Pathology Flashcards
What is the role of the autopsy?
Who was the deceased?
When did they die?
Where did they die?
How did they come about their death?
What is the structure of an autopsy?
- History
- External examination
- Evisceration
- Internal examination
- Reconstruction
Name the three types of death referred to the coroner?
Presumed Natural (Cause not known
Presumed Iatrogenic
(Caused by care or surgery)
Presumed Unnatural
Define acute inflammation
Initial and transient series of tissue reactions to injury of short duration that normally resolves
Define chronic inflammation
Subsequent and prolonged tissue reactions following initial response (Sequel to acute that may never resolve)
What are the 5 cells involved in inflammation?
Neutrophil polymorphs Macrophages Lymphocytes Endothelial cells Fibroblasts
Describe the roles of neutrophil in inflammation
- Short lived - first cells on scene
- Cytoplasmic granules full of bacteria killing enzymes
- Die at the scene of inflammation
- Release chemicals that attract other inflammatory cells (Macrophages)
Describe the role of macrophages in inflammation
- Long lived (Weeks to months)
- Phagocytic
- Ingest bacteria and debris
- May carry debris away
- Present antigens to lymphocytes
Describe the role of lymphocytes in inflammation
- long lived
- Produce chemicals that attract other inflammatory cells
- Immunological memory for past infections and antigens
Describe the role of endothelial cell in inflammation
- Line capillary blood vessels in areas of inflammation
- Become sticky in areas of inflammation so inflammatory cells adhere to them
- Become porous to allow inflammatory cells to pass into tissues
- Grow into areas of damage to form new capillary vessels
Describe the role of fibroblasts in inflammation
Long lived cells that form collagen in areas of chronic inflammation and repair
Name the 6 causes of acute inflammation
- Microbial Infections
- Hypersensitivity reactions
- Physical agents (Trauma, ionising radiation, heat and cold)
- Chemicals (Corrosive, acids, alkalis and reducing agents)
- Bacterial toxins
- Tissue necrosis
Define hypersensitivity Reactions
Reaction which occurs when an altered state of immunological responsiveness causes an inappropriate or excessive immune reaction that damages tissues
What are the 5 characteristic of acute inflammation
- Redness (Dilation of small blood vessels) Rubber
- Heat (Due to increased blood flow) Calor
- Swelling (oedema from accumulation of fluid in the extravascular space) Tumor
- Pain (Due to tissue distortion, pus under pressure in abscess cavity and chemical mediators that induce pain (Bradykinin, serotonin and prostaglandins) Dolor
- Loss of function
Name the three processes involved in the acute inflammatory response
- Change in vessel calibre (width) and increased flow
- precapillary sphincters regulate flow through the capillary bed - Increased vascular permeability and fluid exudate formation
- Formation of cellular exudate due to increased capillary hydrostatic pressure and escape of plasma proteins
Name the 4 outcomes of acute inflammation
1. Resolution = complete restoration of tissue to normal 2. Suppuration = formation of pus 3. Organisation = tissue replaced by granulation tissue 4. Progression to chronic inflammation
What are the 4 causes of chronic inflammation?
- Primary chronic inflammation
- Transplant rejection
- Progression from acute inflammation
- Recurrent episodes of acute inflammation
What are the features of chronic inflammation?
- Cellular infiltrate consists of lymphocytes, plasma cells and macrophages
- Macrophages may form multinucleate giant cells
- Neutrophils are scarce
- Continued tissue destruction - necrosis
What is a granuloma?
Aggregate of epithelioid histiocytes
Name some examples of granulomatous inflammation?
- Tuberculosis
- Leprosy
- Crohns disese
- Sarcoidosis
What causes histolytic giant cells to form?
Accumulation of particulate matter that is indigestible by macrophages
What do fibroblasts produce?
Collagen
Name 6 types of cell that are capable of regeneration
Hepatocytes Pneumocytes All blood cells Gut epithelium Skin epithelium Osteocytes
Name 2 types of cell that do not regenerate
Myocardial cells
Neurones
Define thrombus
Solid mass of blood constituents formed within an intact vascular system during life
Name 3 factors that pre-dispose thrombosis?
Change in the vessel wall = endothelial damage
Change in the constituents of blood = more platelets
Change in the blood flow = laminar to turbulent
Describe the formation of thrombus in veins
Slow blood flow in veins as not pulsatile so blood in stasis - if endothelial wall becomes sticky then thrombus forms but more slowly - most likely to form at valves
What are the 4 potential outcomes once a thrombus has formed
- lysis and resolution
- Organisation = scar tissue by invasion of macrophages which clear away the thrombus and fibroblasts and replane it with collagen
- Recanalise = intimal cells of vessel on which the thrombus lies proliferate, capillaries grow through it and fuse to form larger vessels
- Embolism = bit breaks off
Why does aspirin prevent thrombus formation
Because it is an anti platelet drug so prevents platelets binding to exposed collagen in endothelial wall and prevents further collagen aggregation
Define Embolus
Mass of material in the vascular system that is able to become lodged within a vessel and block its lumen
Define ischaemia
Reduction in blood flow
Define infarction
Death of cells due to reduced blood flow
Describe what happens in reperfusion injury
Limited blood supply has caused cells to become damaged but they have not died. If blood flow is restored to the cells then they may start to produce superoxide ions that cause damage to the cells
Are macrophages associated with acute or chronic infection?
Chronic
Are plasma cells associated with acute or chronic infection?
Chronic
Are neutrophil polymorphs associated with acute or chronic infection?
Acute
Are lymphocytes associated with acute or chronic infection
Chronic
Are giant cells associated with acute or chronic infection
Chronic
Define organisation
The repair of specialised tissues by the formation of a fibrous scar which forms due to the production of granulation tissue and removal of dead tissue by phagocytosis
What is granulation tissue made of?
Capillary loops and myofibroblasts
What is a granuloma
An aggregate of epithelioid histiocytes
Describe the process of repair
- Capillary endothelial cells proliferate into the area forming a series of loops
- Fibroblasts are stimulated and divide and secrete collagen
- Fibroblasts acquire muscle filaments to form myofibroblasts
- Capillary endothelial cells and the myofibroblasts = granulation tissue
Describe the process of healing by first intention
- cut blood vessels either side are occluded by thrombosis and fibrin deposition binds the two sides
- Coagulated blood on surface forms a scab to keep wound clean
- Capillaries proliferate to bridge gap and fibroblasts secrete collagen
- elastic network of dermis fails to reconnect
- Basal epidermal cells proliferate over the gap
When does healing by second intention occur?
When there is tissue loss or the wound margins aren’t apposed
Describe the characteristics of healing by second intention
- Phagocytosis to remove debris
- Granulation tissue to fill in the defects and repair specialised tissue
- Epithelial regeneration to cover the surface
Describe the process of mucosal alteration
- damaged mucosa replaced from margins
- Damaged blood vessels bleed and surface becomes covered with fibrin layer
- Macrophages remove dead tissue by phagocytosis
- Granulation tissue produced in ulcer base as capillaries and myofibroblasts proliferate
- Mucosa regenerates at margins and spreads across ulcer floor
- Fibrous scar tissue replaces the muscle and distorts the stomach upon contraction
Define end artery
Tissues that only have one arterial supply and such if this is blocked there is no possibility of collateral supplies taking over
What two things determine whether ischaemia is reversible or not
- Duration of the ischaemic period
2. Metabolic demands of the tissue
Name the 5 macroscopic appearances of chronic inflammation
- Chronic ulcer - breach of mucosa with a base lined by granulation tissue with fibrous tissue extending through the muscle layers of the wall
- Chronic abscess cavity
- Thickening of the wall of a hollow viscus by fibrous tissue
- Granulomatous inflammation
- Fibrosis
What do B lymphocytes become?
On contact with the antigen they become plasma cells
What do T lymphocytes become
- On contact with antigen they produce cytokines which causes recruitment and activation of other cells
- Responsible for cell mediated immunity
What is granulation tissue?
Important component of healing that comprises small blood vessels in a connective tissue matrix with myofibroblasts
What are the causes of chronic inflammation
Primary chronic inflammation
Transplant rejection
Progression/recurrent episode of acute inflammation
Define atherosclerosis
Disease characterised by the formation of elevated lesions in the intimal of large and medium sized arteries
What is the earliest lesion of an atherosclerotic plaque?
Fatty streak
What is a fatty streak?
Yellow linear elevation of the intimal lining composed of masses of lipid laden macrophages
Where do fatty streaks occur in the body?
In the systemic part of the body which is under higher pressure, not in the pulmonary part because these arteries are under low pressure
Where do atherosclerotic plaques form in the body?
Form at arterial branching points and bifurcations
What are the components of an atherosclerotic plaque?
Central lipid cholesterol core Fibrous tissue Collagen connective tissue cap Bordered by foam cells Lymphocytes (Chronic inflammation) Smooth muscle cells
What are the causes of atherosclerosis
Hypercholesterolaemia Smoking (Nicotine free radicals) Hypertension (Increased shearing forces) Diabetes (If poorly controlled) (Glucose damages endothelium) Hyperlipidaemia (Lipid damages endothelial cells) Low socioeconomic status] Male gender Increasing age
Describe the formation of an atherosclerotic plaque
- Endothelial cell damage leading to increase expression of cell adhesion molecules and increased permeability to LDL
- Inflammatory cells and lipids enter intimal layer and form plaques
- Foam cells phagocytose LDL and die through apoptosis and spill their lipid content in enlarging lipid core
- Plaques contains capillaries that can burst forming thrombi and haemorrhage causing plaque to increase in size
What are the complications of atherosclerosis?
Cerebral/myocardial infarct
Abdominal aortic aneurysm leading to rupture or dilation
Peripheral vascular disease –> Gangrene
Define apoptosis
Programmed cell death - defined sequence of intracellular events that lead to the removal of the cell without the release of products harmful to surrounding cells (enzymatic digestion of nuclear and cytoplasmic contents followed by phagocytosis of breakdown products)
What are the external signals that initiate apoptosis?
Detachment from extracellular matrix
Withdrawal of growth factors
Specific signals from other cells
What are the intracellular signals that initiate apoptosis?
DNA damage
Failure to conduct cell division
What are the characteristics of apoptosis?
