Introduction to Clinical Sciences Flashcards
What is inflammation
cellular reaction to injury involving neutrophils and polymorphs
what are neutrophil polymorphs
they are white blood cells made in the bone marrow. They have a short lifespan (2-3 days), and are called polymorphs cause they have a polylobed nucleus
what do neutrophils contain to remove pathogens
contain lysosomes of enzymes which can kill phagocytosed bacteria
what types of immune cells are the first to arrive at the site of acute inflammation
neutrophils
what is the lifespan of macrophages
months to years
what are features of macrophages
they have a circular nucleus, and acts as antigen presenting cells. They have different names dependent on what tissue they reside
Define exudate
Exudate is fluid that leaks out of blood vessels into nearby tissues. The fluid is made of cells, proteins, and solid materials.
what are lymphocytes
they are T or B cells which are long lives cells which produce chemicals involved in controlling inflammation and production of antibodies. Lymphocytes are the immunological memory of the body
what are plasma cells
they are specialised B cells which are antibody producing
what are fibroblasts
they are cells which produce collagenous connective tissue- spindle shaped cells
what are the features of acute inflammation
injury or infection
early onset - seconds to minutes
short duration - hours to days
cells involved - neutrophils and then macrophages
what are examples of acute inflammation
microbial infections - bacteria and viruses
hypersensitivity reactions - parasites
physical agents - trauma, heat, cold
chemicals - corrosives and acids
bacterial toxins
tissue necrosis – ischemic
what is the sequence of events of chronic inflammation
either progression from acute inflammation or starts as chronic inflammation
there are no or few neutrophils in this case
macrophages and lymphocytes and then fibroblasts involved
can resolve if there is no tissue damage but this often ends up with repair and formation of scar tissue
what is an example of primary chronic inflammation
infection mononucleosis
what is a granuloma
it is a particular type of chronic inflammation with collections of macrophages/histiocytes surrounded by lymphocytes
what are the reasons for granuloma formation
seen in mycobacterial infection such as TB or leprosy, also seen in crohns disease and sarcoidosis
what are the features of endothelial cells
the line blood vessels and produce nitric oxide to prevent platelets sticking to them.
why might an inflamed area be red and swollen
because of the larger blood flow to the area - increased capillary action
what are the outcomes of acute inflammation
resolution
supporation - pus formation
organisation - granulation tissue and fibrosis
progression - excessive inflammaiton - becomes chronic
what is resolution
where the problem causing inflammation is resolved, inflammation is solved and there is no tissue damage
what is first intension healing
it is when the edges of the wound can be joint back together, making it much easier for the body to repair the wound.
initial weak fibrin joint and then collagen joint after
what is second intension healing
when the edges of the wound cant be joint back together which can be either due to trauma or with certain surgeries.. cells have to grow into the wound, with initilal capillary cells, then fibroblasts and then epithelial cells
what is granulation tissue
where capillary loops are growing into wound (looks a bit like granular tissue)
what is tissue repair
when there is replacement of damaged tissue that cant regenerate, collagen is therefore produced by fibroblasts, leaving a scar
- original tissue lost
what cells regenerate within the body
hepatocytes, blood cells, pneumocytes, gut epithelium, skin epithelium and osteocytes
what cells dont regenerate
myocardial cells and neurons
what is the steps of acute inflammation
vascular component = dilation of vessels
exudative component = vascular leakage of protein rich fluid
neutrophil polymorph = cells type recruited to tissue
what is the appearance of acute inflammation
red in colour, heat, swelling, pain and loss of function
what happens during acute inflammation
- migration of neutrophils; increased plasma viscosity and slowing of flow during injury meaning neutrophils migrate to plasmatic zone
- Adhesion of neutrophils to the endothelium
- neutrophil emigration as they pass through the endothelial cells onto the basal lamina
- diapedesis; RBC may also escape from vessels
what are the four outcomes of acute inflammation
- resolution - complete restoration of tissue to normal w/minimal cell death
- suppuration - formation of pus, leads to scarring
- organisation - replacement by granular tissue, new capillaries grow into inflammatory exudate, macrophages migrate and fibrosis occurs
- progression - causative agents is not removes so there is progression to chronic inflammation
what is chronic inflammation
subsequent and prolonged response to tissue injury
what are the cells involved in chronic inflammation
lymphocytes, macrophages, plasma cells
what are causes of chronic inflammation
primary chronic inflammation, transplant rejection, autoimmune conditions, endogenous and exogenous conditions
what is the macroscopic appearance of chronic inflammation
chronic ulcer
crohns abscess cavity
granulomatous inflammation
fibrosis
what is the microscopic appearance of chronic inflammation
lymphocytes, plasma cell, macrophages, continuing destruction and possible necrosis
what is laminar flow
cells travel in the centre of arterial vessels and dont touch the sides
what is a thrombosis
