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
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
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
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
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
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
7
Q
Which organ system is typically avoided in autopsy and why?
A
Avoid the lower GI tract if possible - presents infection risk
8
Q
Hypertrophy
A
Increase in the size of a tissue caused by increase in the size of constituent cells
9
Q
Hyperplasia
A
Increase in size of tissue caused by increase in number of constituent cells
10
Q
Atrophy
A
A decrease in size of tissue due to decrease in number of constituent cells, or decrease in size of cells.
11
Q
Causes of atrophy
A
Disease state or in limb injury, in unused muscles.
12
Q
Metaplasia
A
Change in differentiation of the cell from one fully-differentiated type to another.
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.
14
Q
Dysplasia
A
(Imprecise term) Morphological changes seen in cells in the progression to becoming cancer.
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.
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.
17
Q
Necrosis
A
Traumatic cell death
Destruction of large numbers of cells by an external factor
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.
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.
20
Q
Resolution
A
Initiating factor removed, and the tissue is undamaged or able to regenerate
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
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
23
Q
Inflammation
A
The body’s response to injury or infection using different types of cells and molecules.
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
25
Why can't dividing cells divide forever?
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.
26
Why do non-dividing cells die?
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
27
Congenital
Present at birth
Does not necessarily mean genetic, can be developmental eg foetal alcohol syndrome
28
Acquired
Caused by non-genetic environmental factors, can be congenital (eg foetal alcohol syndrome)
29
Mendelian inheritance types
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)
30
Polygenic inheritance
- 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.
31
Features of Inflammation
**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.
32
Acute Inflammation
- Sudden onset
- Short duration - few hours to a few days
- Usually resolves - Resolution of damage, disappearance of leukocytes, full regeneration of tissue
33
Causes of acute inflammation
- Infection
- Corrosive chemicals
- Physical agents
- Hypersensitivity
- Bacterial toxins
- Tissue necrosis
34
Blood vessel changes in acute inflammation
- 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.
35
Which lymphocytes are involved in acute inflammation?
Neutrophil polymorphs and macrophages
36
What do neutrophils do in acute inflammation?
- 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.
37
What do macrophages do in acute inflammation?
Macrophages arrive after neutrophils and phagocytose bacteria, debris, and dead neutrophils.
May present antigen to lymphocytes to induce a secondary immune reaction
38
Chronic Inflammation
- Slow onset
- Long duration
- May never resolve
39
Causes of chronic inflammation
- 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
40
Sequence of Chronic Inflammation
- 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.
41
Describe the immune system
Made up of organs, tissues, cells including leukocytes, molecules and soluble factors.
Protects from microorganisms, removes toxins, promotes inflammation, destroys tumour cells.
42
Phagocytes
- 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
43
Antigen-presenting cells
Present antigens to T-cells following phagocytosis (MH class 2) or infection (MH class 1)
44
Granulocytes
- contain granules in cytoplasm
- all other than mast cells are polymorphonuclear
45
Which leukocytes are phagocytes?
Neutrophils
Eosinophils
Monocytes
Dendritic cells
Macrophages
46
Which leukocytes are granulocytes?
Basophils
Mast cells
Neutrophils
Eosinophils
47
Which leukocytes are antigen-presenting cells?
Monocytes
Dendritic cells
Macrophages
Lymphocytes
48
Basophils
- 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
49
Mast cells
- Granulocytes, non-phagocytic - involved in the inflammatory response
- Contain histamine in granules - degranulate to release histamine
50
Neutrophils
- 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
51
Eosinophils
- 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
52
Monocytes
- 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
53
Dendritic cells
- 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
54
Macrophages
- 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
55
Lymphocytes
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
56
Innate vs adaptive immunity
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.
57
Innate immunity
- 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
58
How does the immune system detect microbes?
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.
59
Which lymphocytes detect microbes in blood vs tissues?
In blood: monocytes and neutrophils
In tissues: macrophages and dendritic cells
60
Describe secreted and circulating pattern recognition receptors
- Antimicrobial peptides secreted by epithelia and phagocytes which activate complement
- Found within fluids lining epithelial cells eg in the lungs
61
How do secreted and circulating PRRs target bacteria?
