Introductory Clinical Sciences Flashcards
What are the two types of autopsy?
Hospital Autopsy
Medico-legal Autopsy
What are the three ‘types’ of death?
Presumed natural
Presumed iatrogenic
Presumed unnatural
What are the five stages of the autopsy?
History/Scene External examination Evisceration Internal Examination Reconstruction
What are the four questions aimed to be answered by an autopsy?
Who was the deceased?
When did they die?
Where did they die?
How did they come about their death?
Define inflammation.
A reaction to injury or infection involving cells such as neutrophils and macrophages.
What is pus formed of?
Dead neutrophils.
Which cells are first on the scene in acute inflammation?
Neutrophil polymorphs
Which are the second cells to appear in acute inflammation?
Macrophages
What is the usual outcome of acute inflammation?
Resolution
What is the usual outcome of chronic inflammation?
Repair
What is the role of fibroblasts in inflammation?
Form collagen in areas of chronic inflammation and repair.
Which cells are usually involved in chronic inflammation?
Lymphocytes and macrophages
What are five signs of acute inflammation?
Redness (rubor) Heat (calor) Swelling (tumour) Pain (Dolor) Loss of function
What is a granuloma?
A collection of macrophages surrounded by lymphocytes (appear in chronic inflammation).
Give 3 medications that can be used to treat inflammation.
Aspirin
Ibuprofen
Steroids
What is a histiocyte?
A stationary phagocytic cell present in connective tissue.
Which cells usually appear in a bacterial infection?
Neutrophils
Which cells usually appear in a viral infection?
Lymphocytes
What are the three hallmarks of inflammation?
Increased blood supply
Increased vascular permeability
Increased leukocyte transendothelial migration (extravasation)
How does blood flow increase in inflammation?
Cytokines open pre-capillary sphincters to increase blood flow to a tissue.
Are neutrophils long or short-lived?
Short lived.
They usually die at the scene of inflammation.
Are macrophages long or short-lived?
Long lived
Describe resolution
Initiating factor is removed and the tissue is undamaged or able to become exactly the same as before.
Describe repair.
Initiating factor is still present and the tissue is damaged and unable to regenerate.
What is a labile cell?
Give an example.
High regenerative ability
High turnover
Eg - Epithelium
What is a stable cell?
Give an example.
High regenerative ability
Low turnover
Eg - Hepatocytes
What is a permanent cell?
Give an example.
No regenerative ability
Eg - Neurones
Give an example of repair.
Liver cirrhosis
Hepatocytes can usually regenerate after liver damage but after continuing damage (cirrhosis) repair has to occur instead.
Give an example of regeneration.
Lobar pneumonia
Acute inflammation causes the alveoli to fill with neutrophils but the alveolar walls are still in tact so the pneumocytes regenerate.
What is granulation tissue?
Capillary loops and myofibroblasts which can contract to reduce the wound.
Describe how an abrasion resolves.
Abrasion removes epidermis and scab forms over the surface.
Epidermis regrows from the adnexa, protected by the scab.
Epidermis continues to grow and scab comes off.
Describe healing by first intention.
Edges of skin are held together (sutures).
Gap fills with blood and fibrin joins skin weakly.
Epidermis regrows and dermis fills with collagen.
Describe healing by second intention.
Unable to bring edges of the skin together.
Capillaries and myofibroblasts form granulation tissue.
Collagen produced and epithelium grows in from the edges.
Granulation tissue contracts to reduce wound size.
How does repair occur?
Replacement of damaged tissue by fibrous tissue.
Collagen produced by fibroblasts.
What is gliosis?
Fibrosis in the brain
Name some cells that regenerate.
Hepatocytes Blood cells Osteocytes Pneumocytes Gut epithelium Skin epithelium
Name some cells that don’t regenerate.
Myocardial cells
Neurones
Nephrons
Why doesn’t blood clot under normal conditions?
Endothelial cells are non-sticky (due to NO and glycocalyx coating)
Cells flow in the centre of the vessels (laminar flow)
Briefly describe the steps in thrombus formation.
Damage to endothelium Exposed collagen Platelets stick Red blood cells trapped Thrombus formation Fibrin deposition
Define thrombus.
Solid mass of blood constituents formed within an intact vascular system during life.
What is Virchow’s triad?
3 elements that increase the risk of thrombus formation.
What are the three elements of Virchow’s triad?
Change in vessel wall
Change in blood flow
Change in blood constituents
What are two risk factors for arterial thrombosis?
Smoking
Atherosclerosis
Why does venous thrombosis occur?
Slower blood flow (stasis) occurs so cells touch the sides of the vein.
How can venous thrombosis be prevented using medication?
Low dose aspirin
What is an embolus?
Mass of material in the vascular system able to become lodged within a vessel and block it.
What are three things that can act as emboli?
A bit of thrombus
Gas
Talcum powder (IV drug users)
Where does an embolus get stuck if it enters the venous system?
Pulmonary arteries
Where does an embolus get stuck if it enters the arterial system?
Anywhere downstream of the point of entry
What are three inhibitors of thrombosis?
Protein S/Protein C
Anti-thrombin III
Tissue factor pathway inhibitor
Define ischaemia.
Reduction in blood flow to a tissue without any other implications.
Describe the consequences for the tissue in ischaemia.
Cells furthest from the blood supply become ‘unhappy’ but don’t necessarily die.
Define infarction.
Reduction in blood flow to a tissue that is so reduced that it cannot even support mere maintenance of cells so they die.
What are the consequences of infarction?
Necrosis and inflammatory response.
Name some organs with a dual artery supply.
Lungs (pulmonary and bronchial arteries)
Liver (portal vein and hepatic arteries)
Brain (circle of Willis)
Describe reperfusion injury.
Calcium ions build up in the cell (transport mechanisms have been disrupted).
This triggers oxygen-dependent free radical systems.
Macrophages and neutrophils also bring free radicals to the area.
This causes tissue damage associated with infarction.
Define atheroma.
Degeneration of the walls of the arteries caused by accumulated fatty deposits and scar tissue, and leading to restriction of the circulation.
Where does atherosclerosis occur?
Exclusively in high pressure arteries.
Not in pulmonary arteries, and usually at a bifurcation
What’s in an atherosclerotic plaque?
Fibrous tissue
Lipids (cholesterol)
Lymphocytes
What are four risk factors for atherosclerosis?
Smoking
Hyperlipidaemia
Hypertension
Diabetes
Describe the endothelial damage theory of atherosclerosis formation.
Endothelial cells are delicate.
They get damaged and platelet aggregation begins plaque formation.
How does smoking cause endothelial damage?
Free radicals
Nicotine
Carbon monoxide
How does hypertension cause endothelial damage?
Shearing forces on endothelial cells
How does diabetes cause endothelial damage?
Superoxide ions
Glycosylation products
How does hyperlipidaemia cause endothelial damage?