it is the formation of a solid mass from blood constituents in an intact vessel in a living person
what is the first stage of thrombosis formation
platelet aggregation - platelets release chemicals when they aggregate which causes other platelets to migrate and stick - starts of a positive feedback cascade
what are the three things that can cause thrombosis formation
- change in the vessel wall
- change in the blood flow
- change in the blood constituents
what is an embolism
the process of a solid mass in the blood being carried through the circulation to a place where it gets stuck and blocks a vessel
what is the most common cause of embolism
a thrombus
what are some less common causes of embolism
air, cholesterol crystals, tumours, amniotic fluid, fat
what happens if an embolus enters the venous system
will travel to vena cava, through the right side of the heart and lodge in the pulmonary arteries, causing pulmonary oedema
what is ischemia
a reduction in blood flow to a tissue
what is infarction
a reduction in blood flow to a tissue that results in cell death
what is end arterial supply
when an organ/tissue only has a single artery supplying it
what are the few organs with a duel arterial supply
the lungs, liver and parts of the brain
what are the granules that platelets contain
alpha and dense
what is the function of alpha granules
platelet adhesion - fibrinogen
what is the function of dense granules
platelet aggregation - ADP
How does a thrombus form
a change in the vessel wall will cause a plaque to form there, which will protrude into the lumen and cause some turbulence. this results in the loss of intimal cells. Clumping will occur and fibrin is deposited. this structure will continue to protrude into the lumen
do thrombi form in veins
not likely as there is lower pressure in veins - can occurs around valve sites
what are the clinical features of arterial thrombi
loss of pulse distal to thrombus, area becomes cold and pale and painful. there could be gangrene
what is the fate of thrombi
- resolution
- organised - becomes a scar with slight narrowing
- recanalisation - intimal cells proliferate and capillaries may grow into the thrombus
- embolus - fragments break off into circulation
what could a venous thrombus lead to
DVT
what is an atherosclerosis
accumulation of fibrolipid plaques systemic arteries
what is the time course of atherosclerosis
birth - none
late teen/early 20s - fatty streaks in aorta, may not progress to established atherosclerosis
30s/40s/50s - development of established atherosclerotic plaques
40s -80s - complications of atherosclerotic plaques
what are rick factors of atherosclerosis
hypertension
hyperlipidemia
cigarette smoking
poorly controlled diabetes
what is the pathogenesis of atherosclerosis
endothelial damage theory - endothelial cells are delicate and can become damaged by cigarette smoke, shearing forces, hyperlipidemia, glycosylation products
what can cumulative damage of the endothelial barrier lead to
it leads to endothelial ulceration, microthrombi and eventual development of established atherosclerotic plaques
what are the complications of atherosclerosis
blocked vessels - infarct
embolism leading to cerebral infarction, carotid atheroma, myocardial infarction, aortic aneurysm, peripheral vascular disease and gangrene
how does atherosclerosis form
- endothelial cell dysfunction (lots of cholesterol damages wall)
- High levels of LDLs will begin to accumulate
- macrophages are attracted to the site of damage at take up lipid to form foam cells
- platelet aggregation and the plaque starts to protrude into the artery lumen disrupting flow. thinning of media occurs
- fibrin mesh and red blood cell trapping occurs
- fibrous cap forms over smooth muscle cap forming a stable atheroma
what are preventative measures for atherosclerosis
smoking cessation
blood pressure control
weight reduction
low dose aspirin
statins - cholesterol reducing
what is apoptosis
it is programmed cell death - orderly event without the release of products harmful to surrounding cells
what is the purpose of apoptosis
it is a process in normal cell turnover which prevents cells with accumulated genetic damage from dividing and producing cells which might eventually develop into cancer
what protein detects DNA damage
p53
what is the function of p53
it is a protein in cells which detects the level of DNA damage which will trigger apoptosis if DNA damage is high
how does a cell apoptose
the cell triggers a series of proteins which leads to the release of enzymes called caspases which auto digests the cell
when does apoptosis occur in health
development - removal of cells during development such as interdigital webs
cell turnover - removal of cells during normal turnover, such as the intestinal villi
when does apoptosis occur in disease
cancer - cells in tumours often dont apoptose due to accumulation of genetic mutations, including those in the p53 gene
HIV - HIV can induce apoptosis in CD4 T helper cells to produce an immunodeficient state
what is necrosis
it is the traumatic loss of cells - uncontrolled
what are clinical examples of necrosis
infarction due to loss of blood supply
frostbite
pancreatitis
what are the inhibitors of apoptosis
growth factors, extracellular cell matrix, sex steroids
what are the inducers of apoptosis
glucocorticoids, free radicals, ionising radiation, DNA damage
what is the intrinsic pathway of apoptosis
this uses pro and anti apoptotic members of the Bcl-2 family. Bax forms Bax-Bax dimers which enhance apoptotic stimuli. the Bcl-2:Bax ratio determines the cells susceptibility to apoptotic stimuli.