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
62
What do PRRs on cell surfaces do?
Cell surface receptors typically detect bacteria, and induce the release of pro-inflammatory cytokines.
63
What do PRRs on organelles do?
Endosomal PRRs (on organelles) typically detect abnormal RNA and DNA, and induce release of type 1 interferons, which have antiviral effects
64
Why do these receptors dimerise?
Most receptors dimerise with themselves or other receptors, to expand the amount of ligands they can bind to.
65
Types of cell-surface PRRs
Lectin receptors
Toll-like receptors
Scavenger receptors
66
Lectin receptors
- expressed by macrophages and dendritic cells
- bind to certain foreign carbohydrates on microbes (Many types, Many microbes)
- use carbohydrate recognition domains (CRD)
67
Toll-like receptors
Many types - recognise different common foreign molecules on microbes eg flagella, foreign molecule DNA and RNA
68
Scavenger receptors
- large family of receptors
- mainly bind to foreign lipids and lipoproteins, but a variety of ligands
69
Types of endosomal PRRs
RIG-I-like receptors
NOD-like receptors
70
RIG-I-like receptors
- 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
71
NOD-like receptors
- detect cytoplasmic bacteria
- regulate inflammatory and cell death responses
- NOD1 + NOD2 recognise peptidoglycan in Bacterial cell walls
72
Damage associated molecular patterns
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
73
The damage chain reaction
- 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
74
Stages of extravasation (diapedesis)
- 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
75
Innate immunity responses to microbes
- Phagocytosis
- Release of free radicals
- Release of nitric oxide
- Release of enzymes eg lysozymes
- Proteins such as defensins
- pH changes
- Apoptosis
76
Adaptive Immunity
- Significantly slower than innate (the first time)
- highly specific cells with immunologic memory which circulate around tissues and lymph
77
Why is adaptive immunity needed?
- 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
78
Cell-mediated response
- 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
79
Typical use of MCH molecules
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.
80
When are antigens presented on MHC molecules?
- 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)
81
How do T-cells respond to each type of MHC presenting antigens?
- 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
82
What occurs when T-cells activate?
- 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
83
What do T-cell differentiate into depending on the environment?
MHC1 receptor detected: CD8 cytotoxic cells
MCH2 receptor detected: CD4 cells
High interleukin 12: CD4 -> TH1 cells
Low interleukin 12: CD4 -> TH2
84
Action of CD8 cells
- 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
85
Action of TH1 cells
Secrete interferon gamma to help antigen-presenting cells phagocytose
86
Action of TH2 cells
TH2: humoral response - secretes interleukins 4,5,10, which help B-cells produce antibodies.
87
Humoral response
- 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.
88
B-cells as antigen presenting cells
- 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
89
TH2 cells activating B-cells
- 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)
90
Soluble factors
Complement, cytokines, chemokines, and antibodies. Make up the immune system alongside Leukocytes and lymphoid organs and tissues.
91
Complement
Group of around 20 serum proteins secreted (in an inactive form) by the liver that need to be activated to be functional
92
Complement cascade
One complement molecule gets activated and is converted to an enzyme, which activates another complement protein, process repeats
93
Models of action of complement proteins
- Direct lysis
- Chemotaxis: attract more leukocytes to the site of Infection
- Opsonisation: Coat the invading organism
94
How can complement be activated? (3)
- 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
95
C3A + C5A action
Complement proteins which bind to receptors on leukocytes to draw them to sites of infection
96
C3B action
Opsonisation: Inserts itself into the membrane of bacteria, to attract white blood cells to bind to the bacteria.
97
MAC action
Four complement proteins which form pores in the membrane of pathogens, leading to osmolysis.
98
Cytokines
- proteins secreted by immune and non-immune cells
- regulate immune response
- can be pro-inflammatory and anti-inflammatory
99
Types of cytokines
- interferons
- Interleukins
- Colony stimulating factors
- Tumour necrosis factors
- Chemokines
100
Interferons
- 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
101
Interleukins
- 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.
102
Colony stimulating factors
- 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
103
Tumour necrosis factors
- not just involved in tumour necrosis!!
