microbes in blood vs tissues?

A

In blood: monocytes and neutrophils
In tissues: macrophages and dendritic cells

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60
Q

Describe secreted and circulating pattern recognition receptors

A
  • Antimicrobial peptides secreted by epithelia and phagocytes which activate complement
  • Found within fluids lining epithelial cells eg in the lungs
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61
Q

How do secreted and circulating PRRs target bacteria?

A

Target bacteria by:
- damaging the cell membrane to burst the cell open
- invading into the cell and damaging from within
- bind to receptors to impair movement of ions
- bind to flag the bacterium for phagocytosis

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62
Q

What do PRRs on cell surfaces do?

A

Cell surface receptors typically detect bacteria, and induce the release of pro-inflammatory cytokines.

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63
Q

What do PRRs on organelles do?

A

Endosomal PRRs (on organelles) typically detect abnormal RNA and DNA, and induce release of type 1 interferons, which have antiviral effects

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64
Q

Why do these receptors dimerise?

A

Most receptors dimerise with themselves or other receptors, to expand the amount of ligands they can bind to.

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65
Q

Types of cell-surface PRRs

A

Lectin receptors
Toll-like receptors
Scavenger receptors

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66
Q

Lectin receptors

A
  • expressed by macrophages and dendritic cells
  • bind to certain foreign carbohydrates on microbes (Many types, Many microbes)
  • use carbohydrate recognition domains (CRD)
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67
Q

Toll-like receptors

A

Many types - recognise different common foreign molecules on microbes eg flagella, foreign molecule DNA and RNA

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68
Q

Scavenger receptors

A
  • large family of receptors
  • mainly bind to foreign lipids and lipoproteins, but a variety of ligands
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69
Q

Types of endosomal PRRs

A

RIG-I-like receptors
NOD-like receptors

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70
Q

RIG-I-like receptors

A
  • detect viral RNA in the cytoplasm
  • some recognise short strands, some long strands
  • cause production of interferons, which have anti-viral effects, and pro-inflammatory cytokines
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71
Q

NOD-like receptors

A
  • detect cytoplasmic bacteria
  • regulate inflammatory and cell death responses
  • NOD1 + NOD2 recognise peptidoglycan in Bacterial cell walls
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72
Q

Damage associated molecular patterns

A

Endogenous molecules created by self cells to alert the host to tissue injury to initiate repair. eg molecules broken off from the cell, or internal molecules released in damage

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73
Q

The damage chain reaction

A
  • in some cases, DAMPs can be harmful - tissue damage releases DAMPs, which attach to toll-like receptors and induce release of pro-inflammatory mediators
  • pro-inflammatory mediators can cause tissue damage however, creating a vicious cycle of tissue damage
  • high levels of DAMPs are associated with many inflammatory and autoimmune diseases
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74
Q

Stages of extravasation (diapedesis)

A
  • Tethering: Neutrophil tethers to the surface of endothelial cells, slows down
  • Firm adhesion: becomes static on the endothelium
  • Transmigration: Passes through the gaps in the endothelial wall
  • Locomotion: Moves along a chemokine gradient to the site of infection
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75
Q

Innate immunity responses to microbes

A
  • Phagocytosis
  • Release of free radicals
  • Release of nitric oxide
  • Release of enzymes eg lysozymes
  • Proteins such as defensins
  • pH changes
  • Apoptosis
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76
Q

Adaptive Immunity

A
  • Significantly slower than innate (the first time)
  • highly specific cells with immunologic memory which circulate around tissues and lymph
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77
Q

Why is adaptive immunity needed?

A
  • Microbes can evade innate immunity, eg with proteases and decoy proteins
  • Intracellular viruses and bacteria can ‘hide’ from innate immunity
  • The innate immune response is slower than the secondary adaptive response
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78
Q

Cell-mediated response

A
  • Interlay between antigen presenting cells and T-cells, which requires intimate cell to cell contact
  • T lymphocytes only respond to presented antigens, not soluble antigens
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79
Q

Typical use of MCH molecules

A

Typically, cells are constantly presenting self antigens on MHC molecules - all nucleated cells have MHC class 1 - but only antigen-presenting cells have MHC class 2.

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80
Q

When are antigens presented on MHC molecules?

A
  • When Infection occurs, a microbe antigen is presented on the MHC molecule
  • This is either in the case of a virus invading a cell (presented on MHC1), or following phagocytosis (presented on MHC2)
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81
Q

How do T-cells respond to each type of MHC presenting antigens?

A
  • Typical cells, presenting on MHC class 1, will be killed by a cytotoxic T cell to kill the intracellular pathogens
  • Antigen-presenting cells, with MHC2, will activate T-helper cells
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82
Q

What occurs when T-cells activate?

A
  • Clonal expansion - cells replicate into millions of copies
  • Differentiation, to make T cells more active and give them effector functions
  • Induce B cells to make antibodies to the pathogen
  • Form memory cells for faster secondary response
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83
Q

What do T-cell differentiate into depending on the environment?

A

MHC1 receptor detected: CD8 cytotoxic cells
MCH2 receptor detected: CD4 cells
High interleukin 12: CD4 -> TH1 cells
Low interleukin 12: CD4 -> TH2

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84
Q

Action of CD8 cells

A
  • Naive cell finds its complementary antigen on a MHC1 receptor (infected cell)
  • develops into cytotoxic T-cell
  • finds infected host cells with the same antigen and uses perforin and granulysin to kill them
  • releases interferon gamma which activates macrophages and causes them to increase phagocytosis
  • recruits other inflammatory cells via chemotaxis
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85
Q

Action of TH1 cells

A

Secrete interferon gamma to help antigen-presenting cells phagocytose

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86
Q

Action of TH2 cells

A

TH2: humoral response - secretes interleukins 4,5,10, which help B-cells produce antibodies.