it responds to growth factors and biochemical stress.
the p53 gene induces cell cycle arrest and DNA damage repair, and if it cant be fixed it induces apoptosis
what is the extrinsic apoptotic pathway
this involves ligand binding to death receptors on the cell surface. this includes the TNFR1, CD95 and the main one the Fas-FasL
the ligand binding causes the clustering of receptor molecules on the cell surface and the initiation of signal transduction cascades
caspases are activated and triggers apoptosis
what is coagulative necrosis
most common type - ischemia
what is liquefactive necrosis
occurs in brain due to lack of supportive stroma
what is caseous necrosis
causes ‘cheese’ pattern - TB characterised by this
what is gangrene
necrosis with rotting tissue - affected tissue is black due to deposition of iron sulphate
What is the definition of hypertrophy
It is the increase in cell size without cell division.
what is the definition of hyperplasia
Increase in cell number by mitosis - this can only happen in cells that can divide `
what cells cant undergo hyperplasia
Myocardial cells or nerve cells
what is the definition of atrophy
The decrease in the size of an organ or cell which can be reduction in cell size or number
when is there natural atrophy in the body
Occurs during the development of the GU tract
what is the definition of metaplasia
the change in differentiation of a cell from one fully differentiated cell type to another
what are examples of metaplasia
Barretts oesophagus - squamous epithelium to columnar epithelium
what is the definition of dysplasia
morphological changes seen in cells in the progression to becoming cancer
not cancer but could become cancer
what is a genetic disease
a disease that occurs primarily from a genetic abnormality
what is a single gene disorder
abnormality of a single gene causes a disease - can be recessive or dominant
what are the two further classifications of single gene disorder
autosomal or sex linked
what is polygenic gene disorder
a genetic disease which is the result of the interaction of several different genes (usually on different chromosomes)
what is a congenital disease
a disease which someone is born with - but can also be acquired. This will often be a disease which is due to environmental factors but it may be a strong genetic background
what is a homeobox gene
genes which code for particular region of the body and control migration of cells
what is benign prostatic hyperplasia
smooth muscle in the prostate divides and causes the prostate to crow and constricts the urethra
when do you have combined hypertrophy and hyperplasia
in the uterus during pregnancy
what is a classic example of atrophy in aging
dementia
What is the limit of aging
number of times a cell can divide
what are the limiting factors of cell division
telomerase length - telomeres get shorter after each cell division which then limits the amount of divisions that can occur
what things can induce apoptosis in cells
crosslinking or mutation of DNA
accumulation of toxic by products of metabolism
telomere shortening
time dependent activation of aging and death genes
free radical generation
crosslinking of proteins
damage to mitochondrial DNA
loss of DNA repair mechanism
what is dermal elastosis
the accumulation of abnormal elastic in the dermis of the skin, which is the result of prolonged or excessive sun exposure. This is because UVB light causes protein cross linking
what is osteoporosis
caused by the loss of coupling in the bone remodeling process with increased bone resorption and reduced bone formation. the bone matrix is mineralised as normal but the trabeculae are thinned
what is cataracts and its cause
it is the formation of opaque proteins within the lens which usually results in the loss of lens elasticity. It is caused by UVB light causing protein cross linking
what causes dementia
plaques and neurofibrillary tangles in the brain
what is sarcopenia
it is decreased growth hormone, decreased testosterones and increased catabolic cytokines. This causes involuntary loss of skeletal muscle mass and strength
what is the cause of deafness in age
the hair cells cant divide or regenerate in the ear which means once damage occurs it cant be undone
What cancer only invades locally
basal cell carcinoma - doesnt metastasize
what is the cure for basal cell carcinoma
complete local excision of the cancer
what type of cancer is leukemia
it is the cancer of white blood cells
what has to happen before cancer removal surgery
they generally do an ultrasound of the area to ensure that there is no growth into surrounding lymph nodes. Can also send a lymph node sample to the lab
what cancers commonly spread to the bone
breast, prostate, thyroid, lung and kidney cancers commonly spread to the bone
what biopsy can be done to check if cancer is present
a needle core biopsy