- Switch in cell determines time to die
- Release internal enzymes that cause nucleus to shrivel, organelles moved to membrane bound vesicles
- Macrophages eat this and no scar tissue remains
What causes DNA damage and triggers apoptosis?
cosmic rays and UV light
Which gene identifies DNA damage, induces cell cycle arrest and triggers the chemicals that switch on apoptosis
P53
What enzymes does p53 cause to be released to trigger apoptosis
Caspase
What is the affect of BCL2 on apoptosis?
Inhibiting caspases
What is the affect of Bax proteins on apoptosis?
Promote caspases
What is the affect of FAS ligand on apoptosis?
Stimulates caspases
Why is apoptosis important in development?
- Interdigital cell death to separate fingers
- Cell death to remove redundant tissue following palatine fusion during mouth of the roof development
- Cell death to close the dorsal neural tube
- Urachus cell death to remove redundant tissue between bladder and umbilicus
Define necrosis
Unintended cell death in response to cellular injury - traumatic process which induces inflammation and repair
Give 5 examples of necrosis
Toxic spider venom Frost bite Cerebral infarction Avascular necrosis of bone (Head of the femur and scaphoid) Pancreatitis
Define hypertrophy
Increase in the size of the tissue due to increases in the size of constituent cells
Define hyperplasia
Increase in the size of a tissue due to increases in the numbers of constituent cells
Give some examples of hyperplasia
Prostate
Endometrial
Endothelial
Neuronal
When does a mix of hyperplasia and hypertrophy occur
In the uterus where the placental cells increase in size but also divide
Define atrophy
Decrease in the size of tissue caused by a decrease in the number of the constituent cells or a decrease in their size
Define metaplasia
Change in the differentiation of a cell from one fully differentiated type to a different fully differentiated type
Give two examples of metaplasia
Normally the lining of the bronchius is ciliated columnar epithelium but heavy smoking causes this epithelium to change to simple squamous
Barrett’s oesophagus - cells at the Lower end of the oesophagus change from stratified squamous epithelium to columnar
Define dysplasia
Imprecise term for morphological changes seen in the cells progression to becoming cancer
Why does the incidence of disease increase with age?
- Probability of contact with an environmental cause increases with duration of exposure risk
- Disease may depend on the cumulative effects of one or more environmental agent
- Impaired immunity with ageing increases susceptibility to some infections
- Latent interval between the exposure and appearance of symptoms may take decades
Define autosomal dominant
One copy of the gene is required for an individual to be affected
Define autosomal recessive
Both copies of the paired gene are required to be abnormal for expression of the disease
Define acquired disease
Caused by non genetic environmental factors ie. foetal alcohol syndrome
Name 5 mechanisms that cause cellular damage
Protein cross linking
DNA cross linking
DNA mutations that functionally alter the genes
Mitochondrial damage
Defects in oxygen and nutrient utilisation
What is the importance of telomeric shortening?
Telomere is non-coding region at end of chromosome - this sequence is not fully copied prior to mitosis
As the cells divide the telomeres get shorter and shorter to the point the cell can no longer divide further
Name 6 age related conditions
- Dermal elastosis - UVB hight causes collagen protein cross linking = wrinkles
- Osteoporosis = loss of bone matrix due to lack of oestrogen
increased resorption and decreased formation - Cataracts = UVB light crosslinks proteins making them opaque
- Senile dementia - Brain atrophy
- Sarcopenia = lack of muscle due to decreased growth hormone, decreased testosterone and increased catabolic cytokines
- Deafness as the cilia in ears aren’t replaced - loss of hair cells
What is the name of the main effector cell in acute inflammation
Neutrophil polymorph
What is the name of the cell that produces collagen in fibrous scarring?
Fibroblast
Which of the following is an example of acute inflammation Glandular fever Leprosy Appendicitis Tuberculosis
Appendicitis
What are the crystals deposited in joints in gout?
Uric acid
In which of the following does granulatomous inflammation occur? Crohns disease Acute appendicitis Infectious mononucleosis Lobar pneumonia
Crohns disease
What Is the specific name of calcification in diseased as opposed to normal tissues?
Stenosis
Which of the following is a chronic inflammatory process from its start? Appendicitis Cholecystitis Infectious mononucleosis Lobar Pneumonia
Infectious mononucleosis
What is the name given to cells that produce antibodies?
Plasma cells
What is the main cause of basal cell carcinoma?
Ultra violet light damaging the skin
What is the treatment for basal cell carcinoma and why is it the most appropriate option
Complete local excision because BCC only invades the skin locally
What is leukaemia?
Tumour of the WBC’s so WBC circulate round the body and so will any tumours of the white blood cells
What are some of the symptoms of leukaemia?
Weight loss Fever Frequent infections Muscular weakness Pain and tenderness in the joints and bones Fatigue Loss of appetite Swelling of lymph nodes Enlarged spleen Night sweats Easy bleeding and bruising Purple patches or spots
What is the treatment for leukaemia?
Chemotherapy
Which cancers most commonly spread to the bone?
Breast, prostate, lung, thyroid and kidney
What is adjuvant therapy?
Extra treatment given after surgical resection
Name two ways to confirm a diagnosis of breast cancer?
Mammogram
Biopsy using core needle
How can you determine if breast cancer has spread to the axillary lymph nodes?
Ultrasound of the axilla
How can you check if breast cancer has spread to the rest of the body?
Bone and CT scan
What are the adjuvant therapies for breast cancer following lumpectomy?
Anti-oestrogen therapy
Radiotherapy
Herceptin
Define carcinogenesis
Transformation of normal cells to neoplastic cells through permanent genetic alterations or mutations
Define carcinogen
agents known or suspects to cause tumours by acting on DNA (Mutagenic)
What experimental evidence can be used to determine if something is a carcinogen?
Incidence of tumours in laboratory animals
Cell/Tissue cultures
Mutagenicity testing in bacterial cultures
What are the 5 classes of carcinogens?
- Chemical
- Viral
- Ionising and non-ionising radiation
- Biological agents = Hormones, parasites and mycotoxins
- Miscellaneous
What sort of cancers is exposure to polycyclic aromatic hydrocarbons associated with?
Lung cancer
Skin cancer
What sort of cancer is exposure to aromatic amines associated with
Bladder cancer
What sort of cancer is exposure to nitrosamines associated with
Gut cancer
What sort of cancer is exposure to alkylating agents associated with?
Leukaemia
Increase exposure to UVA and UVB in ultraviolet light increases the risk of what conditions?
Basal cell carcinoma
Melanoma
Squamous cell carcinoma
Xeroderma pigmentosum
Name three classes of biological agent that are carcinogens
Hormones
Mycotoxins
Parasites
Name 2 types of hormone that are considered carcinogens and the cancers they are associated with
Increased oestrogen = increased mammary/endometrial cancer
Anabolic steroids = hepatocellular carcinoma
Name a type of mycotoxin that is a carcinogen and what type of cancer it is associated with
Aflatoxin B1 –> Hepatocellular carcinoma
Name two types of parasites that are considered carcinogens and the cancers they are associated with
Chlonorchis sinensis –> Cholangiocarcinoma
Shistosoma –> Bladder cancer
Name 2 types of miscellaneous carcinogens and the cancers they are associated with?
Asbestos = mesothelioma, asbestosis, lung cancer
Metals
Name some host factors that may determine susceptibility to carcinogenesis
Race Diet Constitutional factors = Age, inherited predisposition, gender Premalignant lesions Transplacental exposure
Define tumour
Any abnormal swelling
Define Neoplasm
A lesion resulting from the autonomous or relatively autonomous abnormal growth of cells which persists after the initiating stimulus has been removed
Which processes initiate the formation of neoplasms
Accumulation of genetic alterations such as mutations, translocations, rearrangements, amplifications and epigenetic changes that enable the cell to escape normal growth regulatory mechanisms
What are the two main components of a neoplasm?
- Neoplastic cells - synthesise and secrete collagen, mucin and keratin that accumulate in the tumour
- Stroma
Where are neoplastic cells derived from
Monoclonal nucleated cells that have a growth pattern similar to the parent cell
Where is the purpose of the stroma component of a neoplasm?
mechanical support
Intracellular signalling
Nutrition to neoplastic cells
How is the stroma component of a neoplasm formed?
Connective tissue fibroblast proliferation by growth factors from the tumour cells
Which growth factor induces angiogenesis?
Vascular endothelial growth factor
What is the maximum size of a tumour before angiogenesis occurs and why is the case?
1-2mm because without blood vessels its supply of nutrients is limited due to the constraints of effective diffusion
What are the 6 types of tumour shape?
Sessile Polypoid Papillary Exophytic/fungating Ulcerate Annular
Give two reasons why we classify neoplasms?
To determine the appropriate treatment
To provide prognostic information
What are the two main ways of classifying neoplasms?
Behavioural = benign or malignant Histogenetic = cell of origin
What are the characteristics of a benign neoplasm?
Localised and non-invasive Slow growth rate Low mitotic activity Close resemblance to the normal tissue Encapsulated by thin layer of connective tissue Nuclear morphometry normal Necrosis rare Ulceration rare Growth of mucosal surfaces often exophytic (Upwards an outwards from surface)
Why should we worry about benign neoplasms?
- Pressure on adjacent structures - lead to necrosis
- Obstruct flow
- Production of hormones (benign thyroid tumour causing thyrotoxicosis)
- Transformation to malignant neoplasm
- Anxiety to patient
What are the characteristics of a malignant tumour?
Invasive Metastases Rapid growth compared to benign Do not resemble the parent tissue as much as benign neoplasms do Poorly defined or irregular border Hyperchromatic nuclei Pleomorphic nuclei Increased mitotic activity necrosis common Ulceration common Growth on mucosal surfaces is endophytic (Inwards and downwards from surface)
Why should we worry about malignant neoplasms?
Destruction of adjacent tissues
Metastases leading to formation of secondary tumours
Blood loss from ulcerated surfaces
Obstruction of blood flow
Hormone production (ACTH and ADH)
Paraneoplastic effects - symptoms not just due to cancer at that site (Weight loss)
Anxiety and pain
Why do malignant tumours show central necrosis?