- mainly a pro-inflammatory molecule (eg TNF alpha and beta)
- mediate inflammation and cytotoxic reactions
104
Chemokines
- 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
105
Antibodies
- 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
106
Classes of antibodies
* IgG
* IgA
* IgM
* IgE
* IgD
107
IgG
- 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
108
IgM
- 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
109
IgA
- 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
110
IgD
- Only 1% of Ig in serum
- Can be bound as a monomeric form to mature B cells as mIgD, similar to mIgM
111
IgE
- 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
112
Hypersensitivity
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.
113
Types of hypersensitivity
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.
114
Type I hypersensitivity
Type I hypersensitivity is an immediate reaction to environmental antigens mediated via IgE antibodies.
115
Allergens
Allergens are antigens which trigger allergic reactions, with the ability to induce a strong IgE response.
116
Features of allergens
- 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
Atopy
Atopy is an inherited trait for type I hypersensitivity, tendency to develop exaggerated reactions.
118
Hypersensitivity I - initial allergen contact
- 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
Hypersensitivity I - second allergen contact
- 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
Acute anaphylaxis
Type I hypersensitivity
Only anaphylaxis if airways, breathing, or circulation are affected
Occurs within minutes and lasts 1-2 hours
121
Anaphylaxis symptoms
- vasodilation
- increased vascular permeability
- bronchoconstriction
- Urticaria
- Angio-oedema
122
Passive immunisation
- 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
Approaches to active immunisation
3 main approaches:
- Whole microbe
- Parts of virus that trigger the immune system
- Just the genetic material of a virus
124
Carcinogenesis
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
How does neoplastic transformation occur?
- 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
Oncogenesis
Development of the neoplasm, process resulting in benign as well as malignant tumours.
127
Tumour
A tumour is any abnormal swelling including:
- Neoplasm
- Inflammation
- Hypertrophy
- Hyperplasia
128
What is a neoplasm?
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
Features of neoplasia
Neoplasia is:
- Autonomous: not reliant on homeostatic mechanisms to regulate growth
- Abnormal: not healthy
- Persists: after removal of initiating stimulus
- New growth
130
How is the stroma made?
- 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
How does angiogenesis affect a tumour?
- 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
How do neoplasms have uncontrolled proliferation?
- 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
Invasive carcinoma
Cells pass through the basement membrane, and can invade into lymphatics and veins.
134
What do the neoplastic cells need in order to invade?
The cells must produce collagenases, and must be motile (tumour cell derived motility factors)
135
Micro-Invasive carcinoma
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
What do the neoplastic cells need to do to metastasise?
- 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
Why might neoplastic cells metastasise in the lungs?
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
Why might neoplastic cells metastasise in the liver?
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
Why might neoplastic cells metastasise in bone?
Some metastases combine with adhesion molecules on blood vessels in bone (prostate, breast, thyroid, lung, and kidney cancers)
140
Why might neoplastic cells metastasise elsewhere in the body?
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
Features of benign neoplasms
- 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
Carcinoma in situ
The neoplastic cells have not passed the basement membrane, so cannot pass into lymphatics or blood vessels.
143
How do benign neoplasms grow on mucosal surfaces?
- Ulceration of mucosal surface is rare
- Growth on mucosal surfaces is often exophytic, with a circumscribed/ encapsulated edge
144
How can benign neoplasms be damaging?
- 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
Malignant neoplasms definition
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
Features of malgnant neoplasms
- 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
How do malignant neoplasms grow on mucosal surfaces?
Growth on mucosal surfaces and skin is often endophytic. There is an irregular infiltrative edge and vascular permeation. The surface is ulcerated.
148
How do malignant tumours grow in organs?
Malignant tumours in solid organs tend to have irregular margins, often with tongues of neoplastic tissues penetrating adjacent normal structures.
149
How do malignant neoplasms cause morbidity?
- 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)
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The specific cell of origin of a tumour
Histogenesis
151
When cell type cannot be determined, the neoplasm is said to be
anaplastic
152
Neoplasm of non-glandular non-secretory epithelium
Papilloma (eg squamous cell papilloma)
153
Neoplasm of glandular or secretory epithelium
Adenoma (eg thyroid adenoma)
154
Malignant epithelial neoplasms
Carcinoma
155
Carcinoma of glandular epithelium
Adenocarcinoma
156
How are connective tissue neoplasms named?