Direct damage to endothelial cells
Describe how platelet aggregation leads to atherosclerosis.
Thrombus forms with red blood cells and fibrin.
Thrombus heals to leave a plaque.
Plaques have capillaries so they can bleed (size increases).
Incremental damage causes atherosclerosis.
What medication can be used to prevent atherosclerosis?
Aspirin
What are some complications of atherosclerosis?
Cerebral infarction Carotid atheroma Myocardial infarction Aortic aneurysm Peripheral vascular disease Gangrene
Define apoptosis
Programmed cell death
Name a protein which detects DNA damage.
p53
What happens in apoptosis?
Cell shrinks Membrane blebs Nucleus degenerates Proteins break down cellular components Cell breaks into small pieces Adjacent cells remove pieces
Which enzymes are involved in apoptosis?
Caspases
Which proteins in a cell can regulate enzymes involved in apoptosis?
BcL2
Which ligand and receptor induces apoptosis in a cell?
FAS ligand/FAS receptor
What are four ways that apoptosis is involved in normal development?
Removal of webbed fingers.
Closure of spinal cord to prevent spina bifida.
Prevents cleft palate.
Prevents ventricular septal defects.
How is apoptosis involved in normal function?
Regeneration of gut epithelium
How can apoptosis cause disease?
Lack of apoptosis in cancer
Too much apoptosis in HIV
Define necrosis.
The traumatic death of many cells in a tissue.
Give five clinical examples of when necrosis occurs.
Toxic spider venom Frostbite Cerebral infarction Avascular necrosis of bone Pancreatitis
What is coagulative necrosis?
Dead tissue preserved and appears sticky.
Typically caused by ischaemia.
What is liquefactive necrosis?
Tissue transformed into viscous mass.
Associated with bacterial/fungal infections.
What is caseous necrosis?
Tissue maintains ‘cheese-like’ appearance.
Associated with TB.
Describe the mechanism of necrosis.
Energy failure.
Impairment or cessation of ion homeostasis.
Lysosomes leak lytic enzymes.
What are some inhibitors of apoptosis?
Growth factors
Extracellular matrix
Sex steroids
Some viral proteins
What are some inducers of apoptosis?
Growth factor withdrawal Free radicals Loss of extracellular matrix attachment DNA damage Glucocorticoids Ionising radiation Some viruses Ligand binding at 'death receptors'
What is the intrinsic pathway of apoptosis stimulation?
Stimuli alter relative levels of members of the BcL-2 family.
What is the extrinsic pathway of apoptosis stimulation?
Ligand binding on ‘death receptors’ (eg - TNFR1 and FAS)
What are homeobox genes?
Genes which code for proteins that bind to DNA (transcription factors) to regulate development.
What does ‘congenital’ mean?
Present at birth.
May or may not be inherited.
What does ‘inherited’ mean?
Caused by an inherited genetic abnormality.
What does ‘acquired’ mean?
Caused by non-genetic environmental factors.
May be congenital.
Which protein is produced in excess in trisomy 21?
beta amyloid protein (encoded by gene on chromosome 21).
This accumulates in the brain.
What is the principal of Mendelian Inheritance?
Single gene alterations are inherited.
Define ‘polygenic inheritance’.
A characteristic is controlled by more than one gene.
Which protein is produced in excess in Huntington’s disease?
Huntingtin.
This accumulates in the brain.
What is the likely diagnosis if someone is in proportion but very small?
Growth hormone deficiency
What is the likely diagnosis if someone is very tall?
Growth hormone excess from pituitary adenoma.
What is acromegaly?
A growth hormone excess after puberty.
These people have very large hands and feet.
Which mutation can cause achondraplasia?
Mutation in the fibroblast growth factor receptor 3 gene.
What is trisomy 18?
Edwards’ syndrome
What is trisomy 13?
Patau’s syndrome
Define hypertrophy.
Increase in size of a tissue caused by an increase in size of the constituent cells.
Give an example of hypertrophy.
Body builders’ muscles
Define hyperplasia.
Increase in size of a tissue caused by an increase in number of the constituent cells.
Give some examples of hyperplasia.
Benign prostatic hyperplasia
Endometrial hyperplasia
Endothelial hyperplasia
Neuronal hyperplasia
Give an example of when hypertrophy and hyperplasia occur together?
Myometrium in pregnancy
How is apoptosis involved in hyperplasia?
It is decreased
Define atrophy.
Decrease in size of a tissue caused by a decrease in number of the constituent cells or a decrease in their size.
Give an example of atrophy.
Loss of brain tissue in Alzheimer’s dementia.
Muscle atrophy.
Define metaplasia.
Change in differentiation of a cell from one fully-differentiated type to a different fully-differentiated type.
What is metaplasia a response to?
An altered cellular environment.
Give an example of metaplasia.
Ciliated columnar epithelium to squamous epithelium in the bronchi of a smoker.
Define dysplasia.
An imprecise term for the morphological changes seen in cells in the progression to becoming cancer.
It results in an abnormal architecture and arrangement.
Define angiogenesis.
New blood vessels grow into damaged, ischaemic, or necrotic tissues.
Define vasculogenesis.
Blood vessel proliferation that occurs in the developing embryo/foetus.
What is a telomere?
A repetitive nucleotide sequence at the end of each chromosome.
What happens to telomeres when DNA replication occurs?
They get shorter.
What is the Hayflick limit?
The number of times a cell population is able to divide.
What is progeria?
Accelerated aging, caused by dysfunction of prelamin A in the nuclear membrane.
Give 10 ways that cells wear out.
Cross-linking/mutations of DNA Loss of calcium influx controls Loss of DNA repair mechanisms Free radical generation Telomere shortening Cross-linking of proteins Damage to mitochondrial DNA Peroxidation of membranes Time-dependent activation of ageing and death genes Accumulation of toxic by-products of metabolism
Describe dermal elastosis.
Wrinkles caused by UVB cross-linking collagen
What causes osteoporosis?
Lack of oestrogen causes increased bone resorption and decreased bone formation.
What causes cataracts?
UVB light causes protein cross-linking.
What 3 things cause senile/Alzheimer’s dementia?
Neuronal loss
Neurofibrillary tangles
beta amyloid plaques
Define sarcopaenia.
Degenerative loss of skeletal muscle mass, quality, and strength, due to decreased growth hormone, decreased testosterone, and increased catabolic cytokines.
What causes deafness?
Loss of hair cells in the cochlea.
Which type of cancer never spreads?
Basal cell carcinoma of the skin
Which type of treatment is required for high grade lymphoma?
Chemotherapy
Where is the first site that carcinomas usually spread to?
Local lymph nodes
Which cancers commonly spread to bone?
Breast Prostate Lung Thyroid Kidney
Why is extra treatment sometimes still required after a tumour is completely excised?