Inadequate perfusion
Define histogenesis?
Specific cell of origin of a tumour
What neoplasm arises from epithelial cells
Carcinomas
What neoplasm arises from connective tissues?
Sarcomas
What neoplasm arises from lymphoid/haemopoietic organs
Lymphomas
What is a papilloma?
A benign tumour of non-glandular, non-secretory epithelium such as squamous cell papilloma
What is an adenoma?
A benign tumour of glandular or secretory epithelium such as colonic adenoma
What is a carcinoma?
A malignant epithelial neoplasm of non-glandular epithelial cells ie. transitional cell carcinoma
What is an adenocarcinoma?
A malignant epithelial neoplasm of glandular epithelium such as adenocarcinoma of the breast or prostate
Name 7 types of benign connective tissue neoplasm?
- Lipoma = adipocytes
- Chondroma = cartilage
- Osteoma = bone
- Angioma = vascular
- Rabdomyoma = striated muscle
- Leiomyoma = Smooth muscle
- Neuroma = benign neoplasm of nerves
Name 6 types of malignant connective tissue neoplasm
- Liposarcoma = adipocytes
- Rhabdomyosarcoma = striated muscle
- Leiomyosarcoma = smooth muscle
- Chondrosarcoma = cartilage
- Osteosarcoma = bone
- Angiosarcoma = blood vessels
What is a melanoma?
Malignant neoplasm of melanocytes
What is a mesothelioma?
Malignant tumour of mesothelial cells
What is a lymphoma?
Malignant neoplasm of lymphoid cells
What is Burkitts lymphoma
B-cell lymphoma associated with Epstein Barr virus
What is Ewings sarcoma?
Malignant tumour of the bone
What is Grawitz tumour?
Renal cell carcinoma
What is Kaposi sarcoma?
Malignant neoplasm derived from vascular endothelium commonly associated with AIDS
What are the three ways of grading a malignancy?
Low grade = looks like parent tissue
High grade= doesn’t look like parent tissue
Anaplastic = unknown origin cell type
What is carcinoma in situ?
When the cancer divides quicker than the normal cells and doesn’t apoptosis but is yet to invade
What enzymes are required for cancers to invade through the basement membrane
Matrix metalloproteinases
Collagenases
Cathepsin D
Urokinase-type plasminogen activator
What is metastasis?
Metastasis is the process by which a malignant tumour spreads from its primary site of origin to produce secondary tumours at distant sites
What are the three factors influencing tumour invasion?
- decreased cellular adhesion
- Secretion of proteolytic enzymes
- Abnormal or increased cellular motility
Describe the process of cancer cell metastasis
- Detachment of tumour cells from their neighbours
- Invasion of the surrounding connective tissue to reach conduits for metastasis (blood and lymphatic vessels)
- Intravasation into the lumen of vessels
- Evasion of host defence mechanism such as natural killers cells In the blood
- Adherence to the endothelium at remote location
- Extravasation of cells from the vessel lumen into the surrounding tissue
Name three ways in which cancer cells avoid the host immune defence
- Aggregate with platelets so body cant detect it
- Shedding surface antigens so not recognised
- Adhesion to other tumour cells – ‘safety in numbers’
Name two factors that promote angiogenesis
Vascular endothelial growth factor
Basic fibroblast growth factor
Name three factors that inhibit angiogenesis
Angiostatin
Endostatin
Vasculostatin
What are the three possible routes for metastasis?
Hamatogenous - bloodstream
Lymphatic
Transcoelomic - pleural, pericardial and peritoneal cavities
Where do sarcomas commonly metastasise to?
Lung
Where does colorectal cancer normaly end up
Liver
Where to tumours of the colon, stomach, pancreas, and intestine normally end up?
liver
Where do tumours of the prostate, breast, thyroid, lung and kidney normally metastasise to?
bone
Define inflammation
A local physiological response to tissue injury
Give a benefit of inflammation
Inflammation can destroy invading micro-organisms and can prevent the spread of infection
Give a disadvantage of inflammation
Inflammation can produce disease and can lead to distorted tissues with permanently altered function
Define exudate
A protein rich fluid that leaks out of vessel walls du to increased vascular permeability
What does viral infection result in?
Cell death due to intracellular multiplication
What does bacterial infection result in?
Release of exotoxins involved in initiation of inflammation or endotoxins
How can acute inflammation be diagnosed histologically?
By looking for the presence of neutrophil polymorphs
Give three endogenous chemical mediators of acute inflammation?
- Bradykinin
- Histamine
- Nitric oxide
What are the 4 systemic effects of acute inflammation?
- Fever
- Feeling unwell
- Weight loss
- Reactive hyperplasia of reticuloendothelial system
What cells are involved in chronic inflammation
Macrophages and plasma cells (B and T lymphocytes)
What are 4 macroscopic features of chronic inflammation
- chronic ulcer
- Chronic abscess cavity
- Granulomatous inflammation
- Fibrosis
What is the difference between resolution and repair
Resolution is when the initiating factor is removed and the tissue is able to regenerate. In repair the initiating factor is still present and the tissue is unable to regenerate
Give 2 reasons why thrombosis formation is uncommon?
- Laminar flow
2. Non-sticky endothelial cells
Why are tissues with an end arterial supply more susceptible to infarction
Because they have a single arterial supply and if this becomes interrupted then infarction is likely
Give three examples of organs with a dual arterial supply
- Lungs (Bronchial and pulmonary veins
- Liver hepatic arteries and portal veins
- Some areas of the brain around the circle of Willis
What are the consequences of a venous embolus
Embolus in the venous system goes to vena can and through the pulmonary arteries becoming lodged in the lungs and causing a pulmonary embolism which decreases perfusion to the lungs
Give an example of a disease where there is a lack of apoptosis
Cancer, mutations In p53 mean cell damage isn’t detected
Give an example of a disease where there is too much apoptosis
HIV
Give three differences between apoptosis and necrosis
- Apoptosis is programmed cell death whereas necrosis is unprogrammed
- Apoptosis tends to effect a single cell whereas necrosis affects a number of cells
- Apoptosis is a response to DA damage whereas necrosis is triggered by an adverse event
Give three examples of events that can lead to necrosis
- Frost bite
- Avascular necrosis
- Infarction
Why is adjuvant therapy often used in the treatment of carcinomas
Micrometastes are possible even if the tumour is excised so adjuvant therapy is given to suppress the secondary tumour formation
Give an advantage and disadvantage of conventional chemotherapy
Advantage = Works well for treatment against fast dividing tumours
Disadvantage = non selective for tumour cells resulting in effects such as diarrhoea and hair losss
What type of carcinomas would be targeted chemotherapy be most effective against
Slower dividing tumours ie. lung, colon and breast
What is the theory behind targeted chemotherapy
It exploits the differences between cancer cells and normal cells
What kind of drugs can be used in targeted chemotherapy?
Monoclonal antibodies (MAB) and small molecular inhibitors (SMI)
What Is required for a tumour to invade through the basement membrane
- Proteases
2. Cell motility
What is required for a tumour to enter the blood stream (Intravasation)
- Collagenases
2. Cell motility
What is required for a tumour to exit the blood steam (extravasation)
- Adhesion receptors
- Collagenases
- Cell motility
What causes the pain associated with acute inflammation
- Stretching and distortion of tissues due to oedema and pus under high pressure in an abscess cavity
- Chemical mediators such as bradykinin and prostaglandins which induce pain
Define carcinogenesis
A multistep process in which normal cells become neoplastic cells due to mutations
What percentage of cancer risk is due to environmental factors?
85%
Give an example of a situation when transplacental exposure leads to an increase in cancer risk
Daughters of mothers who had taken diethylstilbestrol for morning sickness had an increased risk of vaginal cancer
Define carcinoma
Malignant epithelial neoplasm
Define sarcoma
Malignant connective tissue neoplasm
What are the 4 characteristics of innate immunity?
Instinctive Non-specific Does not depend on lymphocytes Present from birth Immediate, rapid response
What are the 3 characteristics of adaptive immunity?
Specific/Acquired immunity
Requires lymphocytes and antibodies
Slower response
What are the three observable layers when blood is centrifuged?
- Upper plasma layer containing 90% water, electrolytes, proteins, lipids and sugars
- Middle white fluffy layer containing lymphocytes
- Lower layer (45%) containing erythrocytes and platelets
What is serum?
Plasma without fibrinogen and other clotting factors
Which cell is the cell of origin of immune cells
Multipotent Haemopoietic stem cell (Haemocytoblast)
Draw a diagram to show the origin of immune cells
Find diagram on internet
What chemical stimulates stem cells to differentiate into blood cells?
Cytokines
What are the three types of polymorphonuclear leukocytes
Neutrophil
Eosinophil
Basophil
What are the three types of mononuclear leukocytes and what do they become
Monocyte –> becomes macrophage when moves from blood to tissue
T cell becomes T-Reg, T-Helper (CD4) or cytotoxic (CD8)
B-cell becomes plasma cells when activated which become antibodies
What is complement
Group of 20 serum proteins secreted by the liver that need to be activated to be functional as part of the immune system
What are the three modes of action of the complement system?
- Direct lysis (Membrane attack complex that makes a hole in pathogen)
- Attract more leukocytes to the site of infection (Chemotaxis)
- Coat invading organisms to make it more easy for them to be engulfed by phagocytic cells (Opsonisation)
what do antibodies bind to?
Antigens
What are the 5 classes of antibody?
IgG IgA IgM IgD IgE
Describe the properties of IgG
Most predominant in human
70-75% of antibodies
Can get anywhere in the body
Only Ig that can cross the placenta
Describe the properties IgA
Monomer
Accounts for 15% in serum
Predominant Ig in mucous secretions including milk, saliva, bronchiolar and genitourinary secretions
Describe the properties of IgM
Pentagon molecule
Mainly resides in the blood serum because its so large
Primary immune response
Accounts for 10% of Ig in serum
Describe the properties of IgD
1% of serum
Expressed on naive B cells and acts as B-cell antigen receptor
Describe the properties of IgE
0.05% in serum
Basophils and mast cells express IgE receptor so have high affinity for IgE
IgE associated with hypersensitivity allergic reactions and defence against parasites
binding antigen triggers release of histamine by basophils and mast cells
What are cytokines
Proteins secreted by immune and non-immune cells that acts as stimulatory or inhibitory signals between the cells
Give 4 examples of cytokines
Interferons
Interleukins
Colony stimulating factors
Tumour necrosis factors
Describe the function of interferons and give two examples
Induce a state of antiviral resistance in unaffected cells and limit the spread of infection
IFNa and IFNb
IFNy
What cells produced IFNa and IFNb
Virus infected cells
What cells produce IFNy
Activated Th1 cells
What is the function of Interleukins?