Names after what structures they look like, with -oma
If malignant, -sarcoma is added
157
Neoplasm of adipocytes
Lipoma
158
Neoplasm of cartilage
Chondroma
159
Neoplasm of bone
Osteoma
160
Neoplasm of vascular system
Angioma
161
Neoplasm of striated muscle
Rhabdomyoma
162
Neoplasm of smooth muscle
Leiomyoma
163
Neoplasm of nerves
Neuroma
164
How is tumour grade determined?
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.
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How are tumours investigated?
- Radiology guided biopsy: access to tumour, risk of complications
- Frozen section: histopathology can assess under microscope
166
What is TNM staging?
Tumour; size and extent of spread,
Nodes; extent of lymph node metastases,
Metastases; extent of spread to other parts of the body
167
Carcinogens
Agents known or suspected to cause cancer, by acting on DNA (mutagenic).
168
Features of chemical carcinogens
- 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
Viral carcinogens features
- Cause around 10-15% of all cancers
- Most oncogenic viral infections don't result in cancer, just a risk
170
Radiation carcinogens features
- 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
Other biological carcinogens
- hormones (eg oestrogen)
- parasites
- Mycotoxins
172
Why are carcinogens hard to identify?
- 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.
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Lifestyle cancer risk factors
- 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)
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Pharmacodynamics
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
Agonists
bind to receptors and activate them
176
Antagonist
binds to receptor and prevents agonists from binding - less activation, alone have no effect
177
Allosteric ligands
bind to a different site, and regulate the activity of the receptor
178
Inverse agonist
bind to the same receptor as an agonist, but have the opposite effect of the agonist
179
Factors governing a drug's pharmacodynamics
* Target receptor
* Target tissue
* Tolerance
* Desensitisation
* Efficacy
* Potency
* Selectivity
180
Affinity
* how well the drug binds to the target
* property of both agonists and antagonists
* some drugs bind irreversibly
181
Tissue related factors affecting drug action
- Number of receptors
- Signal amplification
- Signal cascade and cellular response
182
Tolerance
Reduction in agonist effect over time due to continuously, repeatedly, high concentrations
183
Desensitisation
Rapid development of tolerance (ie over minutes instead of weeks)
Can occur with the initial dose of a medication
184
Efficacy
The drug's ability to induce a response, as a % it can reach
185
Full agonists
reach 100% response, maximum efficacy
186
Partial agonists
less than 100% response, never reaches maximum
187
Potency
How much drug is needed to induce a response
188
Which drug is more potent, and which is more efficacious?
(look at notes)
Compound D is more potent, compound A is more efficacious
189
Selectivity
how much the drug binds only to its intended target
190
Pharmacokinetics
the fate of a chemical substance administered to a living organism, aka what the body does to the drug
191
Pharmacokinetics ADME
A: Absorption
D: Distribution
M: Metabolism
E: Excretion
192
What does ADME tell us about a given drug?
- 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
Absorption
Transfer of drug molecule from site of administration to the systemic circulation
194
Bioavailability
the proportion of the administered dose which reaches the systemic circulation
195
Bioavailability of IV and IA vs other drugs
- 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
What is IV, IA, IM, and SC?
IV - intravenous
IA - intra-arterial
IM - intramuscular
SC - subcutaneous
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What are PO, SL, and INH?
PO - oral
SL - sublingual
INH - inhaled
198
What are PR and PV?
PR - rectal
PV - vaginal
199
What is TOP and TD?
TOP - topical
TD - transdermal
200
What is IT?
Intrathecal - injection directly into the spinal cord CSF
201
Mechanisms for drugs to permeate membranes
- 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)
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How does drug ionisation affect absorption?
- 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
Where are weak acids vs bases absorbed best orally?
- weak acids are best absorbed in the stomach
- weak bases are best absorbed in the intestine
204
Obstacles for drugs in the stomach
- 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
How can drug structure affect absorption in the small intestine?
- lipid soluble/ unionised molecules diffuse down concentration gradient
- large or hydrophilic molecules are poorly absorbed
206
How can medicine formulation affect absorption in the small intestine?