Micro metastases could still be present
What is adjuvant therapy?
Extra treatment for a tumour given after surgical excision.
If a tumour is oestrogen receptor positive what type of treatment can be given?
Anti-oestrogen therapy
If a tumour has a mutation in the HER2 gene what type of treatment can be given?
Herceptin
Define carcinogenesis.
The transformation of normal cells to neoplastic cells through permanent genetic alterations or mutations.
How does carcinogenesis differ from oncogenesis?
Carcinogenesis applies to malignant neoplasms only, whereas oncogenesis applies to both benign and malignant neoplasms.
What are carcinogens?
Agents known or suspected to cause tumours.
What is the difference between ‘carcinogenic’ and ‘oncogenic’?
Carcinogenic = cancer causing Oncogenic = tumour causing
Where do carcinogens act?
On DNA
How much cancer risk is environmental and how much is inherited?
85% environmental
15% inherited
What are the problems with identifying carcinogens?
Latent interval may be decades
Complexity of environment
Ethical constraints
What are the four types of evidence for carcinogens?
Experimental
Direct
Epidemiological
Occupational/behavioural risks
Give some examples of experimental evidence of carcinogens.
Cell/tissue cultures
Mutagenicity testing in bacterial cultures
Incidence of tumours in lab animals
Give some examples of direct evidence of carcinogens.
Thorotrast (angiosarcoma in liver)
Chernobyl (thyroid cancer)
Give some examples of epidemiological evidence of carcinogens.
Hepatocellular carcinoma (increased in areas with HepB/C and mycotoxins. Oesophageal carcinoma (related to diet).
Give some examples of occupational/behavioural evidence of carcinogens.
Increased scrotal cancer in chimney sweeps.
Lung cancer in smokers.
Bladder cancer in alanine dye & rubber industries.
Describe the three steps of carcinogenesis.
Initiation - a carcinogen induces genetic alterations.
Promotion - stimulation of clonal proliferation of the transformed cell.
Progression - invasion and metastatic behaviour.
What are three genetic mechanisms of carcinogenesis?
Telomerase expression
Tumour suppressor gene inactivation
Oncogene activation
Describe Knudson’s Hypothesis.
Cancer is the result of multiple accumulated mutations to a cell’s DNA.
What are the classes of carcinogens?
Chemical Viral Ionising/Non-ionising radiation Hormones/parasites/mycotoxins Miscellaneous
Describe how chemical carcinogens work.
Most require metabolic conversion from pro- to active forms.
Enzyme required may be ubiquitous or confined to certain organs.
What cancers does UV light (non-ionising radiation) cause?
Basal cell carcinoma
Melanoma
Squamous cell carcinoma
Which condition can further increase cancer risk after exposure to UV light?
Xeroderma pigmentosum
What cancers can ionising radiation increase the risk of?
Skin cancer (radiographers) Lung cancer (uranium miners) Thyroid cancer (Ukranian children)
Give some examples of how hormones can act as carcinogens.
Oestrogen increases mammary/endometrial cancer.
Anabolic steroids increase hepatocellular carcinoma.
Give an example of how mycotoxins act as carcinogens.
Aflatoxin B1 increases hepatocellular carcinoma.
Give some examples of how parasites act as carcinogens.
Chlonorchis sinensis increases cholangiocarcinoma.
Shistosoma increases bladder cancer.
Give some examples of miscellaneous carcinogens.
Asbestos
Metals
Give three diseases that asbestos causes.
Asbestosis
Mesothelioma
Lung cancer
What are some host factors that can alter the risk of cancer in an individual?
Race Diet Constitutional factors Premalignant lesions Transplacental exposure
Define ‘lesion’.
A region in an organ/tissue which has suffered damage.
A localised abnormality.
Give four types of chemicals which are carcinogens.
Polycyclic aromatic hydrocarbons
Aromatic amines
Nitrosamines
Alkylating agents
Define tumour and give some examples.
Any abnormal swelling.
Neoplasm, inflammation, hypertrophy, hyperplasia
Define neoplasm.
A lesion resulting from the autonomous or relatively autonomous abnormal growth of cells which persists after the initiating stimulus has been removed.
Give four characteristics of neoplasia.
Autonomous
Abnormal
Persistent
New growth
What percentage of the population are affected by neoplasia?
25%
What percentage of deaths is neoplasia responsible for?
20%
What is the most common type of cancer in men and women?
Prostate (men)
Breast (women)
What is the most common cause of cancer death in men and women?
Lung (both men and women)
Give an example of a borderline tumour.
Some ovarian lesions are classified as borderline.
What are the two components of a neoplasm?
Neoplastic cells and stroma.
Describe a neoplastic cell.
Usually monoclonal cells derived from nucleated cells.
Growth pattern and synthetic activity related to parent cell.
What is the role of the stroma of a neoplasm, and what does it usually contain?
Connective tissue framework.
Mechanical support.
Nutrition.
Keeps neoplastic cells alive.
It usually contains fibroblasts and blood vessels.
How large can tumours grow before they need their own blood supply?
2mm
Why is central necrosis often seen in large, rapidly-growing tumours?
The tumour outgrows its blood supply.
Why can’t angiogenesis currently be used as a target for cancer therapy?
It is essential for normal processes (menstruation and regeneration/repair).
What is the purpose of tumour classification?
Determine appropriate treatment.
Provide prognostic information.
What does the behavioural classification of tumours encompass?
Benign or malignant (or borderline)
What does the histogenetic classification of tumours encompass?
Cell of origin
Define pleomorphic.
Altered shape/size
What is the difference between exophytic and endophytic?
Exophytic = grows into lumen Endophytic = grows into tissue
Describe benign tumours. Include: - Localisation/invasiveness - Growth rate - Mitotic activity - Resemblance to normal tissue - Borders/capsules - Nuclear morphometry - Necrosis - Ulceration - Growth on mucosal surfaces
- Localised/non-invasive
- Slow growth rate
- Low mitotic activity
- Close resemblance to normal tissue
- Circumscribed/encapsulated
- Nuclear morphometry often normal
- Necrosis rare
- Ulceration rare
- Growth on mucosal surfaces often exophytic
Describe malignant tumours. Include: - Localisation/invasiveness - Growth rate - Mitotic activity - Resemblance to normal tissue - Borders/capsules - Nuclear morphometry - Necrosis - Ulceration - Growth on mucosal surfaces
- Invasive/metastases
- Rapid growth rate
- High mitotic activity
- Variable resemblance to normal tissue
- Poorly defined/irregular border
- Hyperchromatic/pleomorphic nuclei
- Necrosis common
- Ulceration common
- Growth on mucosal surfaces often endophytic
What are the consequences of benign neoplasms?
- Pressure on adjacent structures
- Anxiety
- Obstruct flow
- Production of hormones
- Transformation to malignant neoplasm
What are the consequences of malignant neoplasms?