what is adjuvant therapy
it is extra treatment given after the surgery to help prevent the regrowth of cancer
what is the name of the main effector cell in acute inflammation
Neutrophil polymorphs
What is the name of the cells that produce collagen in fibrous scarring
fibroblasts
what is a common example of acute inflammation
acute appendicitis
what is the pattern of differentiation of neoplastic cells lining the bronchi of cigarette smokers
respiratory epithelium to stratified squamous
what process is is defined by the formation of a solid mass of blood constituents within an intact vascular system during life
thrombosis
what is the definition of carcinogenesis
normal cells to neoplastic cells via permanent genetic mutation or alteration
where in the cell do all carcinogens act
the level of the DNA
what are the different classes of carcinogen
chemical, viral, radiation, hormones, parasites, mycotoxins and miscellaneous
they all act on DNA
what type of neoplasms do carcinogens produce
malignant
cancer causing
what is oncogenesis
the formation of benign and malignant tumours
- tumour causing
what are carcinogens
agents which are known or suspected to cause tumours
what are occupational or behavioral risks for cancer
lung cancer - strong association with smoking
bladder cancer - increased incidence in aniline dye and rubber industries
scrotal cancer - increased incidence in chimney sweeps
what are chemical carcinogens
they show no common structural features, where some act directly. Most require metabolic conversation from pro-carcinogens to ultimate carcinogens. Enzymes are required for this which may be ubiquitous or confined to certain organs (meaning you can only get cancer in those organs)
what is a tumour
it is any abnormal swelling
what are examples of chemical carcinogens
polycyclic aromatic hydrocarbons - found in soot, cigarette smoke and pollution
nitrosamines - processed meats
alkylating agents - used as chemotherapeutic agents to treat other cancers
what are examples of viral carcinogens
HepB - liver cancer
HHV8 - Kaposi sarcoma
EBV - Birkett lymphoma, nasopharyngeal carcinoma
HPV - cervix, penis, anus, head and neck
MCV - merkel cell carcinoma
HTLV-1 - leukemia
HCV - hepatocellular carcinoma
what type of radiation can cause cancer
UV light - increases all kinds of skin cancer
ionising radiation - can cause cancer over long term exposure
what biological agents can cause cancer
oestrogen - breast and endometrial
anabolic steriods - hepatocellular carcinoma
what are miscellaneous carcinogens
arsenic, asbestos and metals
what host factors can affect cancer risk
ethnicity - more melanin decreases melanoma incidence
diet and lifestyle - alcohol excess increases risk of cancers of the mouth, liver and colon
obesity - breast, oesophagus, colon (exercise reduces this risk)
inherited predisposition - retinoblastoma and FPC
age - increased age increases the risk
biological sex will impact on certain cancer risk
what is pre-malignant condition
a localised abnormality which increases the risk of developing cancer such as polyps, ulcerative colitis and undescended testicles
what is an example of placental transmission
diethylstilbestrol - was sued for morning sickness which increased the risk of vaginal cancer in the foetus
what percentage of all cancer risks are inherited
15%
what does in situ mean, in terms of cancer
where the cancer hasnt invaded surrounding tissue, and is still within the area it started. No access to blood or lymphatic vessels
In situ only applies to epithelial neoplasms and the BM is intact
how do you treat an in situ cancer
you can excise it
what is an invasive carcinoma
where the cancer has invaded the surrounding tissues - has access to blood or lymphatic vessels
what is a micro-invasive cancer
one that has invaded surrounding tissues, but not very far
what enzymes will cancers need to produce to move through the basement membrane
metalloproteinases - collagenase, cathepsin D
what are the stages of metastasis
tumour grows and invades the basement membrane and the extracellular matrix. It will then travel in either the lymphatic or blood vessel, and will then move back into a tissue elsewhere and invade another extracellular matrix to grow there
how large must a tumour be for it to need its own blood supply
larger than 1mm
what can tumours do to remain undetected by immune cells in the blood
- tumours can aggregate with platelets
- they can shed surface antigens which can be taken up by lymphocytes rather than the tumour cell itself
- they can adhere to other tumour cells to increase size
what can tumour cells produce to promote angiogenesis
VEGF and BFGF
what cancers commonly spread to the lungs
sarcomas
what cancers often invade the liver
colon, stomach, pancreas, carcinoid tumours of the intestine
what cancers commonly metasasise to the bone
prostate, breast, thyroid, lung and kidney