- Capsule/ tablet coating can control time between administration and drug release
- Modified release controls the rate of absorption (less frequent dosing needed)
207
How can P-glycoprotein affect absorption in the small intestine?
- Substrates are removed from intestinal endothelial cells back into the lumen through p-glycoprotein
- This reduces absorption
208
First pass metabolism
Metabolism of drugs preventing them from reaching the systemic circulation
209
Examples of first pass metabolism
- Degradation by enzymes in the intestinal wall
- absorption from the intestine into the hepatic portal vein, then metabolism by liver enzymes
210
How can first pass metabolism be avoided?
Avoid by giving routes that avoid splanchnic circulation eg rectally, sublingually
211
What does bioavailability depend on?
- 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
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What factors affect drug distribution?
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
Volume of distribution (Vd)
- 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
What reduces distribution to the cerebrospinal fluid?
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
What can increase distribution to the CNS?
- drugs with high lipid solubility
- Intrathecal administration (injection into subarachnoid space)
- inflammation causes barrier to become leaky
216
How can obesity complicate drug dosing?
- 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
Metabolism
Modification of chemical structure to form new chemical entity (metabolite)
218
Drug elimination
The process by which the drug becomes no longer available to exert its effect on the body
219
Phase I vs phase II metabolism
Phase 1: Oxidation/reduction/hydrolysis to introduce reactive group to chemical structure
Phase 2: Conjugation of functional group to produce hydrophilic, inert molecule
220
Phase I metabolism
- 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
How can CYP450 function vary?
- genetic variation
- reduced function in severe liver disease
- interactions: enzyme inhibiting/inducing drugs or food can reduce/increase enzyme activity
222
Phase II metabolism
- 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
How is drug metabolism relevant in liver failiure?
- the metabolism of the drug may be reduced
- additional dose or frequency needed?
- additional monitoring required?
- avoid?
224
How are liquids, solids, and gases excreted?
Liquids (small, polar molecules): urine, bile, sweat, tears, breast milk
Solids (large molecules): faeces (through biliary excretion)
Gases (volatiles): expired air
225
Which drugs are excreted in glomerular filtration?
- free/unbound drug molecules
- very large molecules excluded
226
Which drugs are excreted in active tubular secretion?
- drug molecules transported by carrier systems eg organic anion transporter, organic cation transporter
- can clear protein-bound drug
- Most effective renal clearance mechanism
227
Which drugs are reabsorbed in passive reabsorption?
- diffusion down concentration gradient from tubule back into peritubular capillaries
- hydrophobic drugs diffuse easily
- highly polar drugs will be excreted
228
First order kinetics
- 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
What is Cmax and tmax?
Cmax: maximum plasma concentration reached
tmax: time taken to reach Cmax
230
Clearance (CL)
Efficiency of removal of drug by all eliminating organs
231
How are Cmax and tmax affected in modified release oral doses?
Slower absorption, therefore lower Cmax, and higher tmax.
232
Half life (t1/2)
* Time taken for plasma drug concentration to fall by 50%
* Different doses of the same drug will have the same half life
233
What is half life dependent on?
- 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
When is a drug considered cleared?
A drug will be 97% cleared from the body after 5 x half lives - this is considered cleared in clinical practice.
235
How does half life affect dosing?
- 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
Steady state (IV) meaning
Rate of drug input is equal to rate of drug elimination
237
Css and time to Css meaning
Css: drug plasma concentration at steady state
Time to Css: 5x t1/2 (after treatment initiation and after a dose increase)
238
How are Css and time to Css changed by a 50% dose?
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
Zero order kinetics
- 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
Druggable
a protein which can be used as a target for a drug
241
Types of drug targets
- receptors
- enzymes
- transporters
- ion channels
242
What is a receptor?
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
Describe G-protein coupled receptors
- 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
Describe kinase-linked receptors
- 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
Describe cytosolic receptors
- steroid hormones
- work by modifying gene transcription
- ligand binding causes a conformational change allowing the receptor to bind to DNA
246
What is an enzyme inhibitor?
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
Irreversible enzyme inhibitors
usually react with the enzyme and change it chemically (e.g. via covalent bond formation)
248
Reversible enzyme inhibitors
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
How can drugs affect ion channels?