- Destruction of adjacent tissue
- Hormone production
- Metastases
- Paraneoplastic effects
- Blood loss from ulcers
- Anxiety and pain
- Obstruction of flow
Define histogenesis.
The specific cell of origin of a tumour.
A tumour formed from well-differentiated cells is ________ grade tumour.
Low
Where can neoplasms arise from?
Epithelial cells
Connective tissues
Lymphoid/haemopoietic organs
What is a tumour called if the cells are so poorly differentiated that the cell-type of origin is unknown?
Anaplastic
What would a benign neoplasm from secretory epithelium be called?
Adenoma
What would a benign neoplasm from non-secretory epithelium be called?
Papilloma
What would a malignant neoplasm from secretory epithelium be called?
Adenocarcinoma
What would a malignant neoplasm from epithelium be called?
Carcinoma
What is the suffix for a benign neoplasm of connective tissue?
-oma
What is the suffix for a malignant neoplasm of connective tissue?
-sarcoma
Give three examples of malignant tumours which don’t end in carcinoma/sarcoma.
Melanoma (melanocytes)
Mesothelioma (mesothelial cells)
Lymphoma (lymphoid cells)
What is the proper name for fibroids?
Leiomyoma
What is the cell of origin of Burkitt’s lymphoma?
B cells
Where is Ewing’s sarcoma found?
Bones
What is another name for Grawitz tumour?
Renal cell carcinoma
Where does Kaposi’s sarcoma manifest and what is it caused by?
In skin/mouth.
Caused by herpes 8 virus.
Name 6 -omas or -sarcomas and their cells of origin.
Lipoma/Liposarcoma (adipose tissue) Chondroma/Chondrosarcoma (cartilage) Osteoma/Osteosarcoma (bone) Angioma/Angiosarcoma (vascular) Rhabdomyoma/Rhabdomyosarcoma (striated muscle) Leiomyoma/Leiomyosarcoma (smooth muscle)
What are two conditions that contribute to ‘cancer cell’ growth?
More cell division.
Less apoptosis.
What is the name for a carcinoma which is contained within a basement membrane?
Carcinoma in situ
When is a carcinoma classed as invasive?
When it has breached the basement membrane.
What is a mico-invasive carcinoma?
A carcinoma which has not invaded very far.
There is low risk of further spreading.
What causes invasion?
Reduced cellular cohesion.
Production of proteolytic enzymes.
Abnormal cell motility.
What are the six steps of metastasis?
- Invasion of basement membrane
- Invasion of extracellular matrix
- Intravasation
- Evasion of host immune defense
- Extravasation
- Growth and angiogenesis
What are the two factors that allow invasion of the basement membrane and extracellular matrix?
Proteases and cell motility
Which enzymes allow invasion of the basement membrane and extracellular matrix?
Matrix metalloproteinases
Collagenase
Cathepsin D
Urokinase-type plasminogen activator
What factors contribute to cell motility?
Tumour cell derived motility factors.
Breakdown products of extracellular matrix.
What contributes to intravasation?
Collagenases and cell motility
How do neoplastic cells evade the host immune defense?
- Aggregation with platelets
- Shedding of surface antigens
- Adhesion to other tumour cells
What contributes to extravasation?
Adhesion receptors (on inside of vessels).
Collagenases.
Cell motility.
How do tumour cells divide at the new site of metastasis?
Autocrine growth factors
Name two angiogenesis promoters.
- Vascular endothelial growth factor
- Basic fibroblast growth factor
Name three angiogenesis inhibitors.
Angiostatin
Endostatin
Vasculostatin
Which cancers usually spread to the lungs?
Sarcomas, any common cancers
How do tumours spread to the lungs?
Enter lymph/venous channels. Empties into thoracic duct/vena cava. Enters right side of the heart. Enters pulmonary arteries. Invades lungs then enters pulmonary veins and left side of heart.
Which cancers usually spread to the liver?
Colon
Stomach
Pancreas
Carcinoid tumours of the intestine
How do tumours spread to the liver?
Venous drainage to liver via hepatic portal vein.
Metastases form in liver.
How do tumours spread to bone?
Some tumour cells may recognise adhesion receptors in blood vessels in bone so that’s where they exit the blood stream.
Is the primary tumour or the metastases more likey to kill a patient?
Metastases
How could the p53 protein be involved in cancer?
It detects DNA damage but it could be mutated in cancer.
What is telomerase and how could it be involved in cancer?
Enzyme present in germ cells and stem cells which prevents telomeric shortening.
It could be present in neoplastic cells.
Give three symptoms of conventional chemotherapy.
Myelosuppression
Hair loss
Diarrhoea
Which types of tumours is conventional chemotherapy good for?
Fast dividing tumours
Give the names of four drugs used for conventional chemotherapy.
Vinblastine
Etoposide
Ifosamide
Cisplatin
What is the concept of targeted chemotherapy?
It exploits some difference between cancer cells and normal cells to target drugs to cancer cells.
It is more effective and has less side effects.
Name three drugs that have been developed for targeted chemotherapy.
Cetuximab
Herceptin
Gleevec
How do tumour cells evade the immune checkpoint?
Programmed cell death protein 1 is expressed on the surface of self-cells to downregulate the immune system.
Some tumour cells produce lots of this protein.
Describe the TNM system of tumour classification.
T = size or local anatomical extent N = lymph node status M = metastases
What is the role of neutrophils in the innate immune system?
Phagocytosis
What receptors do neutrophils have?
Complement receptors
Fc receptors
What is the role of monocytes & macrophages in the immune response?
Phagocytosis and antigen presentation.
What receptors do monocytes & macrophages have?
Complement receptors
Fc receptors
Pattern-recognition receptors
Which cells are the first line of non-self recognition?
Macrophages
Which types of infections are eosinophils involved with?
Parasitic infections and allergy.
What receptors do eosinophils have?
Fc receptors with a strong affinity for IgE.
How are basophils involved in the immune response?
Involved in immunity to parasitic infections and allergy.
Which molecule is expressed as the T cell co-receptor?
CD3
Which receptor do Th cells express?
CD4
Which receptor do cytotoxic t cells express?
CD8
Which receptor do Treg cells express?
CD25
What is the name of the transcription factor in Treg cells which is vital to their proper function?
FOXP3
How do B cells act as antigen presenting cells?
B cells can recognise soluble antigens using their receptors, internalise them, and then present them on MHCII proteins.
What is the role of Natural Killer cells?
Recognise and kill virus infected cells and tumour cells by apoptosis.
What is the role of dendritic cells?
Process antigens and present them to T lymphocytes.
Name the ‘professional’ antigen presenting cells.
Monocytes/macrophages
B lymphocytes
Dendritic cells
What is the role of Fc receptors?
Recognise the Fc region of antibodies
What is the role of complement receptors?