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87
Q

Humoral response

A
  • B-cells express membrane-bound antibodies (IgM or IgD monomer) - each B cell can only make one antibody, which will only bind to one epitope on one antigen.
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88
Q

B-cells as antigen presenting cells

A
  • B cells can also function as an antigen-presenting cell to TH2 cells via MHC2
  • antigen binds to antibody on the surface of the B-cell
  • the B-cell takes up the antigens
  • presents antigens on MHC2 to activate T cell
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89
Q

TH2 cells activating B-cells

A
  • B-cell displays an antigen on MHC2
  • TH2 binds to peptide displayed by B-cell and causes secondary activation
  • The TH2 cell sends signals to the B-cell to divide (clonal expansion)
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90
Q

Soluble factors

A

Complement, cytokines, chemokines, and antibodies. Make up the immune system alongside Leukocytes and lymphoid organs and tissues.

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91
Q

Complement

A

Group of around 20 serum proteins secreted (in an inactive form) by the liver that need to be activated to be functional

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92
Q

Complement cascade

A

One complement molecule gets activated and is converted to an enzyme, which activates another complement protein, process repeats

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93
Q

Models of action of complement proteins

A
  • Direct lysis
  • Chemotaxis: attract more leukocytes to the site of Infection
  • Opsonisation: Coat the invading organism
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94
Q

How can complement be activated? (3)

A
  • Classical: antibody bound to a antigen on a microbe
  • Alternative: complement itself binds to the microbe
  • Lectin: Lectin binds to a microbe, and activates complement
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95
Q

C3A + C5A action

A

Complement proteins which bind to receptors on leukocytes to draw them to sites of infection

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96
Q

C3B action

A

Opsonisation: Inserts itself into the membrane of bacteria, to attract white blood cells to bind to the bacteria.

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97
Q

MAC action

A

Four complement proteins which form pores in the membrane of pathogens, leading to osmolysis.

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98
Q

Cytokines

A
  • proteins secreted by immune and non-immune cells
  • regulate immune response
  • can be pro-inflammatory and anti-inflammatory
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99
Q

Types of cytokines

A
  • interferons
  • Interleukins
  • Colony stimulating factors
  • Tumour necrosis factors
  • Chemokines
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100
Q

Interferons

A
  • induce a state of antiviral resistance in uninfected cells and limit the spread of viral infection
  • interferon alpha and beta are produced by virus infected cells
  • interferon gamma is released by activated macrophages and T-helper 1 cells
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101
Q

Interleukins

A
  • produced by many cells, over 30 types
  • can be pro-inflammatory (eg IL1) or anti-inflammatory (eg IL10).
  • Can cause cells to divide, differentiate and secrete factors.
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102
Q

Colony stimulating factors

A
  • involved in directing the division and differentiation on bone marrow stem cells in haematopoiesis
  • can drive production of different types of immune cells depending on the type of Infection
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103
Q

Tumour necrosis factors

A
  • not just involved in tumour necrosis!!
  • mainly a pro-inflammatory molecule (eg TNF alpha and beta)
  • mediate inflammation and cytotoxic reactions
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104
Q

Chemokines

A
  • Chemotactic cytokines
  • Group of around 40 proteins that direct the movement of leukocytes from the bloodstream into the tissues or lymph organs by binding to specific receptors on cells.
  • Like magnets, drawing cells to the site of infection
  • Different types attract different types of leukocytes - depends on type of infection or injury
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105
Q

Antibodies

A
  • bind specifically to antigens - soluble - secreted - some bind to antibody receptors on the surface of immune cells - bind to an epitope on an antigen with high affinity
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106
Q

Classes of antibodies

A
  • IgG
  • IgA
  • IgM
  • IgE
  • IgD
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107
Q

IgG

A
  • Most abundant antibody - around 70%
  • Constant region Fc binds to receptors on the surface of white blood cells (docking site)
  • Fab region binds to non-cell elements, 2 binding sites
  • 4 subclasses, IgG1-4
  • Held together with disulphide bonds between heavy and light chains
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108
Q

IgM

A
  • Around 10% of Igs in serum
  • Pentamer
  • Mainly found in blood as it is too large to cross endothelium (+ blood-brain barrier)
  • Responsible for the primary immune response, initial contact with antigen, IgG comes in after
  • Can have a monomeric form mIgM, used as an antigen-specific receptor on B-cells
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109
Q

IgA

A
  • Around 15% of Igs in serum
  • 80% of serum IgA is as a monomer
  • Main antibody in bodily mucous secretions eg saliva, genitourinary, bronchial, milk, colostrum as a dimer - secretory IgA or sIgA
  • 2 subclasses , IgA1+2
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110
Q

IgD

A
  • Only 1% of Ig in serum
  • Can be bound as a monomeric form to mature B cells as mIgD, similar to mIgM
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111
Q

IgE

A
  • Only 0.05% of Ig in serum
  • Mainly membrane-bound on mast cells
  • Basophils and mast cells express IgE specific receptors with high affinity for IgE
  • Binding to antigen causes release (degranulation) of histamine by these cells
  • Involved in allergy response
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112
Q

Hypersensitivity

A

The recognition of foreign antigen by the immune system causing tissue damage alongside destruction of the antigen. Overreaction to exogenous antigens leads to allergy, overreaction to endogenous antigens causes autoimmunity.