what are the two types of bone metastasis
sclerotic metastasis (gain of bone)
lytic metastasis (loss of bone)
what is a neoplasm
a lesion resulting from the autonomous, or relatively autonomous abnormal growth of cells which persists after the initiating stimulus has been removed (a new growth)
what do solid neoplasms contain
neoplastic cells and stroma (supporting network) - except leukemia
what are the behavioral classification of neoplasms
malignant, borderline or benign
what are the features of benign neoplasms
Localised, non invasive, slow growth rate. They have a low mitotic rate. They have a close resemblance of normal tissue. They are well circumscribes of encapsulated.
what is an example of malignant neoplasms
squamous cell carcinoma and prostate cancer
what are features of malignant neoplasms
INVASIVE. they can metastases. They have a rapid growth rate and have some varying resemblance to normal tissue. They have a poorly defined boarder.
where can neoplasms arise from
epithelial cells, connective tissues, lymphoid or haemopoietic organs
what is an adenoma
a benign tumour of glandular or secretory epithelium
- add prefix to add what type it is
what is a papilloma
a benign tumour of non glandular non secretory epithelium
-can add a prefix to add what type it is
what is a carcinoma
a malignant epithelial neoplasm
- this is a common exam question
what is a lipoma
adipocyte neoplasm (benign)
what is a chondroma
cartilage neoplasm (Benign)
what is an osteoma
a bone neoplasm (benign)
what is an angioma
vascular neoplasm (benign)
what suffix do benign connective tissue neoplasm have
- oma
what suffix do malignant connective tissue neoplasms have
- sarcoma
what is a liposarcoma
an adipose tissue neoplasm
what is a rhabdomyosarcoma
a striated muscle neoplasm
what is a leiomyosarcoma
smooth muscle neoplasm
what is a carcinoma in situ
a malignant epithelial neoplasm that has not yet invaded through the original basement membrane
How can a metastasis occur
via blood vessels, lymphocytes, across body cavities, along nerves or as a direct implantation of neoplastic cells during surgery
what must a tumour have to undergo extravasation
adhesion receptors, collagenases and cell motiity
what are examples of angiogenesis inhibitors
angiostatin ,endostatin and casculostatin
what are the consequences of a malignant neoplasm
they can cause destruction of adjacent tissue, metastasis, blood loss from ulcers, obstruction of flow, hormone productions, paraneoplastic affects, anxiety
what are the consequences of benign neoplasm
They can cause morbidity and mortality cause they can cause obstruction, cause pressure on adjacent structures, produce hormones and can transform. Can cause anxiety
what is an anaplastic neoplasm
where the cell - type of origin is unknown
what is serum
plasma without fibrinogen and other clotting factors
what is the most common white blood cell
neutrophils
what white blood cell has a kidney shaped nucleus
monocytes
what are the primary lymphoid organs
Bone marrow: origin for all and the B cell maturation site
Thymus: T-cell maturation site
what are the secondary lymphoid organs
the lymph nodes: site of DC, B and T cell interactions
Spleen: site of removal or RBC and bacteria
what are tertiary lymphoid organs
transient formation of germinal centers which are usually pathology related
what is the definition of hematopoiesis
production of all cellular components of blood and blood plasma
what stem cell produces all types of white blood cells
hematopoietic stem cells
what progenitor cell descendants can be considered as the innate branch of the immune system
the common myeloid progenitor cells
what progenitor cell descendants can be considered cells of the adaptive immune response
the common lymphoid progenitor cells
what causes ALL
lymphoid progenitors causing increased amounts of immature lymphocytes
what causes CLL
increased naive mature B cells
what is lymphoma
cancer involving expansion of mature naive T cells and B cells in germinal centres
what is multiple myeloma
cancer of the plasma cells
what are 7 key points about the innate immune system
- it is primitive and broad
- it is fast
- there is little regulation
- there is no amplification
- there is no self discrimination
- it is short (days)
- it has no memory
what are the 7 key points about the adaptive immune system
- it is highly specific
- it is slow
- it has lots of regulation
- there is amplification
- it shows high self discrimination
- it is long
- it can produce memory
what cells are polymorphonuclear leukocytes
neutrophils, eosinophils, basophils
what are mononuclear leukocytes
monocytes, T cells and B cells
what immune cell has a kidney shaped nuclei
monocytes
what is the role of monocytes in immunity
they play a role in both innate and adaptive immunity as they phagocytose and present antigens.