Can produce a pro inflammatory (IL1) or anti-inflammatory (IL-10) response the can cause cells to divide, differentiate and secrete factors
What is the function of colony stimulating factor?
Involved in directing the division and differentiation on bone marrow stem cells - precursors to leukocytes
What is the function of tumour necrosis factor and give 2 examples
Mediate inflammation and cytoxic reactions
TNFa and TNFb
What are chemokines
Group of 40 proteins that direct the movement of leukocytes from the bloodstream into tissues or lymph by binding to specific receptors on cells
What are the 8 characteristics of the innate defence mechanism?
- Non specific
- 1st line of defence
- Provides barrier to antigen
- Instinctive
- Present from birth
- Slow response
- No memory
- Does not depend on immune recognition by lymphocytes
What are the 5 characteristics of the adaptive defence mechanism?
- Specific
- Response to a specific antigen
- Learnt behaviour
- Memory to specific antigen
- Quicker response
What is the innate immunity composed of?
Physical and chemical barriers Phagocytic cells (Neutrophils and macrophages) Blood proteins (Complementt)
What are the physical barriers to infection?
- Lysozymes in tears
- Skin
- Skin sebum secretions
- Acidic pH in vagina
- Acidic pH in gut
- Removal of particles by passing air over turbinates bones
- Mucus and cilia in bronchi
What are the 7 stages of the response to inflammation?
- Stop bleeding
- Acute inflammation (Leukocyte recruitment)
- Kill pathogen, neutralise toxins and limit pathogen spread
- Clear pathogens and dead cells (Phagocytosis)
- Proliferation of cells to repair the damage
- Remove blood clot and remodel the extracellular matrix
- Re-establish normal structure and function of tissue
Define inflammation
Series of reactions that brings cells and molecules of the immune system to sites of infection or damage
What are three signs of inflammation
- Increased blood supply
- Increased vascular permeability
- Increased leukocyte transendothelial migration
Define acute inflammation?
Complete elimination of a pathogen followed by resolution of damage, disappearance of leukocytes and full tissue regeneration
Define chronic inflammation?
Persistent unresolved inflammation
What senses microbes in the blood?
Monocytes and neutrophils
What senses microbes in the tissues?
macrophages and dendritic cells
Where are pattern recognition receptors found
On immune cells
Where are pathogen associated molecular patterns found
On the microbe
Describe the process of extravasation?
- Microbe in tissue with macrophage bound
- Macrophage secretes pro-inflmmatory TNFa
- TNF interacts with endothelium making it sticky
- Neutrophil sticks to endothelium and rolls along its surface
- TNFa causes secretion of chemokines that stick to molecules on endothelial surface and cause neutrophil to stop rolling
- Neutrophil is held on the endothelial surface by adhesion molecules and then squeezes through endothelium and moves up concentration gradient of cytokines to the site of infection
Describe the process of phagocytosis
- Bacteria binds to the macrophage
- Engluflment
- Phagosome formation
- Phagolysosome
- Membrane disruption
- Secretion of H2O2, NO and TNFa
- MHC class II antigen presentation
What are the two pathways present in neutrophils and macrophages for microbial killing?
- Oxygen dependent
2. Oxygen independent
Describe 3 methods of O2 dependent method of microbial killing
- Killing using reactive oxygen intermediates
- Superoxides are converted to H2O2 then OH free radical
- Nitric oxide which causes vasodilation increasing extravasation so more neutrophils in the tissue to kill pathogens
Describe the O2 independent method of microbial killing
Enzymes (Lysozyme)
Proteins (Defensins inserted into membrane)
pH
Name three characteristics that adaptive immunity has?
Antigen specificity and diversity
Immunological memory
Specific self and non-self recognition
What must the immune system do in order to be effective
Discriminate between self and non self
What is the function of lysozyme?
Destroys bacterial cell walls
In which primary lymphoid tissue do T cells mature?
Thymus
IN which primary lymphoid tissue do B cells mature?
Bone marrow
How do T cells recognise antigens?
For T cell recognition, antigens must be displayed by an antigen presenting cell bound to MHC1/2 - T cells cant recognise soluble antigens
What is the function of T-helper 1 (CD4)?
Helps the immune response against intracellular pathogens and secretes cytokines
What is the function of T-Helper 2 (CD4)
Helps to produce antibodies against extracellular pathogens and secretes cytokines
What is the function of cytotoxic T cell CD8
Kills cell directly by binding to antigens, inducing apoptosis
Which cells express MHC class I and why is it required
All nucleated cells ie a virus infected cell or cancer cell except erythrocytes
CD8 Cytotoxic T cells required antigen to be associate with MHC I before they kill cell containing intracellular pathogen
Which cells express MHC class II and why is it required
Antigen presenting cells ONLY ie. macrophages, B cells and dendritic cells
Helper T cells (CD4) requires MHC II before they help B cells to make antibodies to the extracellular pathogen
Which MHC would an intracellular antigen (Endogenous) lead to expression of?
MHC1
Which MHC would an extracellular antigen (Exogenous) lead to expression of?
MHC2
What type of T cell binds to MHC1
Cytotoxic T cells (CD8)
What type of T cells bind to MHC2
Helper T cells (CD4)
What does a helper T cell bind to?
A T cell receptor which is bound to an antigen epitope which bound to MHC2 on an APC
What happens to B cells that recognise ‘self’?
They are killed in the bone marrow
Describe the process of a T helper cell binding to a B cell
- A B cell binds an antigen
- Phagocytosis
- Epitope is displayed on the surface of the B-cell bound to an MHC2
- TH2 binds the B cell
- Cytokines secretion induces B cell clonal expansion
- Differentiation into plasma cells and memory B cells
Which region of an antibody binds to antigens?
FAB region
Which region of an antibody binds to B cells
Fc region
Give examples of secondary lymphoid tissue
Spleen
Lymph nodes
Mucosa associated lymphoid tissue (MALT)
Where are complement system plasma protein derived from?
The liver
What activates the classical complement pathway?
Antibodies
What compound prevents excessive activation of the classical complement pathway
C1 inhibitor
What activates the lectin path of the complement pathway
mannose binding protein
What activates the alternate pathway of the complement pathway
Bacterial cell walls and endotoxin
What are PRR’s a receptor for?
PAMPs
Name the three receptors that make up the PRR family
- Toll like receptors
- Nod-like receptors
- Rig-like receptors
What is extravasation
Leukocyte migration across the endothelium
What do macrophages at the tissue secrete to initiate extravasation
TNFalpha
Define humoral immunity
Humoral immunity is immunity from serum antibodies produced by plasma cells that kills extracellular microbes
Define Cell mediated immunity
cell-mediated immunity can be acquired through T cells from someone who is immune to the target disease or infection. “Cell-mediated” refers to the fact that the response is carried out by cytotoxic cells - kills intracellular microbes
What are the two types of adaptive immunity?
Cell mediated
Humoral
What happens to T cells that recognise self?
They are killed in the foetal thymus
Intrinsic antigens are associated with which MHC class
Class I
Extrinsic antigens are associated with which MHC class
Class II
If the concentration of IL-12 is high, what does CD4 T cell become?
TH1
If the concentration of IL-12 is low, what does the CD4 T cell become?
TH2
Which of the following malignant tumours never metastasises?
- malignant melanoma
- Small cell carcinoma of the lung
- Basal cell carcinoma of the skin
- Breast cancer
Basal cell carcinoma of the skin
What is the name given to a malignant tumour of the striated muscle
Rhabdomyosarcoma
Which of the following tumours does not commonly metastasise to bone?
- Bone cancer
- Lung cancer
- Prostate cancer
- Liposarcoma
Liposarcoma
What term describes cancer that has not invaded through the basement membrane?
Carcinoma in situ
What is the name given to a benign tumour of glandular epithelium?
Adenoma
Which of the following cancers does not have a screening programme in the UK? 1. Breast 2. Colorectal 3. Cervical 4, Lung
Lung cancer
Which of the following is not a known carcinogen to humans?
a. Hepatitis C (Will cause hepatocellular carcinoma)
b. Ionising radiation
c. Aromatic amines
d. Aspergillus niger
Aspergillus Niger
What is the name of benign tumour of fat cells?
Lipoma
What is the name given to a malignant tumour of the glandular epithelium?
Adenocarcinoma
Which of the following is not a feature of malignant tumours?
a. Vascular invasion
b. Metastasis
c. Increased cell divisions
d. Growth related to overall body growth
Growth related to overall body growth
Can radon gas causes lung cancer?
YEs
Is a transitional carcinoma of the bladder a malignant tumour?
YEs
What is the name of a benign tumour of the smooth muscle
Leiomyoma
Which lifestyle factor is most likely to cause cancer?
a. Drinking half. Bottle of wine a day
b. Being obese
c. Running for 20 mins twice a week
d. Smoking 20 a day
Smoking 20 a day
Which tumour has the shortest median survival
a. Basal cell carcinoma of the skin
b. Malignant melanoma of the skin
c. Breast cancer
d. Anaplastic carcinoma of the thyroid
Anaplastic carcinoma of the thyroid
Does ovarian cancer commonly spread to the peritoneum?
Yes
Activation of naive T cells is best achieved by which antigen presenting cell?
- Neutrophil
- Mast cells
- Macrophages
- Dendritic cells
Dendritic cells
Which of the following cell types is located exclusively in tissues, has an important role in both the innate and adaptive immune system, are antigen presenting cells and have phagocytic properties
- Macrophage
- Neutrophil
- Eosinophil
- Mast cell
- Fibroblast
Macrophage
Which of the following is not a barrier in the innate immune mechanism?