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113
Q

Types of hypersensitivity

A

Four main types:

  • Type I: Immediate hypersensitivity due to activation of IgE antibody on mast cells or basophils
  • Type II: antibody to cell-bound antigen
  • Type III: immune complex reactions
  • Type IV: delayed hypersensitivity mediated by T-cells.
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114
Q

Type I hypersensitivity

A

Type I hypersensitivity is an immediate reaction to environmental antigens mediated via IgE antibodies.

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115
Q

Allergens

A

Allergens are antigens which trigger allergic reactions, with the ability to induce a strong IgE response.

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116
Q

Features of allergens

A
  • features of a protease, allowing the allergen to pass through the surface epithelium
  • cause reduction in IL-12, so more Th2 are produced
  • have a protein structure which binds to antigen-presenting cells
117
Q

Atopy

A

Atopy is an inherited trait for type I hypersensitivity, tendency to develop exaggerated reactions.

118
Q

Hypersensitivity I - initial allergen contact

A
  • Antigen comes into contact with body surface, eg skin, GI tract, lungs, and is taken up by the physical barrier.
  • Detected, taken up, and presented by antigen presenting cell on an MH2 receptor
  • Naive T cell detects the antigen, converts to T-helper cell 2
  • Produces interleukin 4 and 13, which stimulates B cells to produce antibodies, specifically IgE through class switching
  • The IgE antibodies bind to high affinity receptors on mast cells and basophils, sensitising them to the antigen.
119
Q

Hypersensitivity I - second allergen contact

A
  • When the antigen enters the body again, it cross-links the IgE bound to the sensitised cells, and induces degranulation.
  • causes release of histamine, cytokines, prostaglandins and other inflammatory mediators
  • histamine causes vasodilation, increased capillary permeability, chemokinesis in lungs causes bronchoconstriction
  • Tryptase is released, which is a powerful protease
  • Clinical manifestations of allergy are due to the contents of the granules
120
Q

Acute anaphylaxis

A

Type I hypersensitivity
Only anaphylaxis if airways, breathing, or circulation are affected
Occurs within minutes and lasts 1-2 hours

121
Q

Anaphylaxis symptoms

A
  • vasodilation
  • increased vascular permeability
  • bronchoconstriction
  • Urticaria
  • Angio-oedema
122
Q

Passive immunisation

A
  • Administration of pre-formed immunity from one person/animal to another person
  • Limitation: only humoral (antibody) mediated
  • Gives immediate protection, effective on immunocompromised patients
  • Short-lived
123
Q

Approaches to active immunisation

A

3 main approaches:
- Whole microbe
- Parts of virus that trigger the immune system
- Just the genetic material of a virus

124
Q

Carcinogenesis

A

The transformation of normal cells to neoplastic cells through permanent genetic alterations or mutations, which occur sporadically, due to carcinogens, or inherited generic mutations.

125
Q

How does neoplastic transformation occur?

A
  • occurs in any nucleated cell in the body
  • Multiple DNA hits - accumulated damage over time.
  • a series of genetic mutations, allowing cells to escape from normal growth regulatory mechanisms.
  • the mutations promote cell survival and prevent cell death.
126
Q

Oncogenesis

A

Development of the neoplasm, process resulting in benign as well as malignant tumours.

127
Q

Tumour

A

A tumour is any abnormal swelling including:

  • Neoplasm
  • Inflammation
  • Hypertrophy
  • Hyperplasia
128
Q

What is a neoplasm?

A

A neoplasm is a lesion (localised abnormality) resulting from the autonomous / relatively autonomous abnormal growth of cells which persists after the initiating stimulus has been removed.

129
Q

Features of neoplasia

A

Neoplasia is:

  • Autonomous: not reliant on homeostatic mechanisms to regulate growth
  • Abnormal: not healthy
  • Persists: after removal of initiating stimulus
  • New growth
130
Q

How is the stroma made?

A
  • depending on the functional resemblance to the parent tissue, the neoplastic cells may continue to synthesise and secrete cell products such as collagen, mucin, or keratin, which can accumulate within the tumour.
  • neoplastic cells are embedded in and supported by the stroma made up of these connective tissues.
131
Q

How does angiogenesis affect a tumour?

A
  • If the neoplasm does not create its own blood supply, it can only gain nutrients through diffusion, so can only grow up to 2mm.
  • Angiogenesis (growth of new blood vessels) is induced by factors secreted by the tumour cells.
132
Q

How do neoplasms have uncontrolled proliferation?

A
  • Autocrine growth stimulation due to abnormal gene expression, intracellular signalling proteins, and inactivation of tumour suppressor genes
  • Reduced apoptosis due to abnormal expression of apoptosis genes
  • Telomerase prevents telomeric shortening with each cell cycle.
133
Q

Invasive carcinoma

A

Cells pass through the basement membrane, and can invade into lymphatics and veins.

134
Q

What do the neoplastic cells need in order to invade?

A

The cells must produce collagenases, and must be motile (tumour cell derived motility factors)

135
Q

Micro-Invasive carcinoma

A

Only a few cells exit out into the stroma, and do not cause much damage (can be removed with the same treatment as carcinoma in situ)

136
Q

What do the neoplastic cells need to do to metastasise?