what is the main function of neutrophils in immunity
innate immunity - they have two main intracellular granules. Primary lysosomes kill microbes but secreting toxic substances and secondary granules.
what is the main function of macrophages in immunity
they are involved in innate and adaptive immunity. they reside in tissues and have a long lifespan. their main role is removal of foreign and self material as well as antigen presentation to T cells
what is the main function of eosinophils
mainly associated with parasitic infections and allergic reactions. they can activate neutrophils, inducing histamine release from mast cells
what is the main function of basophils
mainly involved in immunity to parasitic infections and allergic reactions. they bind to IgE and cause de-granulation releasing histamine
what is the function of mast cells
they are only found in tissues and induce release of histamine via IgE
what are the four main types of T cell
T helper 1 - CD4
T helper 2 - CD4
cytotoxic T cell - CD8
Treg
what is the function of natural killer cells
they recognise and kill by apoptosis - tumour cells and viral infected ones
what percentage of lymphocytes are natural killer cells
about 15%
what are the types of soluble factors in immunity
complement, antibodies and cytokines and chemokines
what is compliment function in immunity
direct lysis of pathogen
attraction of leukocytes to sites of infection
opsinisation - coat organisms and aid in phagocytosis
what are the five distinct classes of antibodies
- IgG
- IgA
- IgD
- IgE
- IgM
what is the most predominant antibody
IgG
what antibody can cross the placenta
IgG
where is IgA antibody found
it is the predominant antibody found in secretions such as saliva, milk, vaginal and bronchiolar secretions
where is IgM predominantly found
found in the blood - makes up a pentamer so cant cross endothelium and it is the primary response
what are the features of IgE
Basophils and mast cells express an IgE-specific receptor that has high affinity for IgE – binding triggers release of histamine
Associated with allergic response and defence against parasitic infections
what is an epitope
it is the part of the antigen that binds to the antibody/receptor binding site
what are cytokines
they are proteins secreted by the immune and non-immune cells. they influence the behaviour of cells
what do interferons do
they are important in antiviral immunity
what do interleukins do
over 30 types - they can stimulate cells to divide, differentiate and secrete factors
what is colony stimulating factors
it is involved in directing the division and differentiation on the bone marrow stem cells - precursors of leukocytes
what is tissue necrosis factors
it mediates inflammation and cytotoxic reactions
what are chemokines
40 proteins that direct movement of leukocytes and attract leukocytes to sites of infection or inflammation
what three factors are in the innate immune system
- physical and chemical barriers
- phagocytic cells
- serum proteins
what are anatomical barriers to infection
- skin
- sebum
- intact skin
What physical barriers are there to infection (mucous membranes)
Saliva, tears, low pH, commensals of vagina, mucous secretions, mucous, cilia, commensal colonies
what are physiological barriers to infection
temperature
fever response
pH
Gastric acidity
what is inflammation
a series of reactions that brings cells and molecules of the immune system to sites of infection or damage
what is the response to a barrier being breached - tissue damage or infection
- stop bleeding
- acute inflammation
- kill pathogens, neutralise toxins and limit spread
- clear pathogens or dead cells
- proliferation of cells to repair damage
- removal of blood cot
- re-establish normal structure
what are the hallmarks of inflammation
increased blood supply, increased vascular permeability and increased leukocyte trans-endothelial migration extravasion
what complement factor is required for opsonisation
C3b
what are the stages of phagocytosis
- binding
- engulfment
- phagosome formation
- lysosome fusion
- membrane disruption
- antigen presentation/secretion
What are MHCs
major histocompatibility complex - displays peptide from self or non self proteins on the cell surface - invasion alert
where is MHCI found
found on all nucleated cells
where is MHCII found
only on antigen presenting cells
what do MHCI do
Intrinsic (intracellular) - this interacts with CD8 cells which then kils the infected cells with intracellular pathogens
what do MHCII do
extrinsic - interacts with CD4 T helper cells, which helps to make B cells to make antibodies
what interactions need to occur for cell mediated immunity
interaction between antigen presenting cells and T cells. it requires MHC, intrinsic/extrinsic antigens and the recognition of self or non self
what is a summary of B cell activation