- Anatomic barriers
- Phagocytic
- Inflammatory mechanisms
- Antibody production
- Skin
Antibody production
T cells recognise antigens
- In solution in plasma
- When presented on RBC’s
- Following presentation on antigen presenting cells
- In a 3-dimensional form
- Following presentation on pattern recognition receptors
Following presentation on antigen presenting cells
Influenza vaccine is targeted towards at risk groups in the Uk. Which of the following are classified as at risk?
- Over 65
- 16 years
- Obese of any age
- Teenagers
- Under 2 years old
Over 65
Under 2 years old
Which of the following is administered as a live attenuated vaccine in the uk?
- Hep A
- Measles, Mumps, Rubella
- Tetanus
- Flu
- Polio
Measles, mumps and rubella
Complements are the proteins that are involved in the clearance of antigen/bacteria. Which of the following is not part of the elimination phase of complement activation
- Opsonisation
- Target cell lysis
- Chemoattraction of leukocytes
- Production of interferons
- Phagocytosis
Production of interferons
Which of the following is a polyssacharide vaccine
- Anthrax
- Hib vaccine (Haemophilus influenza type b)
- Rabies vaccine
- Hepatitis A
Hib vaccine
Which of the following are features of the adaptive immune response?
- Does not require prior contact with the pathogen
- It works with B and T lymphocytes
- Lacks Specificity
- Distinguishes self from non-self
- Enhanced by complement
It works with B and T lymphocytes
What are the two types of immune response in humans?
Innate and Acquired
Which of the following is not an organ specific auto-immune disease?
- Ulcerative collitis
- Type 1 diabetes mellitus
- Graves disease
- Hashimoto’s Thyroiditis
- Sjorgens syndrome
Ulcerative colitis
Which of the following is not a classical PAMP?
- Peptidoglycan found in bacterial cell walls
- Flagellin, a protein in bacterial flagella
- Lipopolysaccharide from the outer membrane of gram negative bacteria
- Interleukin 12
- Nucleic acids such as viral DNA or RNA
Interleukin 12
How do antibodies protect against infection?
Neutralise toxins Immobilise motile microbes Prevent binding to and infection of host cells Form complexes Activate complement (IgG, IgM) Bind Fc receptors
Binding of Fc receptors to phagocytes causes what?
Enhanced phagocytosis
Binding of FC receptors to mast cells causes what?
Release of inflammatory mediators
Binding of FC receptors to NK cells causes what?
Enhanced killing of infected cells
What is the role of T helper cells (CD4+ve)
Help B cells make antibody
Activate macrophages and NK cells
help the development of cytotoxic T cells
What is the role of T cytotoxic cells (CD8+ve)
Recognise and kill infected host cells
What is the role of T regulatory cells
Suppress immune responses
What sort of antigens do B cells recognise?
Soluble, free and native antigens
What sort of antigens do T cells recognise?
Cell-associated processed antigen
Which gene codes for major histocompatibility proteins?
Major histocompatibility complex on chromosome 6 otherwise known as human leucocyte antigen (HLA)
What are the two subsets of Cd4 cells?
TH1 and Th2 cells
What Is the role of TH1 cells
- Produce IL-2, y-interferon and TNFb
- Activate macrophages leading inflammation
- promote production of cytotoxic T cells
- Induce B cells to make IgG antibodies
What is the role of TH2 cells
- Produce IL-4,5,6,10 and 13
- Activate eosinophils and mast cells
Induce B cells to make iGE - promotes the release of inflammatory mediators ie. histamine from mast cells
How does the body handle bacteria and fungi?
Phagocytosis
How does the body handle viruses?
Cellular shut down
Self-sacrifice
Cellular resistance
What are the patterns that enable our immunity to determine between self and non-self?
- Limited characteristics
- Gram +ve bacteria have thick wall with no outer envelope
- Gram -ve bacteria have thinner wall with outer envelope
- DsRNa (Way of detecting viral infection
- CpG motifs
What are the two types of pattern recognition receptors
Secreted and circulating
Cell associated
Name three receptors that’s make up the PRR family
- Toll like receptors
- Nod like receptors
- Rig like receptors
What is the main function of TLRs
TLRs send signals to the nucleus to secrete cytokines and interferons. These signals initiate tissue repair
Enhanced TLR signalling I= improved immune response
What is the main function of NLRs
NLRs detect intracellular microbial pathogens
They release cytokines and can cause apoptosis if the cell is infected
What disease is caused by a non-functioning mutation in NOD2?
Crohns disease
What is the main function of RLR’s?
RLR’s detect intracellular double stranded RNA
This triggers interferon production and an antiviral response
TLRs are adapted to recognise damaged molecules. What characteristics do these damaged molecules often have in common
They are hydrophobic
What kind of TLRs can be used in vaccine adjutants?
TLR4 agonists
Give 3 examples of diseases that can be caused by PRRs failing to recognise pathogens
- Atherosclerosis
- COPD
- Arthritis
Give examples of 3 extracellular PRR?
- Mannose receptors
- Scavenger receptors
- TLRs
What is the function of mannose and scavenger extracellular receptors?
Induce pathogen engulfment
Give an example of an intracellular PRR
NLR
Where are circulating PRRs secreted from?
Epithelia, phagocytes and the liver where they can activate the complement cascade and induce phagocytosis
Give 2 examples of secreted and circulating PRRs
Antimicrobial peptides ie. Defensins and Cathelicidin
Lectins and collectins ie. mannose binding lectin
What are cell associated PRRs and what is the main family?
Receptors that are present on the cell membrane on in the cytosol of cells
TLRs
What is the ligand for TLR1/2
Gram positive lipopeptides
What is the exogenous ligand for TLR3
Double stranded RNA
What is the endogenous ligand for TLR3
mRNA
What is the exogenous ligand for TLR4
LPS
Pneumolysin
Viral Proteins
What are the endogenous ligands for TLR4
Heat shock proteins
HMGB1
Hyaluronan
Fibrinogen
What is the exogenous ligand for TLR5
Flagellin
What is the exogenous ligand for TLR2/6
Gram positive lipopeptides
What are the exogenous ligands for TLR7
Single stranded RNA
What are the exogenous ligands for TLR8
Single stranded RNA
What are the exogenous ligands for TLR9
CpG DNA
What are the three types of membrane bound PRR
Mannose receptor on macrophages
Lectin 1
Scavenger receptors on macrophages
What do NLRs detect?
Peptidoglycan and muramyl dipeptide
What disease does a hyper functioning mutation in NOD2 lead to?
Blau Syndrome
What is the role of RLRs and give two examples
detect intracellular double stranded viral DNA and RNA
RIG-I and MDA5
Name three extracellular damage molecules
Fibrinogen
Hyaluronic acid
Tenascin C
Name 5 intracellular damage molecules
HMGB1 mRNA Heat shock proteins Uric acid and uric acid crystals Stathmin
Define passive immunisation
Give antibodies
Define active immunisation
Given dead/attenuated pathogens
What are the advantages of passive immunisation?
Immediate protection
Effective in immunocompromised patients
what are the advantages of active immunisation?
Dead- no risk of infection
Attenuated - immune response close to real thing
Disadvantages of passive immunisation
Short lived
Serum sickness
Does not activate immunological memory
What are the disadvantages of active immunisation?
Dead - just the humour response activated
Attenuated - possible reversion to virulence
Cant be given to an immunocompromised patient
Give some examples of passive immmunisation
Cross placement transfer of antibodies from mother to child (Natural)
Treated with immunoserum or pooled human IgG (Artificial)
- Human hepatitis B Ig
- Varicella Zoster Ig
Give 2 examples of active immunisation
Non-living = Pertussis, infleunza, diphtheria and tetanus
Attenuated = BCG, MMR, poliomyelitis
What are 5 patient risk factors when administering drugs?
- polypharmacy
- Old age
- Genetics
- Hepatic disease
- Renal disease
What are 3 drug risk factors
- Narrow therapeutic index
- Steep dose/response curve
- Saturable metabolism
What are the three types of adsorption?
Precipitation
Chelation
Neutralisation
What are the 4 types of drug interaction
- Synergy
- Antagonism
- Summation
- Potentiation
What is bioavailability
How much of the oral drug is in the system compared to how much of the IV drug
Does the ionised or unionised portion of a drug cross the bilayer?
Unionised
Where are most drugs metabolised?
Liver
Describe the metabolism of morphine?
Morphine metabolised by CYP450 pathway to morphine 6 glucuronide which enables excretion by the kidney
What is the effect of phenytoin on morphine metabolism
Phenytoin induces CYP450 enzymes leading to increased metabolism of morphine to active morphone 6 glucuronide = ENZYME INDUCTION
What is the effect of metronidazole on morphine metabolism?
Metronidazole slows CYP450 and reduces production of morphine 6 glucuronide so its less potent = ENZYME INHIBITION
Are weak basic drugs cleared faster if the urine is acidic or alkaline?
Acidic
Are weak acids drugs cleared faster if the urine is acidic or alkaline?
Alkaline
What drugs can induce acute kidney injury?
NSAIDs
Gentamicin
Furosemide
ACEi
What is the affect of grapefruit juice in patients taking warfarin?
Affects CYP450 and warfarin ability to bind to proteins
Define a drug
A medicine or other substance which has a physiological effect when ingested or otherwise introduced into the body
Define pharmacology
Branch of medicine concerned with the use, effects and modes of action of drugs
Define pharmacodynamics
How the drug affects the body
Define pharmacokinetics
How the disposition of a compound within an organism - how the body affects a drug (ADME)
What is the main target for drugs
Proteins
Name 4 types of drug targets
receptors
enzymes
transporters
Ion channels
Define receptor
Cell component that interacts with a specific ligand that initiates a change of biochemical events leading to observed effects
Give an example of a ligand gated ion channel
Nicotinic ACh receptor
Give an example of a GPCR
Muscarinic and β2 adrenoceptor.
Give an example of kinase-linked receptors
Receptors for growth factors
Give an example of cytosolic/nuclear receptors
Steroid receptors - modify gene transcription
Describe how GPCRs work
Activity regulated by factors that control the ability to bind and hydrolyse GTP to GDP
Give 2 examples of GPCRs
Muscarinic 3-receptor (Gq)
B2-AR (Gs)
What are kinase linked receptors?