A
  • The cells travel through lymphatics and venous blood.
  • In these spaces, they are often attacked by lymphocytes or macrophages.
  • If the cells are able to evade the host immune defence, they can reattach at a different site and form another tumour (using growth factors)
137
Q

Why might neoplastic cells metastasise in the lungs?

A

Tumour cell invades into a capillary, then through veins to the vena cava. Then through the pulmonary circulation and lodges into a capillary (acts as an embolus). Then the tumour can grow in this space.

138
Q

Why might neoplastic cells metastasise in the liver?

A

Tumour cell begins in the gut, and is moved in the portal circulation to the liver, where it gets trapped in a hepatic capillary. (common in colon, stomach, pancreas, and carcinoid tumours of the intestine)

139
Q

Why might neoplastic cells metastasise in bone?

A

Some metastases combine with adhesion molecules on blood vessels in bone (prostate, breast, thyroid, lung, and kidney cancers)

140
Q

Why might neoplastic cells metastasise elsewhere in the body?

A

Tumour cell invades into a capillary, then through veins to the vena cava. The tumour cell could then pass through the pulmonary circulation, and gain access to the systemic circulation, where it can get lodged in a systemic capillary.

141
Q

Features of benign neoplasms

A
  • Benign neoplasms are localised and non-invasive (only push into surrounding structures).
  • They have a typical cell morphology, with close resemblance to normal tissue.
  • They have a slow growth rate and low mitotic activity.
  • Nuclear morphology oftennormal
  • Necrosis is rare
  • Ulceration of mucosal surfaces is rare
142
Q

Carcinoma in situ

A

The neoplastic cells have not passed the basement membrane, so cannot pass into lymphatics or blood vessels.

143
Q

How do benign neoplasms grow on mucosal surfaces?

A
  • Ulceration of mucosal surface is rare
  • Growth on mucosal surfaces is often exophytic, with a circumscribed/ encapsulated edge
144
Q

How can benign neoplasms be damaging?

A
  • Pressure on adjacent structures
  • Obstruct flow
  • Produce hormones like their normal cell counterpart, but not regulated by body
  • May transform to malignant neoplasm
  • Anxiety for patient, who thinks it could be cancer!
145
Q

Malignant neoplasms definition

A

They possess additional potentially lethal abnormal characteristics which enable them to invade and metastasise (spread) to other tissues. - Not all malignant tumours metastasise, but all are invasive.

146
Q

Features of malgnant neoplasms

A
  • they are able to pass through basement membranes.
  • they have an abnormal cell morphology with variable resemblance to normal tissue
  • Darker nuclei than normal (hyperchromatic)
  • Larger nuclei than normal
  • Pleomorphic - Rapid growth rate with high mitotic activity.
  • Poorly defined/ irregular border
  • necrosis and ulceration is common as they can outgrow their blood supply
147
Q

How do malignant neoplasms grow on mucosal surfaces?

A

Growth on mucosal surfaces and skin is often endophytic. There is an irregular infiltrative edge and vascular permeation. The surface is ulcerated.

148
Q

How do malignant tumours grow in organs?

A

Malignant tumours in solid organs tend to have irregular margins, often with tongues of neoplastic tissues penetrating adjacent normal structures.

149
Q

How do malignant neoplasms cause morbidity?

A
  • Destruction of adjacent tissue
  • Metastases (formation of secondary tumours)
  • blood loss from ulcerated surfaces
  • Obstruct flow
  • produce hormones
  • Paraneoplastic effects (signs and symptoms of cancer)
  • Anxiety and sometimes pain (late feature)
150
Q

The specific cell of origin of a tumour

A

Histogenesis

151
Q

When cell type cannot be determined, the neoplasm is said to be

A

anaplastic

152
Q

Neoplasm of non-glandular non-secretory epithelium

A

Papilloma (eg squamous cell papilloma)

153
Q

Neoplasm of glandular or secretory epithelium

A

Adenoma (eg thyroid adenoma)

154
Q

Malignant epithelial neoplasms

A

Carcinoma

155
Q

Carcinoma of glandular epithelium

A

Adenocarcinoma

156
Q

How are connective tissue neoplasms named?

A

Names after what structures they look like, with -oma
If malignant, -sarcoma is added

157
Q

Neoplasm of adipocytes

A

Lipoma

158
Q

Neoplasm of cartilage

A

Chondroma

159
Q

Neoplasm of bone

A

Osteoma

160
Q

Neoplasm of vascular system

A

Angioma

161
Q

Neoplasm of striated muscle

A

Rhabdomyoma

162
Q

Neoplasm of smooth muscle

A

Leiomyoma

163
Q

Neoplasm of nerves

A

Neuroma

164
Q

How is tumour grade determined?

A

The tumour grade is determined by the extent to which the tumour resembles its cell of origin.
Less resemblance - higher grade.

  • Grade 1: well differentiated (closer to parent)
  • Grade 2: moderately differentiated
  • Grade 3: poorly differentiated (unlike parent)

Poorly differentiated tumours are more aggressive, and have worse patient prognosis.

165
Q

How are tumours investigated?

A
  • Radiology guided biopsy: access to tumour, risk of complications
  • Frozen section: histopathology can assess under microscope
166
Q

What is TNM staging?

A

Tumour; size and extent of spread,
Nodes; extent of lymph node metastases,
Metastases; extent of spread to other parts of the body

167
Q

Carcinogens

A

Agents known or suspected to cause cancer, by acting on DNA (mutagenic).