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
Drug interactions
When a substance alters the expected performance of a drug. Not only 2 prescribed drugs - can be food eg grapefruit juice, or supplements
251
Why are drug interactions prevalent?
Ageing population and increasing multimorbidity
252
Pharmacodynamic drug interactions
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
Pharmacokinetic drug interactions
When a drug affects the pharmacokinetics (absorption, distribution, metabolism or excretion) of another drug
254
In which ways can one drug affect pharmacokinetics of another?
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
How can one drug affect absorption of another drug?
- drugs which alter the pH of the GI tract
- formation of insoluble drug complexes
- p-glycoprotein induction / inhibition
256
How can one drug affect the distribution of another?
Only unbound drugs will be distributed from the blood plasma - if drugs compete for protein binding, more drug will be distributed
257
How can one drug affect the metabolism of another?
- 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
How can one drug affect excretion of another?
- Drugs can compete for renal tubular excretion
- Both bind to organic anion transporters or organic cation transporters - drug remains in bloodstream
259
How can drug interactions be avoided?
- 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
What are examples of high-risk drugs for drug interactions?
- 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
Why might a patient be high risk for drug interactions?
- Polypharmacy
- kidney or liver impairment
- Extremes of age
262
How can drug interactions be managed?
- 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
Adverse Drug Reactions
A response to a medicinal product, or combination of medicinal products, which is noxious and unintended
264
Impacts of ADRs for patients
- Reduced quality of life
- poor compliance
- Reduced confidence in clinicians and the healthcare system
- Unnecessary investigations or treatments
265
Impacts of ADRs for the NHS
- increased hospital admissions
- Longer hospital stays
- GP appointments
- Inefficient use of medication
266
ABCDEFG classification of ADRs
Augmented
Bizarre
Chronic/ continuing
Delayed
End of use (withdrawal)
Failiure of treatment
Genetic
267
Augmented ADRs
- 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
Bizarre ADRs
- not related to the drugs pharmacology
- not dose related
- serious illness or mortality
- symptoms do not always resolve upon withdrawing drug
269
Chronic/ continuing ADRs
- ADRs that continue after the drug has been stopped - eg osteonecrosis, heart failure
270
Delayed ADRs
- ADRs that become apparent some time after stopping the drug
271
End of use ADRs
ADRs develop after the drug has been stopped
272
Failure of treatment ADRs
- Unexpected treatment failure
- due to drug interaction or drug-food interaction
- or poor compliance with administration instructions
273
Genetic ADRs
- drug causes irreversible damage to genome - eg children of women taking thalidomide
274
DoTS classification of ADRs
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
Pharmacogenomics
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
How can genomics affect parmacodynamics?
- variations in drug receptor
- variations in efficacy
- increased incidence of adverse drug reactions (could be off target)
277
How can genomics affect pharmacokinetics?
- variations in drug metabolism
- variations in efficacy
- increased incidence of adverse drug reactions
278
Which sympathetic nervous system receptors can drugs target?
Alpha 1 + alpha 2
Beta 1 + beta 2
(all adrenergic - adrenaline and noradrenaline)
279
What do sympathetic alpha 1 receptors do?
Found on all smooth muscles, glands, and organs of the sympathetic nervous system. Causes vasoconstriction of peripheral blood vessels.
280
What do sympathetic alpha 2 receptors do?
Found on pre-synaptic terminals of sympathetic neurons. Act in feedback loops to stop noradrenaline release.
281
What do sympathetic beta 1 receptors do?
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
What do sympathetic beta 2 receptors do?
Found on all smooth muscles, glands, and organs of the sympathetic nervous system. Stimulates bronchodilation.
283
Which drugs act on alpha 1 receptors?
Alpha blockers (antagonists) block the effect of the sympathetic nervous system on the blood vessels, causing vasodilation.
284
Which drugs act on alpha 2 receptors?
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
Which drugs act on beta 1 receptors?
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
Which drugs act on beta 2 receptors?
Beta 2 agonists such as salbutamol trigger bronchodilation.
287
What is the bioavailability of oral morphine?
50%
288
How do opioids work?
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