Transmem receptor that are activated when the binding of extracellular ligand causes enzymatic activity on the intracellular side
(Leads to protein phosphorylation)
Define agonist
A compound that binds to a receptor and activates it
Define antagonist
Antagonist decreases the effect of an agonist - shows no response at the receptor
Define potency
Measure of how well a drug works - EC50 = Concentration that gives half the maximal response
Define efficacy (Emax)
Maximum response achievable for a dose (Partial agonist will never achieve a full response)
Define intrinsic activity (Efficacy)
Ability of a drug receptor complex to produce a maximum functional response
(Emax of partial agonist/ Emax of full agonist)
Would an antagonist shift the dose response curve to the left or to the right?
Shift to the right so a higher concentration of the agonist is required to achieve a full response - agonist becomes less potent
Define affinity
How well a ligand binds to a receptor
Define non-competitive antagonism
When the antagonist binds to an allosteric site on the receptor that disrupts its activation
What is the H1 histamine receptor associated with?
Allergic conditions
What is the H2 histamine receptor associated with?
Gastric acid secretion
What is the H3 histamine receptor associated with?
CNS disorders
What is the H4 histamine receptor associated with
Immune system and inflammatory conditions
What is the effect of fewer receptors on receptor response
Receptor response is still 100% due to receptor reserve (Partial agonists don’t have a receptor reserve)
What is the affect of less signal amplification on drug response
Less signal amplification gives a reduced drug response
Define inverse agonism
When a drug binds to the same receptor as an agonist but induces a pharmacological response that is opposite to that of the agonist
Does an antagonist demonstrate efficacy
No, antagonist can have affinity but show zero efficacy. Agonist shows affinity and efficacy
Define tolerance
A reduction in the effect of a drug overtime due to continuous use of repeatedly high concentrations
Name 3 ways in which a receptor can be desensitised
- Uncoupled
- Internalised
- Degraded
Define an enzyme inhibitor
a molecule that binds to an enzyme and decreases its normal activity
What are the two types of enzyme inhibitor
- Irreversible - react with enzyme and change it chemically (Via covalent bond formation)
- Reversible - Bind non-covalently
What do statins do?
Class of lipid lowering drugs that reduce the level of bad cholesterol by blocking’ the rate limiting step in the cholesterol pathway
What is the effect of inhibiting ACE on blood pressue
inhibiting ACE prevents the conversion of Ang 1 to Ang 2 therefore causing a reduction in blood pressure
Name 2 ACE inhibitors
Captopril
Enalapril
What is the precursor molecule for L-DOPA
L-tyrosine
Which enzyme converts L-DOPA to dopamine>
DOPA decarboxylase
How does carbidopa works
Blocks DOPA decarboxylase in the periphery in the periphery which generates more L-DOPA for the CNS pathway
How do peripheral Catechol-O-methyl transferases (COMT) work?
(Tolecapone)
(Entacapone)
Peripheral COMT prevent L-DOPA breakdown therefore generating more for CNS pathway
How to central COMT inhibitors work? (Tolecapone)
Prevent the breakdown of dopamine in the central CNS
How do mono amine oxidase inhibitors such as selegiline and rasagiline work?
Prevent the breakdown of dopamine into DOPAC in the central CNS
How do uniporters work?
Use energy from ATP to pull molecules in
How do symporters work?
Use the movement in of one molecule to pull in another molecule against its concentration gradient
How do anti porters work?
One substance moves against its gradient using energy from a second substance that is moving down its gradient
Give an example of a symporter
NKCC2
How does furosemide work and what its it used for?
Used for oedema and hypertension
Acts by inhibiting luminal NKCC2 in thick ascending limb
Causes sodium, chloride and potassium loss in the urine
How does amiloride work?
Blocks epithelial sodium channels in the collecting ducts thus preventing sodium reabsorption - used as an antihypertensive
Where are voltage gated calcium channels found?
in membranes of excitable cells including muscle, glial cells and neurons
What does amlodipine do?
Calcium channel blocker that inhibits the movement of calcium into the vascular smooth muscle cells and cardiac muscle that inhibits contraction. This causes vasodilation, reduces peripheral vascular resistance and lowers blood pressure
What are the three conformational states a voltage gated sodium channel can be in
Closed
Open
Inactivated
How does lidocaine work?
Blocks the transmission of action potential and blocks signalling in the heart, reducing arrhythmia
Receptor mediated chloride channels respond to what ligands
Neurotransmitters such as GABA which opens the Cl- channel and causes membrane hyper polarisation
What compounds increase the permeability of chloride channels
Barbituates
How does the Na+/K+ ATPase work
Pumps 3Na+ out the cell for every 2K+ it returns to the cell
How does digoxin work?
Inhibits Na+/K+ in the myocardium which increase intracellular Na+ resulting in decreased activity of the Na+/Ca2+ exchanger which increases intracellular Ca2+, lengthening the cardiac action potential leading to a decrease in heart rate
What is the role of the K+/H+ ATPase?
Responsible for the acidification of the stomach and the activation of the digestive enzyme pepsin
How does omeprazole work?
Inhibits irreversibly H+/K+ ATPase
Organophosphates such as insecticides and nerve gas are irreversible inhibitors of what?
Cholinesterases
Aspirin is an irreversible inhibitor of what?
COX
What is a xenobiotic?
A compound foreign to an organisms normal biochemistry such as a drug or a poison
What are the two divisions of the autonomic nervous system
Sympathetic and parasympathetic
What are the 6 regulatory roles of the autonomic nervous system?
- Vascular
- Airway
- Visceral smooth muscle
- Exocrine secretions
- Control of heart rate
- Energy metabolism in the liver
Where are parasympathetic ganglia located?
Near their targets with short post ganglionic fibres and long pre-ganglionic fibres
Where are sympathetic ganglia located?
Near the spinal cord with short pre-ganglionic fibres and longer post-ganglionic fibres
Which cranial nerves are parasympathetic
Oculomotor (CNIII)
Facial (VII)
IX
X
Which hormone Is released on the pre-ganglionic parasympathetic fibres to act on nicotinic receptors
ACh
Which hormone is release on the post-ganglionic parasympathetic fibres to act on muscarinic receptors
ACh
Which hormone is released on the pre-ganglionic sympathetic fibres to act on nicotinic receptors
ACh
Which hormone is released on post-ganglionic sympathetic fibres to act on alpha and beta adrenergic receptors?
Noradrenaline
Which parts of the body are under sympathetic control only?
Sweat glands
Blood vessels
Which part of the body is under parasympathetic control only?
Bronchial smooth muscle
Which parts of the body are under dual sympathetic and parasympathetic control
Gut, bladder, heart
Name 4 non-adrenergic and non cholinergic autonomic transmitters used by the enteric, sympa and parasympathetic NS
Nitric oxide
Vasoactive intestinal peptide
ATP
Neuropeptide Y
Which enzymes is responsible for the breakdown of acetylcholine in the synaptic cleft
Acetylcholinesterase
What type of receptor is muscarinic receptors and how many classes are there?
GPCR
M1-M4
Where are M1 muscarinic found in the body?
Brain
Where are M2 muscarinic receptors found in the body and what does their activation cause
Found in the heart, activation slows the heart (Bradycardias)
- can be blocked with atropine
Where are M3 muscarinic receptors found in the body and what does their activation cause
Found in the glandular and smooth muscle
- cause bronchoconstriction, sweating and saliva secretion
Where are M4 muscarinic receptors found in the body
In the CNS
What does pilocarpine do and when might it be useful
Stimulates salivation - may be useful after radiotherapy of head and neck or sjorgens syndrome
Name a muscarinic antagonist and what condition may it be used to treat
Atropine
Used to prevent bradycardia, prevent BP drop and dry up secretions perioperatively
Name two different types of anti-muscarinics used in the treatment of bronchoconstriction
Short acting - Ipratropium bromide
Long acting - LAMAs including tiotropium and glycopyrrhonium
What is solifenacin and what is it used for?
Anticholinergic
Used to treat overactive bladder
What are suxamethonium and pancuronium and what are they used for?
Inhibit muscle activity and induce relaxation in surgery by inhibiting nicotinic blockers
What are the side effects of anti-cholinergics?
COnstipation Dry mouth blurring of vision Worsening of glaucoma Worsen memory and cause confusion
What is the precursor molecule for adrenaline and noradrenaline
Dopamine
What is the primary agonist of alpha 1 receptors
Noradrenaline > Adrenaline
What is the mechanism of action act alpha 1 adrenergic receptors and what are the consequences
Activation increases intracellular calcium (Gq signalling)
Leads to smooth muscle contraction (pupil, blood vessels) = vasoconstriction
bladder contraction
What is the primary agonist of alpha 2 receptors
Noradrenaline and adrenaline activate equally
What is the mechanism of action at alpha 2 adrenergic receptors and what are the consequences
Gi signalling - Inhibition of cAMP generation
Mixed effects on smooth muscle
What is the primary agonist of beta 1 receptors
Noradrenaline and adrenaline are equal
What is the mechanism of action at beta 1 adrenergic receptors and what are the consequences
Gs - raises levels of cAMP
Increases the chronotropic and inotropic effects on heart
Increased renin release from kidney which increases blood pressure
What is the primary agonist of beta 2 adrenergic receptors
Adrenaline > Noradrenaline
What is the mechanism of action at beta 2 adrenergic receptors and wha are the consequences
Gs - Raises cAMP Relaxes smooth muscle in premature labour and asthma Bronchodilation vasodilation Reduced GI motility
What is the primary agonist at beta 3 adrenergic receptors
Noradrenaline > Adrenaline
What is the mechanism of action at beta 3 adrenergic receptors and what is the consequence
Gs - raises cAMP
Enhances lipolysis and relaxes the bladder detrusor muscle
When might an Alpha 1 agonist be used?
In the treatment of septic shock to cause vasoconstriction and prevent a drop in blood pressure
What is Doxazosin and when is it used?
Alpha 1 antagonist that blocks alpha 1 receptors to lower blood pressure
What is tamsulosin and when is it used
Alpha 1a antagonist used in the prostate to prevent prostatic hypertrophy
What does beta 1 adrenergic receptor activation do?