168
Q

Features of chemical carcinogens

A
  • No common shared structural features amongst chemical carcinogens
  • Some act directly, some require metabolic conversion from ‘pro-carcinogens’ to ‘ultimate carcinogens’
  • Enzyme required for this conversion may be ubiquitous (everywhere) or confined to specific organs
169
Q

Viral carcinogens features

A
  • Cause around 10-15% of all cancers
  • Most oncogenic viral infections don’t result in cancer, just a risk
170
Q

Radiation carcinogens features

A
  • Exposure to UVA or UVB increases risk of BCC, melanoma, and SCC
  • Ionising radiation has a Long term effect, known to cause skin cancer, lung cancer, and thyroid cancer
171
Q

Other biological carcinogens

A
  • hormones (eg oestrogen)
  • parasites
  • Mycotoxins
172
Q

Why are carcinogens hard to identify?

A
  • Latent interval, gap between exposure and development of neoplasm, may Last decades
  • Environmental complexity - food, air, chemicals
  • Ethical constraints, cannot test whether a given substance causes cancer
  • Animals and cell cultures that are tested on may metabolise agents differently to humans.
173
Q

Lifestyle cancer risk factors

A
  • Excess alcohol use increases cancer risk of mouth, oesophagus, liver, colon, breast
  • Obesity increases risk of breast, oesophagus, colon and kidney cancer
  • Exercise reduces risk of colon and breast cancer
  • Unprotected sex increases risk of HPV-related cancer (cervix, penis, oropharyngeal)
174
Q

Pharmacodynamics

A

The biochemical, physiological and molecular effect of a drug on the body, aka what the drug does to the body, which drug targets it affects.

175
Q

Agonists

A

bind to receptors and activate them

176
Q

Antagonist

A

binds to receptor and prevents agonists from binding - less activation, alone have no effect

177
Q

Allosteric ligands

A

bind to a different site, and regulate the activity of the receptor

178
Q

Inverse agonist

A

bind to the same receptor as an agonist, but have the opposite effect of the agonist

179
Q

Factors governing a drug’s pharmacodynamics

A
  • Target receptor
  • Target tissue
  • Tolerance
  • Desensitisation
  • Efficacy
  • Potency
  • Selectivity
180
Q

Affinity

A
  • how well the drug binds to the target
  • property of both agonists and antagonists
  • some drugs bind irreversibly
181
Q

Tissue related factors affecting drug action

A
  • Number of receptors
  • Signal amplification
  • Signal cascade and cellular response
182
Q

Tolerance

A

Reduction in agonist effect over time due to continuously, repeatedly, high concentrations

183
Q

Desensitisation

A

Rapid development of tolerance (ie over minutes instead of weeks)
Can occur with the initial dose of a medication

184
Q

Efficacy

A

The drug’s ability to induce a response, as a % it can reach

185
Q

Full agonists

A

reach 100% response, maximum efficacy

186
Q

Partial agonists

A

less than 100% response, never reaches maximum

187
Q

Potency

A

How much drug is needed to induce a response

188
Q

Which drug is more potent, and which is more efficacious?
(look at notes)

A

Compound D is more potent, compound A is more efficacious

189
Q

Selectivity

A

how much the drug binds only to its intended target

190
Q

Pharmacokinetics

A

the fate of a chemical substance administered to a living organism, aka what the body does to the drug

191
Q

Pharmacokinetics ADME

A

A: Absorption
D: Distribution
M: Metabolism
E: Excretion

192
Q

What does ADME tell us about a given drug?

A
  • How quickly a drug will reach its site of action
  • How quickly will a response be seen
  • drug interactions
  • Dose adjustment
  • What monitoring is needed
193
Q

Absorption

A

Transfer of drug molecule from site of administration to the systemic circulation

194
Q

Bioavailability

A

the proportion of the administered dose which reaches the systemic circulation

195
Q

Bioavailability of IV and IA vs other drugs

A
  • In IV and IA, 100% of the dose reaches systemic circulation
  • With any other route, drugs must cross at least one membrane to reach systemic circulation
196
Q

What is IV, IA, IM, and SC?

A

IV - intravenous
IA - intra-arterial
IM - intramuscular
SC - subcutaneous

197
Q

What are PO, SL, and INH?

A

PO - oral
SL - sublingual
INH - inhaled

198
Q

What are PR and PV?

A

PR - rectal
PV - vaginal

199
Q

What is TOP and TD?

A

TOP - topical
TD - transdermal

200
Q

What is IT?

A

Intrathecal - injection directly into the spinal cord CSF

201
Q

Mechanisms for drugs to permeate membranes

A
  • Passive diffusion through hydrophobic membrane: lipid-soluble molecules
  • Passive diffusion through aqueous pores: very small water-soluble drugs
  • Carrier-mediated transport: proteins which transport sugars, amino acids, neurotransmitters, and trace metals (and some drugs)
202
Q

How does drug ionisation affect absorption?

A
  • Ionised drugs have poor lipid solubility and therefore are poorly absorbed
  • Most drugs are weak acids or weak bases with ionisable groups
  • Proportion of ionisation depends on the pH of the aqueous environment
203
Q

Where are weak acids vs bases absorbed best orally?