B cells become activated upon binding with an antigen. These then go to the lymph nodes where clonal expansion takes place with the cells differentiating into plasma cells. These secrete Ab (usually IgM) which later turn into IgG. B cells divide – clonal expansion and differentiate into plasma cells and memory B cells. Re-stimulation of memory B cells lead to secondary response.
what are the two types of PRR family
- secreted and circulating PRRs
- Cell-associated PRRs (traditional)
what are secreted and circulated PRRs
- antimicrobial peptides secreted in lining fluids from epithelia
- lectins and collectins (carbohydrate-containing proteins that bind carbohydrates or lipids in microbe walls)
what is the function of secreted and circulating PRRs
they activate compliment and improve phagocytosis
what are cell associated PRRs
these are receptors that are present on the cell membrane or in the cytosol of the cells. They recognise a broad range of molecular patterns.
what are the main cell associated PRRs
TLRs are the main ones
other than PAMPs what else can PRRs detect
damage recognition - cellular damage which activates immunity to issue tissue repair (and enhance local antimicrobial signalling)
how are PRRs involved in autoimmunity
they can recognise host molecules as foreign
what are the 5 cardinal signs
- Rubor - redness
- Dolor - pain
- Calor - Heat
- Tumor - swelling
- loss of function
what is neutrophil action in acute inflammation
- margination (migration to edge of BV)
- adhesion (selectins bind neutrophils, and cause rolling)
- emigration and diapedesis (movement out of the BV)
- chemotaxis
what molecule do granulomas secrete
ACE - blood marker
what are the features of an arterial ulcer
punched out holes with little exudate - pale cool skin with low distal pulse
what are the features of a venous ulcer
less demarcated with lots of exudate. warm erythematosus skin
- DVT
how does a venous thrombosis form
though venous stasis
what is found within a plaque
lipid, smooth muscle, macrophages, foam cells, platelets and fibroblasts
how are tumours graded
based on the similarity to the parent cell it came from
1. well differentiated - 75% cells like parent
2. 10-75%
3. poorly differentiated - less than 10% resemble parent
in staging tumours what does TNM stand for
tumour - node - metastases
what cancers are screened for in the UK
cervical, breast and colorectal
what is the common mutation associated with colorectal cancer
familial adenomatosis polyposis - a mutated APC gene causing overexpression of c-MYC and KRAS mutation
what is transcolemic spread of cancer
when there is spread through the pleural, pericardial and peritoneal effusions (via exudative fluid accumulation)
what are the three pathways in the complement system
- classical
- lectin
- alternative
what in the compliment system causes direct lysis of cells
the membrane attack complex formation
what factors in the compliment system are important for inflammation
C3a and C5a
what factor in the compliment system is required for opsonisation
C3b
what TLRs are intracellular
3, 7, 8 and 9
what does TLR2 detect
gram positive bacteria and TB
what does TLR3 detect
intracellular pathogens
what does TLR4 detect
LPS - gram negative
what does TLR 5 detect
flagellin
what does TLR7 detect
single stranded RNA - intracellular
what does TLR9 detect
non methylated DNA
what type of toxin in LPS
its an endotoxin
what 3 things have to occur during immune synapse to activate the T cell
- receptor binding
- co-stimulation (another molecule after primary binding)
- cytokine release
what are the best antigen presenting cell
dendritic cells
what is thymic tolerance
where T cell in the thymus are checked for self reactivity/to see if they are active to anything
what is positive thymic selection
where the T cells are tested to see if they recognise MHC 1 and 2. If they do they are selected for
what is negative thymic selection
if the T cells produce to much of a response to self then they are selected against
what cytokine is associated with Th1 cells
IFN gamma - activates NK cells and macrophages
what cytokine is associated with Th2 cells
IL4 - activates B cells to differentiate into plasma cells
what two factors do Th2 cells release to activate B cells
- IL4 which induces B cell proliferation
- IL5 which induces B cell differentiation into plasma cells
what Ig does IL4 promote class switching to
IgA
what Ig does IL5 promote class switching to
IgE
what are the four types of hypersensitivity
- anaphylaxis
- antigen-antibody complex
- immune complex deposition
- T cell mediated
describe type 1 hypersensitivity
IgE mediated - IgE binds to basophils and mast cells and causes degranulation and release of histamine which causes vasodilation and increased permeability and bronchoconstriction
describe type 2 hypersensitivity
where IgG/M binds to antigens and activates MAC compliment at the site of antigen antibody binding.