Increase HR and chronotropic effects
Increases the risk of arrhythmias
What does propranolol block and what are the consequences
Beta 1 (Heart) and beta 2 (lungs) Slows the HR, reduces tremor and may cause wheeze
What does atenolol block and what are the consequences
Beta 1 (heart) selective Lowers the blood pressure by reducing cardiac output and gradual reduction in sympathetic outflow
What are the uses of beta blockers?
Angina MI prevention High blood pressure Anxiety Arrhythmias Heart failures
What are the side effects of beta blockers
Tiredness Cold extremities Bronchoconstriction Bradycardia Hypoglycaemia Cardiac depression
Define hypersensitivity
Excessive response that can be mediated immediately, acutely or gradually
How many different types of hypersensitivity reaction are there according to Gell and Coombs
4
What is a type 1 hypersensitivity reaction and name some examples
Immunological memory to something causing an allergic reaction - IgE
Anaphylaxis, Asthma and hay fever
What are the two potential routes of exposure in a type 1 hypersensitivity reaction
Local Exposure
- Hayfever from pollens, animals, occupational exposure
Systemic exposure
- Drugs, foods, treatments
What are the effects of histamine release
Vasodilation and capillary leakage
What do mast cell granules contain
Histamine PGD2 Proteases Cytokines IL-4 IL-13 TNFa
Define atopy
Inherited tendency to an exaggerated IgE response to an antigen
What are 4 treatments for hay fever?
Prevent exposure
Anti-histamines
Reduction in local inflammation (Steroids)
Desensitisation
What are the treatments for anaphylaxis
Avoid/cease exposure Stop acute symptoms (anti-histamines) Acute resuscitation (Adrenaline, fluids, bronchodilators) Decrease inflammation (Steroids) Intramuscular adrenaline to maintain circulation
Describe a phase 2 hypersensitivity reaction
Immunoglobulins (IgG) bound to surface antigens which causes the immune system to attack the basement membrane of the kidney and lungs
Give 4 examples type 2 hypersensitivity reaction
Goodpastures syndrome
Mycoplasma Pneumonia
Graves Disease
Myaesenthia Gravis
Describe a type 3 hypersensitivity reaction
Antibodies and target circulate. Little lumps of antibody and target get deposited in the skin, lung and kidneys and activate immunity so phagocytes go and destroy it resulting in capillary damage in lungs and kidneys
Give an example of a type 3 hypersensitivity reaction
Extrinsic Allergic Alveolitis
Formation of precipitating antibodies to organic dusts
What are the 4 types of extrinsic allergic alveolitis
Farmers lung
Malt workers lung
Mushroom workers lung
Pigeon Fanciers Lung
Describe type 4 hypersensitivity reactions
Formation of granulomas dependent on the activation of T cells
Give an example of a type 4 hypersensitivity reaction
TB
Sarcoidosis
Name two opioids that are naturally occurring
Codeine
Morphine
Name three opioids formed from simple chemical modifications
Diamorphine
Oxycodone
Dihydrocodeine
Name 4 synthetic opioids
Penthidine
Fentanyl
Alfentanil
Remifentanil
Name a synthetic partial opioid agonist
Buprenorphine
Name an opioid antagonist
Naloxone
What is the most common route of administration of opioids and what is the normal dose via this method
Oral - 10mg
half the dose for s/c, IM or IV
What is diamorphine otherwise known as?
Heroin
How do opioids work
Use the existing pain modulation system
Inhibit the release of pain transmitters at spinal cord and midbrain and modulate pain perception in higher centres
What are the receptors that opioids bind to?
Mu, delta, kappa
Define tolerance
Downregulation of receptors due to prolonged use - results in a need for higher dose to achieve the same effect
Define dependence
Psychological - craving, euphoria and physical
How long does opioid withdrawal last
72 hours
What are the side effects of opioid administration
- respiratory depression
- Sedation
- Nausea and vomiting
- Constipation
- Itching
- Immune system suppression
- Endocrine effects
What is the treatment for opioid induced respiratory depression
- Call for help
- ABC
- Naloxone - 400ug/ml
- titrate to effect ie. dilute 1ml in 10ml saline - IV fastest route
Give an example of a prodrug
Codeine
Tramadol
Which enzyme is required to metabolise codeine to its active form
CYP2D6
What is morphine metabolised to by CYP2D6
Morphine 6 glucuronide
What enzyme is required to metabolic tramadol into its active form?
CYP2D6
What is tramadol metabolised to by CYP2D6?
O-desmethyl tramadol
Define an adverse drug reaction
Unwanted or harmful reaction following administration of a drug or combination of drugs under normal conditions of use and is suspected to be drug related - needs to be noxious and unintended
Define side effects
Unintended effect of a drug relate to its pharmacological properties and can include expected benefits of treatment
What are the 3 types of adverse drug reaction
- Toxic effects - drug applied beyond therapeutic range
- Collateral effects - Use drug within its therapeutic range
- Hypersusceptibility effects - drug used below its therapeutic range
What are the causes of a toxic ADR?
Administration of a too high dose
Drug excretion reduced by renal or hepatic functional impairment
Interactions with other drugs
What are 4 symptoms of a mild adverse drug reaction?
Nausea
Drowsiness
Itching
Rash
What are 4 symptoms of a severe adverse drug reaction?
Respiratory depression
Neutropenia
Catastrophic haemorrhage
Anaphylaxis
Define a time independent adverse drug reaction
One that can occur at any time during treatment
What are the 6 types of time dependent adverse drug reaction?
- Rapid reaction
- First dose reaction
- Early reaction
- Intermediate Reaction
- Late reaction
- Delayed reaction
What is the Rawlins Thompson adverse drug reaction classification
- Type A = Augmented pharmacological (Predictable and dose dependent - extension of the primary effect)
- Type B = Bizarre or idiosyncratic (Not predictable or dose dependent)
- Type C = Chronic
- Type D = delayed
- Type E = End of treatment
- Type F = Failure of therapy
What is the DoTS classification of an adverse drug reaction?
Dose relatedness (Toxic, collateral or hypersusceptibility)
Timing
Patient susceptibility
What are the patient risk factors for an adverse drug reaction?
Gender (F>M) Elderly Neonates Polypharmacy Genetic disposition Hypersensitivity/allergies Hepatic/renal impairment Adherence problems
What are the drug risk factors for an adverse drug reaction?
Steep dose response curve
Low therapeutic index
Commonly causes ADRs
What are the prescriber risk factors for an adverse drug reaction?
Prescriber may be busy or tired leading them to not realise that two drugs interacting may cause an ADR
What are the 7 causes of an ADR?
- Pharmacological variation
- Receptor abnormality
- Abnormal biological system unmasked by the drug
- Abnormalities in drug metabolism
- Immunological
- Drug-drug interactions
- Multifactorial
Give an example of a type A augmented ADR
Administration of insulin causing hypoglycaemia
Administration of propranolol causing bradycardia
Give an example of a type C continuous ADR
Prolonged use of steroids causes thinning of the bones leading to osteoporosis
Give an example of a type D delayed ADR
teratogenesis - drugs taken in the first trimester ie. thalidomide
Give an example of a type E end of treatment ADR
Get withdrawal seizures when anti-convulsants are stopped
When should we suspect an ADR?
- Symptoms soon after a drug is started
- Symptoms after a dosage increase
- Symptoms disappear when the drug is stopped
- Symptoms when the drug is restarted
What are the most commonly administered drugs that cause ADRs
Antibiotics Anti-neoplastics Cardiovascular drugs Hypoglycaemics NSAIDs CNS drugs
What are the most common systems to be affected by ADRs
GI Renal Haemorrhagic Metabolic Endocrine Dermatologic
What is the role of the medicines and healthcare products regulatory agency
Responsible for ensuring medicines and medical devices work and are acceptably safe
What are the strengths of the yellow card scheme
- Early warning for previously unrecognised reactions
- Provides information about factors which predispose patients to ADRs
- Allows ADR comparison between products of same therapeutic class
- Continual safe monitoring of product throughout life span
What are the weaknesses of the yellow card scheme
- Cannot provide estimate of risk as true number of cases is underestimated and total number of exposed patients is unknown
- Relies on ADR being recognised
- Not all ADRs reported
- May be stimulated by promotion or publicity
- Reporting high for newly marketed drugs and then falls off over time
Why are yellow card reporting rates low
Ignorance Diffidence Fear Lethargy Guilt Ambition Complacency
Why should we report ADRs?
Patient safety Identify ADRs not indentified in clinical trials Identify new ADRs ASAP Compare drugs in same therapeutic class Identify ADRs in at risk groups
What should be reported on a yellow card?
Suspected reactions for herbal medicines and black triangle drugs
All serious suspected reactions for drugs, vaccines, contrast media
What defines a serious adverse drug reaction
is fatal is life threatening Is disabling results in hospitalisation prolongs hospitalisation
Define hypersensitivity
Objectively reproducible symptoms or signs initiated by exposure to a defined stimulus at a dose tolerated by normal subjects and may be caused by immunologic (allergic) or non immunologic mechanisms
Describe what happens in a type 1 hypersensitivity reaction
- Prior exposure to antigen/drug
- IgE antibodies formed after exposure
- IgE becomes attached to mast cell and expressed as cell surface receptor
- Re-exposure causes mast cell degranulation and release of pharmacologically active substances such as histamine
Give an example of a type 1 hypersensitivity reaction
Anaphylaxis
What occurs during an anaphylactic reaction
Vasodilation which causes increased vascular permeability leading to swelling and oedema Bronchoconstriction urticaria Angio-oedema hypotension Wheeze
Describe what happens in a type 2 hypersensitivity reaction
Antibody dependent cytotoxicity -
- Drug combines with protein
- Body treats it as foreign proteins and forms antibodies
- Antibodies combine with antigen and complement activation damages the cells
Describe what happens during a type 3 hypersensitivity reaction
Immune complex mediated
- Antigen and IgG antibody form large complexes and activate complement
- small blood vessels are damaged or blocked
- Leucocytes are attracted to site and release proinflammtory molecules
Give an example of a type 3 hypersensitivity reaction
Glomerularnephritis
Describe what happens in a type 4 hypersensitivity reaction
Antigen specific receptors develop on T-lymphocytes and subsequent administration leads to local tissue allergic reaction
Give an example of a type 4 hypersensitivity reaction
Contact dermatitis
TB
Describe a non-immune anaphylaxis
Direct degranulation of mast cells caused directly by the drug with no previous exposure
- Clinically identical to immune anaphylaxis
Describe the management of anaphylaxis
Begin life support (ABC) Stop the exposure ie. IV fluid Give Adrenaline (500um) High Flow oxygen IV fluids to maintain blood pressure Anti-histamines (Chlorphenamine) Steroids (Hydrocortisone)
What are the effects of adrenaline administration to an individual having anaphylaxis
- Vasoconstriction - increase peripheral vascular resistance to increase bp via A1 adrenoceptors
- Stimulate B1 adrenoceptors to increase chronotropic and inotropic effects on heart
- Reduce oedema and bronco dilate via beta2 adrenoceptors
- Attenuate further release of mediators from mast cells and basophils by increasing intracellular c-AMP which reduces inflammatory mediators
What are the risk factors for hypersensitivity
Protein or polysaccharides based drugs Female > males HIV patients Previous drug reactions Uncontrollled asthma Certain HLA groups Acetylator status
What is the clinical criteria for an allergy to a drug
- Does not correlate with pharmacological properties of drug
- No linear relation with dose
- Reaction similar to those produced by other allergens
- Induction period of primary exposure
- Disappearance on cessation
- Re-appears on re-exposure
- Occurs in minority of patients on drug
What are the two different apoptosis pathways?