A
  • weak acids are best absorbed in the stomach
  • weak bases are best absorbed in the intestine
204
Q

Obstacles for drugs in the stomach

A
  • Gastric enzymes could digest the drug molecule eg insulin, peptides
  • low pH may degrade the molecule
  • food will slow absorption
  • Gastric motility is altered by drugs and disease state
  • Previous surgery eg gastrectomy
205
Q

How can drug structure affect absorption in the small intestine?

A
  • lipid soluble/ unionised molecules diffuse down concentration gradient
  • large or hydrophilic molecules are poorly absorbed
206
Q

How can medicine formulation affect absorption in the small intestine?

A
  • Capsule/ tablet coating can control time between administration and drug release
  • Modified release controls the rate of absorption (less frequent dosing needed)
207
Q

How can P-glycoprotein affect absorption in the small intestine?

A
  • Substrates are removed from intestinal endothelial cells back into the lumen through p-glycoprotein
  • This reduces absorption
208
Q

First pass metabolism

A

Metabolism of drugs preventing them from reaching the systemic circulation

209
Q

Examples of first pass metabolism

A
  • Degradation by enzymes in the intestinal wall
  • absorption from the intestine into the hepatic portal vein, then metabolism by liver enzymes
210
Q

How can first pass metabolism be avoided?

A

Avoid by giving routes that avoid splanchnic circulation eg rectally, sublingually

211
Q

What does bioavailability depend on?

A
  • Dependent on the extent of drug absorption and the extent of first pass metabolism
  • Not affected by the rate of absorption
  • Varies with route of administration (dose adjustment is required when changing formulations)
  • Variation between individuals due to genetics and disease states
212
Q

What factors affect drug distribution?

A

Molecule size: the larger the molecule, the lower the distribution.
Lipid solubility: the more lipophilic, the higher the distribution.
Protein binding: the more protein bound, the lower the distribution.

213
Q

Volume of distribution (Vd)

A
  • the theoretical volume a drug will be distributed in in the body
  • volume of plasma required to contain the total administered dose
  • drugs that are well distributed have high Vd
214
Q

What reduces distribution to the cerebrospinal fluid?

A

The blood-brain barrier:

  • Continuous layer of endothelial cells with tight junctions
  • Efflux pumps remove water-soluble molecules
  • Maintains a stable environment and protects the brain, but poses a challenge for treating CNS conditions
215
Q

What can increase distribution to the CNS?

A
  • drugs with high lipid solubility
  • Intrathecal administration (injection into subarachnoid space)
  • inflammation causes barrier to become leaky
216
Q

How can obesity complicate drug dosing?

A
  • body weight is used to calculate Vd - higher weight, higher dose
  • in obese patients, a lower dose than calculated is needed in drugs with low Vd, as adipose tissue has low blood perfusion
  • if the drug is very lipophilic, it may accumulate in adipose tissue, leading to prolonged release
217
Q

Metabolism

A

Modification of chemical structure to form new chemical entity (metabolite)

218
Q

Drug elimination

A

The process by which the drug becomes no longer available to exert its effect on the body

219
Q

Phase I vs phase II metabolism

A

Phase 1: Oxidation/reduction/hydrolysis to introduce reactive group to chemical structure
Phase 2: Conjugation of functional group to produce hydrophilic, inert molecule

220
Q

Phase I metabolism

A
  • Cytochrome P450 (CYP450) enzymes, mostly in the liver
  • produces a reactive metabolite by creating or unmasking a reactive functional group
  • This is by oxidation, reduction, or hydrolysis
221
Q

How can CYP450 function vary?

A
  • genetic variation
  • reduced function in severe liver disease
  • interactions: enzyme inhibiting/inducing drugs or food can reduce/increase enzyme activity
222
Q

Phase II metabolism

A
  • Conjugation of an endogenous functional group (glycine, sulfate, glucuronic acid) to produce a non-reactive polar (therefore hydrophilic) molecule
  • hydrophilic metabolite can then be renally excreted
223
Q

How is drug metabolism relevant in liver failiure?

A
  • the metabolism of the drug may be reduced
  • additional dose or frequency needed?
  • additional monitoring required?
  • avoid?
224
Q

How are liquids, solids, and gases excreted?

A

Liquids (small, polar molecules): urine, bile, sweat, tears, breast milk
Solids (large molecules): faeces (through biliary excretion)
Gases (volatiles): expired air

225
Q

Which drugs are excreted in glomerular filtration?

A
  • free/unbound drug molecules
  • very large molecules excluded
226
Q

Which drugs are excreted in active tubular secretion?

A
  • drug molecules transported by carrier systems eg organic anion transporter, organic cation transporter
  • can clear protein-bound drug
  • Most effective renal clearance mechanism
227
Q

Which drugs are reabsorbed in passive reabsorption?

A
  • diffusion down concentration gradient from tubule back into peritubular capillaries
  • hydrophobic drugs diffuse easily
  • highly polar drugs will be excreted
228
Q

First order kinetics

A
  • Rate of elimination is proportional to the plasma drug concentration (processes involved in elimination do not become saturated)
  • A constant % of the plasma drug is eliminated over a unit of time
229
Q

What is Cmax and tmax?

A

Cmax: maximum plasma concentration reached
tmax: time taken to reach Cmax

230
Q

Clearance (CL)

A

Efficiency of removal of drug by all eliminating organs

231
Q

How are Cmax and tmax affected in modified release oral doses?

A

Slower absorption, therefore lower Cmax, and higher tmax.