Recognise pathogens coated in C3b from complement
What is the role of Toll-like receptors?
Recognise pathogen-associated molecular patterns expressed by microbes.
What is the role of mannose receptors?
C-type lectin that recognises carbohydrates
What is the role of scavenger receptors?
Bind to various ligands including bacterial cell wall components.
What are the soluble factors involved in the immune response?
Complement factors
Antibodies
Cytokines
Chemokines
What are complement factors?
A group of 20 serum proteins that circulate in an inactive form.
What are the three complement activation pathways?
Classical
Alternative
Lectin
What is the classical pathway of complement activation?
Antibody bound to microbe
What is the alternative pathway of complement activation?
Complement bound to microbe
What is the lectin pathway of complement activation?
Mannose binding lectin bound to carbohydrates on a microbe.
What are the three ways complement contributes to the immune response?
- Lyse microbes directly
- Increase chemotaxis to attract leukocytes
- Opsonisation
Which component of complement is involved in lysing microbes?
Membrane attack complex
Which components of complement are involved in increasing leukocyte chemotaxis?
C3a and C5a
Which component of complement is involved in opsonisation?
C3b
In what three states can antibodies exist?
Soluble
Bound to B lymphocytes
Secreted
What are the 2 sections of an antibody?
Fab region (where antigen binds) Fc region (constant region)
What are the five classes of antibody?
IgG IgM IgA IgD IgE
Which antibody prevents tumour cells expressing the programmed cell death protein 1 checkpoint?
Nivolumab
Define immunosurveillance.
The process by which cells of the immune system look for and recognise foreign antigens.
What are the three stages of cancer immunoediting?
Elimination
Equilibrium
Escape
Describe the elimination stage of cancer immunoediting.
The immune system eliminates the tumour cells that it can.
Describe the equilibrium stage of cancer immunoediting.
The tumour cells which evaded elimination are selected to grow and replicate.
Describe the escape stage of cancer immunoediting.
Tumour cells grow and expand and have now escaped the immune system.
What are tumour specific antigens?
Antigens which are only found on tumour cells.
What are tumour associated antigens?
Antigens which are overexpressed on cancer cells.
Which types of cells can tumour cells promote to help them evade the immune system?
Tregs
Myeloid-derived suppressor cells
Name two methods of active immunotherapy.
Vaccination (using tumour antigens or killed tumour cells).
Augmentation of host immunity to tumours with cytokines and co-stimulators.
Name two methods of passive immunotherapy.
Adoptive cellular therapy.
Anti-tumour antibodies.
Describe adoptive cellular immunotherapy.
- Extract sample of tumour-infiltrating lymphocytes from tumour biopsy.
- Stimulate the cells to grow ex-vivo.
- Inject cells back into patient.
Which antibodies can active complement?
IgG
IgM
Which is the most abundant antibody in serum?
IgG
Which antibody can cross the placenta?
IgG
Which antibodies are involved in the primary and secondary immune responses?
Primary - IgM
Secondary - IgG
Which antibodies are expressed as B cell receptors?
IgM (in its monomer form)
IgD
Which antibodies require the J chain?
IgM
IgA
Which antibody is secreted as a dimer?
IgA
Which antibody has a secretory component?
IgA
Which antibody is usually found bound to basophils and mast cells?
IgE
What is released upon binding of an IgE antibody?
Histamine
Which antibody is associated with allergic response and parasitic infections?
IgE
What is the term used to describe the process of plasma cells changing from producing one class of antibody to another?
Class/isotype switching
Which immunoglobulin type (IgG or IgM) has the higher affinity?
IgG
Which cells are the primary secretors of cytokines?
Th1
Th2
Macrophages
What is the role of interferons (IFNs)?
Induce a state of antiviral resistance in uninfected cells and limit spread of viral infection.
Which cells secrete IFNa and IFNb?
Virus infected cells
Which cells secrete IFNy?
Activated Th1 cells
What is the role of interleukins (ILs)?
Can cause cells to divide, differentiate, and secrete factors.
Name a pro-inflammatory interleukin.
IL1
Name an anti-inflammatory interleukin.
IL-10
What is the role of colony stimulating factors?
Involved in directing division and differentiation on bone marrow pre-cursors of lymphocytes.
What is the role of tumour necrosis factors?
Pro-inflammatory (mediate inflammation and cytotoxic reactions).
Which interleukin is especially involved in regulating the differentiation of T cells?
IL-2
What is the role of chemokines?
To direct the movement of leukocytes from blood to tissues or lymph organs.
Name four types of chemokine.
CXCL
CCL
CX3CL
XCL
What are five hallmarks of innate immunity?
- Primitive (spread across species)
- Integrates with adaptive response
- Does not depend on immune recognition by lymphocytes
- Does not have long-lasting memory
- Unlearned/instinctive response
What are the three components of the innate immune response?
Physical/chemical barriers Phagocytic cells (neutrophils & macrophages) Serum proteins (complement & acute phase proteins)
What physical barriers are part of the innate immune system?
- Bronchi (mucus, cilia)
- Commensals in mouth
- Lysozyme in tears (and other secretions)
- Skin (physical barrier, fatty acids, commensals)
- Low pH and commensals of vagina
- Flushing of urinary tract
- Gut (rapid pH change, acid, commensals)
- Rapid passage of air over nasal turbinates
What mucous membranes contribute to the innate immune system?
Saliva Tears Mucus secretions/entrapment Cilia (beating removes microbes) Commensal colonies
What physiological barriers are part of the innate immune response?
- Temperature (fever inhibits growth)
- pH
- Gastric acidity
- Oxygen (aerobes/anaerobes)
- Inflammation
Which cells sense microbes in blood?
Monocytes
Neutrophils
Which cells sense microbes in tissues?
Macrophages
Dendritic cells
What are four pathogen-associated molecular patters that can be recognised by PRRs?
- Gram +ve/-ve
- Double-stranded RNA
- CpG oligodeoxynucleotides
- Lipopolysaccharides
What are three types of secreted/circulating PRR?
Give examples.
- Antimicrobial peptides secreted in lining fluids (defensins, cathelicidin)
- Lectins & collectins (mannose binding lectin, surfactant proteins A and D)
- Pentraxins (proteins like CRP with some microbial actions)
Name four types of extracellular cell-associated PRR.
- Toll-like receptors
- Dectin-1
- Mannose receptor
- Scavenger receptor
Which TLR recognises lipopolysaccharides?
TLR-4
Which TLR recognises viral RNA?
TLR-3
Which TLR recognises bacterial DNA?
TLR-9
Name two types of intracellular PRR.
Nod-like receptors
Rig-I-like receptors
Name three types of NLR.
NOD1
NOD2
NLRP3
What do NLRs detect?
Intracellular microbial pathogens
Eg - peptidoglycan, muramyl dipeptide
What do RLRs detect?