intrinsic = Bcl-2 and Bax Extrinsic = Fas ligand
Give some examples of disease causes by inherited genetic abnormalities
CF
Sickle cell
huntingtons
Give some examples of diseases caused by spontaneous mutations
Downs = trisomy 21 Edwards = trisomy 18 Pataus = trisomy 13
Give an example of an environmental disease
Foetal alcohol syndrome
Give some examples of mutlifactorial disease
Spina bifida
Anencephaly
Hydrocephaly
Define atrophy
Decrease in the size of cell tissue due to reduction in cell size and number often due to apoptosis
How are malignant tumours classified?
Grade 1 = well differentiated
Grade 2 = moderately differentiated
Grade 3 = Poorly differentiated (Most aggressive)
What is a teratoma
Neoplasm of germ cell origin that forms cells affecting all three germ cell layers
Which cancers are screened for in the UK
Cervical
Breast
Colorectal
What is the function of the immune system?
Discriminate between self and non-self
What is the role of the complement system
Remove or destroy antigens either by direct lysis or opsonisation
Describe the process of complement activation
2 phase
- Activation of C3
- Activation of the lytic pathway
Which enzyme is responsible for cleaving C3 to activate the complement system
C3 convertase
When C3 is cleaved, what are the products
C3b = mediates opsonisation and lysis
C3a = Enhances inflammation by stimulating mast cells to secrete histamines
What are the three pathways that C3 can be cleaved
Classical
Alternative
Lectin
What is an antibody
A protein produced in response to an antigen that can only bind with the antigen that induced its formation
What is an epitope
Part of an antigen that binds to the antibody binding site
Describe the basic structure of an antibody
Four chains, two light and two heavy
Constant and variable region
FAB region binds to antigens
FC region binds complement and Fc receptors on phagocytes and NK cells
What are the functions of antibodies
- Neutralise toxins (IgG and A)
- Immobilise microbe (IgM)
- Increase opsonisation
- Activate complement (IgG and IgM
- Bind Fc receptors on phagocytes, mast cells and NK cells
What are PAMPs, why are they important and give one example
Pathogen associated molecular patterns
Allows the innate immune system to recognise pathogens
LPS
What are the PRRs and what are the two different types
Pattern recognition receptors
- Secreted and circulating
- Cell associated
Name the three different types of secreted and circulating PRRs
Antimicrobials = defensins and cathelicidins
Lectin and collectins
Pentraxin
Name the cell associated PRRs
Toll like receptors
Nod like receptors
Rig like receptors
NLR detect what?
Muramyl dipeptide and peptidoglycan
RLR detect what?
Intracellular double stranded RNA and DNA
Why do we need an adaptive immunity?
Microbes evade the innate
Intracellular viruses and bacteria hide
Need memory to specific antigen
What is the function of MHC
Present antigenic material to T cells
Define Atopy
Inherited tendancy to overproduce IgE in response to common environmental antigens
What is natural passive immunity
Transfer of maternal antibodies across the placenta to foetus
Natural passive immunity provides protection from what diseases
Diptheria Tetanus Streptococcus Rubella Mumps Polio
What are the two types of whole organism vaccine
Live attenuated
Killed inactivated
What diseases does a live attenuated vaccine protect against
Tuberculosis
Pollo sabin
Typhoid
Mumps
What diseases does a killed inactivated vaccine protect against
Anthrax
Cholera
Hep A
What is an adjuvant
Any substance added to a vaccine to stimulate the immune system
What are the two divisions of the peripheral nervous system
Autonomic
Somatic
What are the adverse effects of muscarinic agonists (DUMBELS)
Diarrhoea Urination Miosis (Excessive pupil constriction) Bradycardia Emesis Lacrimation Salivation/sweating
What GPCR is A1 adrenoceptor
Gq + PLC
What GPCR is A2 adrenoceptor
Gi
What GPCR are Beta adrenoceptors
Gs
Name an alpha 2 adrenoceptor antagonist
Yohimbine
Define pain
Unpleasant sensory + emotional experience associated with actual and potential tissue damage
Define absorption
Process of transfer from the site of administration into the general or systemic circulation
What are the routes of drug administration
Oral IV Intra-arterial IM SC Inhalation Topical Sublingual Rectal Intrathecal (Into spinal canal)
How do drugs get across membranes
- Passive diffusion through lipid layer
- Diffusion through pores or ion channels
- Carrier mediated processes
- Pinocytosis
Rate of diffusion is proportional to what?
Area of the membrane
Permeability of the membrane
Rate of diffusion is inversely proportional to what?
Membrane thickness
Carrier mediated transport requires what?
ATP - moves molecules against a concentration gradient
Facilitated diffusion occurs using which gradients
Concentration gradient
Electrochemical gradient
Define pinocytosis
Form of carrier mediated entry into the cytoplasm
Name a drug that is transported by pinocytosis
Amphotericin
What forms are a drug normaly in
Weak acid
Weak base
What does the extent of ionisation depend on
Strength of the ionisable group
pH of the solution
Is the ionised form water or lipid soluble
Water soluble
Is unionised form water or lipid soluble
Lipid soluble
What is the pKa of a drug
pH at which half of the substance is ionised and half is unionised
Where are weak acids best absorbed
In the stomach
Where are weak bases best absorbed
in the intestine
Why is the oral route most commonly preferred
because large surface area with a high blood flow
For a drug to cross the phospholipid bilayer it needs to be what?
Lipid soluble
What factors slow gastric emptying and hence drug absorption?
Food
Drugs
Trauma
What factors increase gastric emptying and hence drug absorption
Gastric surgery
(Gastrectomy)
(Plyloroplasty)
Why can some drugs not be given orally
Because they are unstable at low pH or in the presence of digestive enzymes
What 4 barriers do drugs taken orally have to pass to reach the circulation
- Intestinal lumen
- Intestinal wall
- Liver
- Lungs
What is broken down by enzymes of the intestinal lumen
Peptide drugs broken down by proteases
luminal membrane of enterocytes contain what which can limit the absorption of a drug
P-glycoproteins
1st pass metabolism occurs mainly where?
in liver
How can you avoid first pass metabolism
Give drug to region of the gut not drained by splanchnic ie. mouth or the rectum
Name a drug given transcutaneously
Fentanyl patch in chronic pain (Non potent- non irritant drugs
Delivered slowly
Name a drug given intradermally or subcutaneously
Local anaesthetic
Insulin (Sc)
Can deliberately limit the rate of absorption
What is the issue with IM injections
Dependent of blood Flow and water solubility - increase in either will enhance the removal of the drug from the injection site
Name a benefit of intranasal administration
Large surface area
Name an advantage and one disadvantage of inhalation administration
Large surface area but limited by risk of toxicity to the alveoli
Define distribution
Process by which the drug is transferred from the general circulation to the tissues as the blood concentration increases and then returns from the tissues to the blood when the concentration falls
Describe how IV drugs become distribute
Initial high plasma concentration and drug rapidly enters well perfused tissues but drug will continue to enter less well perfused tissues lowering plasma concentration so concentration in highly perfused tissues then begins to decrease
what are the components of the blood brain barrier
Tight junctions
Small numbers and sizes of pores in the endothelium
Astrocytes
What is the role of efflux transporters in the BBB
Protect the brain by returning drug molecules to the circulation
How are drugs removed from the BBB
Diffusion into the plasma
Active transport in the choroid plexus
Elimination in CSF
Do lipid soluble drugs cross the placenta
Yes
Define elimination
Removal of a drugs activity from the body
Define metabolism
Transformation of a drug molecule into a different molecule
Define excretion
Molecule expelled in liquid, solid or gaseous waste
Describe a phase I reaction
Reaction that involves the transformation of a drug to a more polar metabolite
Addition of functional group
What is the most common phase I reaction
Oxidation - catalysed by cytochrome P450
Where are the CYP450 enzymes located
In the smooth endoplasmic reticulum in the liver
What can induce P450 enzymes
Smoking
Alcohol
Drugs
Food
What is a phase 2 reaction
Conjugation - formation of a covalent bond between the drug or its phase 1 metabolite and an endogenous substrate - resulting products are usually less active and readily excreted by the kidneys
What are phase 1 metabolites usually conjugated with?
Glucuronic acid
Acetyl methyl groups
How are molecular weight polar compounds excreted
In fluids Urine Bile sweat tears Breast milk
High molecular weight compounds are excreted by
Solid
Faecal
Volatile drugs are excreted by
Gas
Write an equation for total excretion
Glomerular filtration + tubular secretion - reabsortption
Describe enterohepatic circulation
HMW molecules taken into hepatocytes and eliminated in the bile
Bile passes down the gut and some drug may be reabsorbed and enters hepatic portal vein via enterohepatic circulation