232
Q

Half life (t1/2)

A
  • Time taken for plasma drug concentration to fall by 50%
  • Different doses of the same drug will have the same half life
233
Q

What is half life dependent on?

A
  • Dependent on clearance (CL) of the drug from the body by all eliminating organs (hepatic, renal, faeces, breath)
  • Dependent of volume of distribution (Vd) - a drug with large Vd will be cleared more slowly than a drug with a small Vd
  • Not dependent on drug dose or drug formulation
234
Q

When is a drug considered cleared?

A

A drug will be 97% cleared from the body after 5 x half lives - this is considered cleared in clinical practice.

235
Q

How does half life affect dosing?

A
  • Short t1/2 will need more frequent dosing
  • Organ dysfunction - t1/2 may be increased, less frequent dosing
  • Adverse drug reactions or management of toxicity - how long will drug take to be removed and symptoms to resolve
  • Short t1/2 increases risk of withdrawal symptoms - drug may need dose weaning on cessation
236
Q

Steady state (IV) meaning

A

Rate of drug input is equal to rate of drug elimination

237
Q

Css and time to Css meaning

A

Css: drug plasma concentration at steady state
Time to Css: 5x t1/2 (after treatment initiation and after a dose increase)

238
Q

How are Css and time to Css changed by a 50% dose?

A

In a continuous IV infusion, 50% dose reduction leads to a 50% reduction in Css, but time to Css remains unchanged (as t1/2 remains the same)

239
Q

Zero order kinetics

A
  • Rate of elimination is NOT proportional to the plasma drug concentration (metabolism processes become saturated)
  • A constant amount of the plasma drug is eliminated over a unit of time
  • Small increases in dose may cause large increases in plasma concentration (caution needed when adjusting)
240
Q

Druggable

A

a protein which can be used as a target for a drug

241
Q

Types of drug targets

A
  • receptors
  • enzymes
  • transporters
  • ion channels
242
Q

What is a receptor?

A

A receptor is a component of a cell which interacts with a specific ligand and initiates a change of biochemical events leading to the ligands observed effects.

243
Q

Describe G-protein coupled receptors

A
  • 7 transmembrane alpha helices
  • G-protein: guanine nucleotide-binding proteins, made up of 3 subunits
  • G-proteins transmit signals from G-protein coupled receptors
  • The ligand binds, then the g-protein catalyses the exchnge of GDP to GTP, which activates downstream signalling
244
Q

Describe kinase-linked receptors

A
  • kinases are enzymes that catalyse the transfer of phosphate groups between proteins
  • the substrate gains a phosphate group donated by ATP
  • the receptors are activated when the binding of an extracellular ligand causes enzymatic activity intracellularly
245
Q

Describe cytosolic receptors

A
  • steroid hormones
  • work by modifying gene transcription
  • ligand binding causes a conformational change allowing the receptor to bind to DNA
246
Q

What is an enzyme inhibitor?

A

An enzyme inhibitor is a molecule which binds to an enzyme and decreases its activity. It prevents the substrate from entering the enzyme’s active site and prevents it from catalysing the reaction.

247
Q

Irreversible enzyme inhibitors

A

usually react with the enzyme and change it chemically (e.g. via covalent bond formation)

248
Q

Reversible enzyme inhibitors

A

bind non-covalently and different types of inhibition are produced depending on whether these inhibitors bind to the enzyme, the enzyme-substrate complex, or both.

249
Q

How can drugs affect ion channels?

A

Drugs can bind to ion channels and block ions from passing through. This can have many effects, eg blocking calcium channels in muscle cells to inhibit contraction.

250
Q

Drug interactions

A

When a substance alters the expected performance of a drug. Not only 2 prescribed drugs - can be food eg grapefruit juice, or supplements

251
Q

Why are drug interactions prevalent?

A

Ageing population and increasing multimorbidity

252
Q

Pharmacodynamic drug interactions

A

When drugs have an effect on the same target or physiological system.
Either synergistic (work together, both have the same effect) or antagonistic (one stops the effect of another, or the drugs compete for the receptor)
Generally predictable

253
Q

Pharmacokinetic drug interactions

A

When a drug affects the pharmacokinetics (absorption, distribution, metabolism or excretion) of another drug

254
Q

In which ways can one drug affect pharmacokinetics of another?

A

Can affect the rate or extent of absorption of another drug (extent more problematic)
Can affect the distribution of the drug throughout the body
Can affect the metabolism of the drug
Can affect excretion of the drug

255
Q

How can one drug affect absorption of another drug?

A
  • drugs which alter the pH of the GI tract
  • formation of insoluble drug complexes
  • p-glycoprotein induction / inhibition
256
Q

How can one drug affect the distribution of another?

A

Only unbound drugs will be distributed from the blood plasma - if drugs compete for protein binding, more drug will be distributed

257
Q

How can one drug affect the metabolism of another?

A
  • enzyme inducer: increases expression of enzyme, leading to more metabolism of the substrate - less effect
  • enzyme inhibitor: decreases expression of enzyme, leading to less metabolism of the substrate - increased effect, could lead to adverse drug reactions of toxicity
  • takes time for the inducers to lead to an effect, whereas only days for inhibitors
258
Q

How can one drug affect excretion of another?

A
  • Drugs can compete for renal tubular excretion
  • Both bind to organic anion transporters or organic cation transporters - drug remains in bloodstream
259
Q

How can drug interactions be avoided?