Intracellular double stranded viral RNA/DNA.
How do RLRs work when activated?
Activate interferon production to stimulate antiviral response.
Name three RLRs.
RIG-I
MDA5
LGP2
Give four ways that PRRs are involved in homeostasis.
- Neutrophil numbers are dependent on TLR-4
- Induction of endotoxin tolerance in newborn gut
- Maturation of normal immune system
- Maintaining balance with commensal organisms
In addition to Pathogen-associated molecular patterns, what else can TLRs recognise?
Molecules that signal cell damage.
What is one feature usually associated with damage-associated molecules?
Hydrophobicity
Name some molecules that can be seen as damage molecules.
- Fibrinogen
- Hyaluronic acid
- Tenascin C
- HMGB1 protein
- mRNA
- Heat shock protein
- Uric acid
Why are many hydrophobic molecules associated with cell damage?
They are usually contained inside cells so when cells are damaged they are released and available to TLRs.
What are heat shock proteins?
Proteins produced by cells in response to stress.
They protect proteins from stress and excess heat.
How are PRRs involved in adaptive immunity?
Activation of PRRs drives cytokine production by APCs to increase likelihood of T cell activation.
How are PRRs used in vaccination?
TLR-4 agonists are used as adjuvants to simulate TLR-4 to enhance the immune system.
Give three ways the PRRs are involved in disease.
- Recognition of host molecules leads to autoimmune disease
- Potential failure to recognise pathogens
- Increased inflammatory response
Which transcription factors can be activated by TLRs?
NF-kB
IRF3
What is the final outcome of TLR activation?
Interferon production and regulation of the immune response.
Which transcription factor pathway does TLR-4 activate?
NF-kB
What is primary immunodeficiency?
Part of the immune system is missing or functions improperly due to a genetic fault.
What is secondary immunodeficiency?
Synthesis of key immune components is suppressed (due to bone marrow infiltration/virus).
How does antibody deficiency usually present?
Recurrent bacterial infections of the respiratory tract.
How does defects in cellular immunity usually present?
Invasive and disseminated viral, fungal, and opportunistic bacterial infections involving any organ.
What are the main cells that carry out phagocytosis?
Neutrophils
Macrophages
What are the six steps of phagocytosis?
- Microbe binding
- Engulfment
- Phagosome
- Phagolysosome
- Secretion of waste
- Antigen presentation (MHCII)
Which receptors do phagocytes have which can bind pathogens for phagocytosis?
Fc receptors
Complement receptors
Mannose receptors
Name the two mechanisms of killing in phagocytosis.
Oxygen dependent
Oxygen independent
What is the respiratory burst?
Phagocyte oxygen consumption increases in phagocytosis so more ROIs produced which are used to kill pathogens.
Which enzyme is used to produce reactive oxygen species?
Superoxide dismutase
Give three ROS and link them.
O2 (superoxide) -> H2O2 (hydrogen peroxide) -> .OH (free radical)
How does the production of NO help phagocytosis?
Causes vasodilation and extravasation, and is also a direct antimicrobial.
What are three elements of the oxygen independent phagocyte killing pathway?
Enzymes (defensins and lysozyme)
PH
TNF (Tumour necrosis factor)
Where are dendritic cells found?
In tissues which are in contact with the external environment, eg - skin.
What is an acute phase protein?
A protein whose serum concentration will increase or decrease in response to inflammation.
Name an acute phase protein.
C Reactive Protein
What is the ultimate aim of complement activation?
Cleavage of C3
Which complement factor cleaves C5?
C3b
What are the four essential characteristics of adaptive immunity?
Specificity
Diversity
Memory
Self/non-self recognition
What are four features of adaptive immunity?
Response specific to antigen
Memory to specific antigen
Quicker response
Requires lymphocytes
Which cells and which microbes are involved in cell mediated immunity?
T cells
Intracellular microbes
Which cells and which microbes are involved in humoural immunity?
B cells
Extracellular microbes
What is primary lymphoid tissue?
Give examples.
Tissue where lymphocytes are formed and mature.
Eg - thymus and bone marrow
What is secondary lymphoid tissue?
Give examples.
Tissue where lymphocytes are activated.
Eg - spleen, lymph nodes, MALT
What is a major histocompatibility complex?
Glycoprotein which displays antigen on cell surface.
Which genes encode major histocompatibility complexes?
Human Leukocyte Antigen (HLA) genes
Describe MHC Class I.
- Which cells is it on?
- Which antigens does it display?
- Which cells respond to it?
- What is the outcome of displaying the antigen?
- Displayed on all nucleated cells
- Presents intracellular antigens
- Tc (CD8+) cells respond
- Outcome is killing of infected cell
Describe MHC Class II.
- Which cells is it on?
- Which antigens does it display?
- Which cells respond to it?
- What is the outcome of displaying the antigen?
- Displayed on APCs
- Presents extracellular antigens
- Th (CD4+) cells respond
- Outcome is helping B cells
What is the difference between antigen recognition by T cells and B cells?
B cells can recognise soluble antigens whereas T cells can only recognise antigens in association with MHC.
What autocrine molecule is secreted by T cells in order to activate the cell?
IL-2
Which receptor on naive T cells as a co-stimulatory molecule in T cell activation?
CD28
Which receptor acts as a co-stimulatory molecule on helper T cells?
CD4
Which receptor acts as a co-stimulatory molecule on cytotoxic T cells?
CD8
What are the four outcomes of T cell activation?
- Division
- Differentiation
- Effector functions
- Memory
What are the roles of a Tc (CD8+) cell?
- Binds to MHCI
- Forms proteolytic granules
- Releases perforins/granulysin
- Induces apoptosis
What are the roles of a Th1 (CD4+) cell?
- Binds to MHCII
- Go to secondary lymphoid tissue and undergo clonal expansion
- Recognises antigen on infected cells
- Secretes INFy to stop virus spread
- Induce apoptosis
What are the roles of a Th2 (CD4+) cell?
- Bind to B cells displaying antigen on MHCII
- Release cytokines to cause B cell clonal expansion
Which is the main cytokine that determines whether a Th cell will become Th1 or Th2?
Il-12
High levels of Il-12 activate Th1, low levels activate Th2
Which types of cells can B cells differentiate to form?
Plasma cells
Memory cells
Where do B cells divide and differentiate?
Lymph nodes
What are the three functions of antibodies?
- Neutralise toxin by binding to it
- Increase opsonisation for phagocytosis
- Activate complement
Define autoimmunity.
Immune response against a self antigen
Define autoimmune disease.
Tissue damage or disturbed function resulting from an autoimmune response.
What is an organ-specific autoimmune disease?
Autoimmune diseases which affect a single organ.
What is a non-organ-specific autoimmune disease?
An autoimmune disease which affects multiple organs.
What are the two types of selection which occur in central (thymic) tolerance?
Positive selection
Negative selection
What is positive T cell selection?
T cells that bind to self antigens associated with MHC in the thymus with low affinity are allowed to mature.
What is negative T cell selection?
T cells that don’t recognise self MHC or bind with high affinity in the thymus undergo apoptosis.
How can central (thymic) T cell tolerance fail?
It can fail if self-peptides are not expressed in high enough concentrations in the thymus.
What are three methods of peripheral tolerance?
- Immunological ignorance
- Anergy
- Tregs
Describe immunological ignorance in relation to peripheral T cell tolerance.
Some self-antigens hide from the immune system.
This can be due to:
- Being in an avascular organ (vitreous humour)
- A limited number of MHC molecules
- Apoptosis keeping self-antigens contained
Describe anergy.
If the CD28 co-stimulator molecule on a T cell is not activated by the APC the T cell will become unresponsive.
Describe how Tregs contribute to peripheral tolerance.
They may suppress T cells if they recognise the same antigen.
What are four ways that treatments for autoimmune diseases can target the self-reactive lymphocyte?
- Inhibition of lymphocyte function
- Reinduction of anergy
- Removal of co-stimulation
- Induction of inhibitory T cells
How can tissue damage caused by an autoimmune disease be treated?
Anti-inflammatory drugs (eg - corticosteroids)
Define passive immunisation.
Transfer of preformed antibodies
Describe the two types of passive immunity.
Natural (transfer of maternal antibodies)
Artificial (Treatment with human IgG or immune serum)
Give four uses of passive immunisation.
- Anti-toxins
- Prophylaxis to prevent infection after exposure
- Anti-venins
- Given to patients with agammaglobulinaemias and immune-compromised patients
Define active immunisation.
Manipulating the immune system to generate a persistent protective response against pathogens by safely mimicking natural infections and establishing immunological memory.
What are the six steps of active immunisation?
- Engage innate immune system
- Elicit danger signals (PAMPs)
- Engage TLR receptors
- Activate APCs
- Engage adaptive immune system
- Generate memory T and B cells
What is somatic hypermutation?
Genes in B cells coding for the antigen binding sites on antibodies undergo rapid mutations during the immune response to create more specific and unique receptors.
How do T and B cell receptors achieve their huge range of diversity?
The genes coding for the antigen receptors are inherited as fragments.
The fragments are joined together to form a complete antigen receptor gene only in individual lymphocytes as they develop.
What are the two vaccine designs that are currently used?
Whole organism
Subunit
What is a live attenuated vaccine?
The pathogen is still alive but the virulence has been reduced.
This sets up a transient infection and engages a full immune response.
Give two examples of live attenuated pathogen vaccines.
Tuberculosis (BCG)
Polio Sabin
Describe whole inactivated pathogen vaccines.
Inactivation of the pathogen usually by chemical treatment (eg - formaldehyde).
No risk of infection so immune response can be weak.
Wide range of antigens present.
Give two examples of whole inactivated pathogen vaccines.
Salk polio, Hepatitis A
What are the three major types of subunit vaccine.
Inactivated exotoxins
Capsular polysaccharides
Recombinant microbial agents
What is the aim of a synthetic peptide vaccine?
To produce a peptide that includes immunodominant B cell epitopes and can stimulate memory T cell development.
*Still being developed
What is the aim of a DNA vaccine?
To transiently express genes from pathogens in host cells to generate an immune response similar to natural infection leading to memory T and B cells.
* Still being developed
What are recombinant vector vaccines?
Genes for pathogenic antigens are introduced into a non-pathogenic microorganism.
*Still being developed
What is an adjuvant in relation to vaccines?
Any substance added to a vaccine to stimulate the immune system.
Give four examples of vaccine adjuvants.
- Aluminium salts form precipitates and increase opsonised phagocytosis
- Chemicals cause irritation and inflammation
- Toxoids and killed organisms send out danger signals
- TLR agonists activate TLR receptors
Give some examples of medical non-adherence.
- Not taking prescribed medication
- Taking a different dose than prescribed
- Taking medication more/less often than prescribed
- Stopping the medicine without finishing the course
- Modifying treatment to accommodate other activities
- Continuing with behaviours against medical advice
What are some unintentional/practical reasons for non-adherence?
- Difficulty understanding instructions
- Problems using treatment
- Inability to pay
- Forgetting
What are some intentional/motivational reasons for non-adherence?
- Patients’ beliefs about their health/condition
- Beliefs about treatments
- Personal preferences
What are four impacts of good doctor-patient communication?
- Better health outcomes
- Better adherence to therapies
- Higher patient and clinician satisfaction
- Decrease in malpractice risk
What are three patient barriers to concordance?
- Do patients want to engage in discussion with their doctor?
- The patient may worry more
- Patients may want the doctor to tell them what to do (especially in complex cases)
What are three health professional barriers to concordance?
- Relevant communication skills
- Time/resources/organisational constraints
- Challenging (patient voice V evidence)
Define adherence.
The extent to which the patient’s actions match agreed recommendations.
What are four ethical considerations when discussing patient adherence?
- Mental capacity
- Decision may be detrimental to a patient’s wellbeing
- Potential threat to the health of others
- Wishes of parent/child
What does the Public Health Act 2010 allow?
Detention and isolation of an infectious individual.
What does section 1 of the Children Act 1989 say?
The child’s welfare shall be the Court’s paramount consideration.
What is a physiochemical drug interaction?
The way two drugs interact with each other.
What can a physiochemical drug interaction cause?
Adsorption
Precipitation
Chelation
Neutralisation
Give an example of a physiochemical drug interaction.
Paracetamol adsorbs to activated charcoal so activated charcoal can be given in a paracetamol overdose.
What are the three ‘types’ of drug interaction?
- Physiochemical
- Pharmacodynamic
- Pharmacokinetic
Define pharmacodynamic.
The effects of a drug on the body.
What are the four types of pharmacodynamic drug interaction?
- Summation
- Synergism
- Antagonism
- Potentiation
What is a summative pharmacodynamic reaction?
The effect of two drugs added together.
What is a synergistic pharmacodynamic interaction?
The effect of the drugs being given together is greater than the sum of the effects of both drugs individually.
What is an antagonistic pharmacodynamic interaction?
Two drugs oppose each other.
Give an example of a synergistic pharmacodynamic interaction.
Giving morphine and paracetamol together amplifies their effect.
Give an example of an antagonistic pharmacodynamic interaction.
Morphine and Naloxone (an opioid reversal drug)
What is potentiation, in terms of pharmacodynamic interactions?
One drug makes the other more powerful, but it doesn’t work the other way round.
Give an example of potentiation, in terms of pharmacodynamic interactions.
Probenecid makes penicillin more powerful.
What are some common drug interactions involving warfarin?