A
  • Need a complete and thorough drug history
  • Look for high risk drugs
  • Look for high risk patients
  • Drug interactions which cause a clinically significant adverse drug reaction should be reported
260
Q

What are examples of high-risk drugs for drug interactions?

A
  • enzyme inducers, inhibitors, and substrates
  • drugs with narrow therapeutic index (a little more could be toxic)
  • New drugs eg biologics have little data on interactions
261
Q

Why might a patient be high risk for drug interactions?

A
  • Polypharmacy
  • kidney or liver impairment
  • Extremes of age
262
Q

How can drug interactions be managed?

A
  • Avoid combination
  • Initiate an alternative drug
  • Temporarily suspend interacting drug
  • Permanently stop interacting drug
  • Caution
  • Additional monitoring
  • Bloods, observations, vigilance for adverse reactions
  • Proceed - No action
263
Q

Adverse Drug Reactions

A

A response to a medicinal product, or combination of medicinal products, which is noxious and unintended

264
Q

Impacts of ADRs for patients

A
  • Reduced quality of life
  • poor compliance
  • Reduced confidence in clinicians and the healthcare system
  • Unnecessary investigations or treatments
265
Q

Impacts of ADRs for the NHS

A
  • increased hospital admissions
  • Longer hospital stays
  • GP appointments
  • Inefficient use of medication
266
Q

ABCDEFG classification of ADRs

A

Augmented
Bizarre
Chronic/ continuing
Delayed
End of use (withdrawal)
Failiure of treatment
Genetic

267
Q

Augmented ADRs

A
  • Most common type of ADR (80%)
  • Exaggerated effect of drugs pharmacology at a therapeutic dose
  • Often not life threatening
  • Dose dependent, and reversible upon withdrawing the drug
268
Q

Bizarre ADRs

A
  • not related to the drugs pharmacology
  • not dose related
  • serious illness or mortality
  • symptoms do not always resolve upon withdrawing drug
269
Q

Chronic/ continuing ADRs

A
  • ADRs that continue after the drug has been stopped - eg osteonecrosis, heart failure
270
Q

Delayed ADRs

A
  • ADRs that become apparent some time after stopping the drug
271
Q

End of use ADRs

A

ADRs develop after the drug has been stopped

272
Q

Failure of treatment ADRs

A
  • Unexpected treatment failure
  • due to drug interaction or drug-food interaction
  • or poor compliance with administration instructions
273
Q

Genetic ADRs

A
  • drug causes irreversible damage to genome - eg children of women taking thalidomide
274
Q

DoTS classification of ADRs

A

Describe each ADR using a description of each:

  • Dose relatedness: hypersusceptibility ie anaphylaxis, side effects, toxic effects eg paracetamol liver damage
  • Timing: rapid administration, first dose only, early during treatment only, after some delay, after repeat exposure, some time after exposure
  • Susceptibility: which patient groups ie age, gender, disease state, physiological state
275
Q

Pharmacogenomics

A

The use of genetic and genomic information to tailor pharmaceutical treatment to an individual. This approach results in improved patient outcomes, and increased cost efficiency.

276
Q

How can genomics affect parmacodynamics?

A
  • variations in drug receptor
  • variations in efficacy
  • increased incidence of adverse drug reactions (could be off target)
277
Q

How can genomics affect pharmacokinetics?

A
  • variations in drug metabolism
  • variations in efficacy
  • increased incidence of adverse drug reactions
278
Q

Which sympathetic nervous system receptors can drugs target?

A

Alpha 1 + alpha 2
Beta 1 + beta 2
(all adrenergic - adrenaline and noradrenaline)

279
Q

What do sympathetic alpha 1 receptors do?

A

Found on all smooth muscles, glands, and organs of the sympathetic nervous system. Causes vasoconstriction of peripheral blood vessels.

280
Q

What do sympathetic alpha 2 receptors do?

A

Found on pre-synaptic terminals of sympathetic neurons. Act in feedback loops to stop noradrenaline release.

281
Q

What do sympathetic beta 1 receptors do?

A

Found on the heart, and kidney juxtaglomerular cells. Act to increase heart rate and contractility, and stimulates juxtaglomerular cells to release renin (leads to increased blood pressure and volume)

282
Q

What do sympathetic beta 2 receptors do?

A

Found on all smooth muscles, glands, and organs of the sympathetic nervous system. Stimulates bronchodilation.

283
Q

Which drugs act on alpha 1 receptors?

A

Alpha blockers (antagonists) block the effect of the sympathetic nervous system on the blood vessels, causing vasodilation.

284
Q

Which drugs act on alpha 2 receptors?

A

Alpha 2 receptor agonists act presynaptically to reduce the amount of noradrenaline released. Receptors are found in the brain and spine. They form the negative feedback loop of the sympathetic system.

285
Q

Which drugs act on beta 1 receptors?

A

Beta blockers (-olol):

  • reduce heart rate and contractility,
  • leading to a decreased workload for the cardiac muscle.
  • Lower heart rate also prolongs diastole,
  • allowing more time for coronary perfusion.
286
Q

Which drugs act on beta 2 receptors?

A

Beta 2 agonists such as salbutamol trigger bronchodilation.

287
Q

What is the bioavailability of oral morphine?

A

50%

288
Q

How do opioids work?

A

Act as endorphins and enkephalins (regulate nociception - pain transmission)
Inhibit the release of pain transmitters at the spinal cord and midbrain, and modulate pain perception in higher centres.

289
Q
A

Phase 2a (7 decks)

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