- Highly protein-bound (giving another highly protein-bound drug at the same time increases effect)
- Metabolised by CYP450 (enzyme inducers/inhibitors alter effects)
What are four drugs that cause acute kidney injury, and why shouldn’t they be given together?
- NSAIDs
- ACE inhibitors
- Gentamicin
- Furosemide
NSAIDs and ACEi have synergistic effects, and so do gentamicin and furosemide.
Define druggability.
The ability of a protein target to bind small molecules with high affinity.
What are the four common drug targets?
Receptors
Ion Channels
Transporters
Enzymes
What is a receptor?
A component of a cell that interacts with a specific ligand and initiates a change of biochemical events leading to the ligands observed effects.
What are the four types of receptor?
- Ligand-gated ion channel
- G protein coupled receptor
- Kinase-linked receptor
- Nuclear receptor
How does a ligand-gated ion channel work?
A ligand binds and causes a conformational change which opens the ion channel.
How do GDP and GTP affect G protein coupled receptors?
They are switched off when bound to GDP and switched on when bound to GTP.
Which enzymes are commonly bound to G protein coupled receptors and which second messengers do they produce?
- Phospholipase C, which produces DAG/IP3
- Adenylyl cyclase, which produces cyclic AMP
Which enzyme is usually present in kinase-linked receptors?
Tyrosine kinase
How to kinase-linked receptors work?
- Ligand binds and receptors dimerise
- Receptors phosphorylate each other (usually tyrosine is phosphorylated)
- Intracellular proteins bind to phosphorylated receptor to become phosphorylated
Which type of ligand usually binds to kinase-linked receptors?
Growth factors
How do nuclear receptors work?
Steroid hormones bind to cause conformational change.
Receptor binds to DNA to modify gene transcription.
Define ligand.
A molecule that binds to another (usually larger) molecule.
Define agonist.
A compound that binds to a receptor and activates it.
Define antagonist.
A compound that reduces the effect of an agonist.
What is potency?
A measure of drug activity expressed in terms of the amount required to produce an effect of given intensity.
What is EC50?
The concentration of a drug that gives half the maximal response.
What is efficacy (Emax)?
The maximum response achievable from a dose of a drug.
It describes how well a ligand activates the receptor.
What is intrinsic activity (IA)?
The ability of a drug-receptor complex to produce a maximum functional response.
(Emax of partial agonist / Emax of full agonist)
What is the role of an antagonist?
To not activate the receptor and reverse the effects of agonists.
Describe competitive antagonism.
The agonist and antagonist compete for binding sites, and increasing the concentration of the antagonist decreases the agonist activity.
Describe non-competitive antagonism.
The antagonist binds to an allosteric on the receptor to prevent activation.
This reduces Emax of the agonist.
Define affinity.
How well a ligand binds to the receptor.
What is an irreversible antagonist?
An antagonist which inactivates receptors and reduces the number of receptors present.
What is the receptor reserve?
Holds for a full agonist in a given tissue (spare receptors with a maximal response).
Define signal transduction.
The transmission of a signal from the exterior to the interior of a cell.
Define signal amplification.
The increase of a signal related to the amount of activation.
What is an inverse agonist?
A compound which downregulates a response.
It shows the opposite response to an agonist.
What is tolerance, in relation to pharmacology?
The reduction in a drug’s effect over time due to continuously, repeatedly, high concentrations.
What can desensitization be caused by?
- Uncoupling
- Internalisation
- Degradation
How should the terms specificity and selectivity be used when describing the actions of drugs and receptors.
No compound is ever truly specific, so selective is a better term to describe activity.
What is an irreversible enzyme inhibitor?
A substance which reacts with the enzyme and changes it chemically.
Eg - via a covalent bond
What is a reversible enzyme inhibitor?
A substance which binds non-covalently to an enzyme, enzyme-substrate complex, or both.
Name an enzyme which is used as a drug.
Streptokinase (a clot buster)
What is the role of HMG-CoA inhibitors?
They block the rate-limiting step in the cholesterol pathway to act as a lipid-lowering medication.
What is the role of ACE inhibitors?
Reduce angiotensin II production to lower blood pressure.
How can enzymes be used in Parkinson’s Disease?
- Enzymes can be used to block L-DOPA breakdown in the periphery so it can cross the blood brain barrier.
- They can also be used to block L-DOPA and Dopamine breakdown in the CNS so more dopamine is available.
Apart from enzymes, what other types of drugs can be used in Parkinson’s disease?
Central dopamine agonists
How does furosemide work?
Blocks NKCC cotransporter in the Loop of Henle to reduce hypertension and oedema.
Name a drug that blocks the Epithelial sodium channel (ENaC) to prevent reabsorption of sodium in the collecting duct.
Amiloride
Name an angioselective drug which blocks Ca channels in smooth muscle and cardiac muscle cells to cause vasodilation and reduce peripheral vascular resistance (and therefore blood pressure).
Amlodipine
How does lidocaine act as a local anaesthetic?
Blocks voltage-gated sodium channels to block the transmission of an action potential.
As well as use an anaesthetic, how else is lidocaine used?
For heart arrhythmia
Repaglinide, nateglinide, and sulfonylurea block metabolic potassium channels. How can they be used as drugs?
Block potassium channels in beta cells in pancreas to stimulate insulin release in type 2 diabetes.
Which neurotransmitter can open receptor-mediated chloride channels on neurones to hyperpolarise the cell?
GABA
Name a type of drug that can be used to increase the permeability of chloride channels in the brain to hyperpolarise neurones and therefore provide more action potential inhibition.
Barbiturates
How does digoxin lengthen the cardiac action potential and what conditions is it used for?
Inhibits Na/K ATPase in myocardium, which increases intracellular calcium.
Used for atrial fibrilliation, atrial flutter, and heart failure.
Describe how omeprazole works.
Proton pump inhibitor which inhibits K/H ATPase in stomach to inhibit gastric acid secretion.
It is metabolised at an acidic pH.
Name three types of drugs which are irreversible inhibitors.
- Organophosphates
- Omeprazole
- Aspirin
What is a pharmacokinetic drug interaction?
What the body does to a drug.
What is bioavailability (F)?
The proportion of a drug which enters the circulation so is able to have an effect.
What is the bioavailability for an IV drug?
100%
How do you work out the bioavailability for an oral drug?
Area under concentration-time curve for oral drug / AUC for IV drug
What are three factors which affect the rate of absorption of a drug?
- Gut motility
- Acidity
- Physiochemical effects
How does gut motility affect drug absorption?
Pain and certain drugs can cause slower peristalsis, so drugs taken orally will be less effective.
How does acidity affect drug absorption.
Drugs exist in equilibrium between ionised and unionised forms.
A change in acidity alters the equilibrium.
Unionised drugs are lipid soluble (can cross cell membrane) but ionised drug are water soluble (can’t cross cell membrane).