- goodpastures
describe type 3 hypersensitivity
IgG/A binds to antigen and activates compliment
SLE
describe type 4 hypersensitivity
Th1 mediated which are activated by APCs leading to a slow response
when treating anaphylaxis what are the steps to take
- Airway - can they breathe
- breathing - is it rapid/wheezy
- circulation - are they pale/cold/clammy
- disability - are they confused and can they move
- exposure
what is the immediate treatment for anaphylaxis
500mcg of IM adrenaline
what else can you give in the case of anaphylaxis
antihistamine or cortisol
where is central immune tolerance performed
in the thymus
where is peripheral immune tolerance performed
in the secondary lymphoid organs
what is autoimmunity
a pathological response to self
what are examples of organ specific autoimmunity
type 1 diabetes - endocrine pancreas - beta cells
multiple sclerosis - oligodendrocytes
pernicious anaemia - parietal cells of the stomach
what are examples of non organ specific autoimmunity
SLE - affects DNA
Rheumatoid arthritis
what are the two ways someone can get immunodeficiency
- inherited - defect in T cells - SCID
- acquired - HIV
what are patterns of immunodeficiency
- decreased CD4 in HIV - increases susceptibility of the disease
- B cells may be deficient
- Neutrophil and macrophage deficiency
- complement deficiency (SLE)
- hyposplenism - lack of function of spleen
what are the different types of vaccine
- live attenuated - MMR
- antigens
- toxins - Tetanus
- constituents - HepB
what is natural active immunity
when the body encounters a pathogen and produces memory cells after infection
what is active artificial immunity
vaccine mimics encountering pathogen and stimulates immunoglobulin production
what is passive natural immunity
maternal Igs pass onto the baby in breast milk or colostrum
what is passive artificial immunity
antivenom - infection of Ig from another organism
what are the two routes of drug administration
- Enteral - GIT involved - oral or rectal
- Parenteral - non GIT - IM, IV, SC, Injections
what are the 4 drug targets
- Receptors
- Enzymes
- Transporters
- Ion channels
what are the two types of receptor targeting drugs
- agonists
- antagonists
what is the most common receptor type
G protein coupled receptor
what is the potency of a drug
how much drug is needed to elicit a response in the body - how well the drug works
what is drug synergy
when the interaction of drugs is such that the total effect is greater than the sum of the two individual effects
what is antagonism
when a substance that acts against and block an action (2 drugs apposing each other)
what is summation
this is an additive reaction - where two drugs have the same affect , where the total effect is the sub or the two drugs together
what is potentiation
the enhancement of one drug by another - 1+1=1+1.5
Define pharmacodynamics
the effect a drug has on the body
define pharmacokinetics
what the body does to the drug - deposition of a compound within an organism
what must you consider when discussing drug pharmacokinetics
- Administration/absorption
- distribution
- metabolism
- excretion
what is a drugs efficacy
the maximal response a drug can get - how well it activates the receptor
what are the properties of an agonist
they have full affinity and full efficacy
what are the propertied of an antagonist
they have full affinity but zero efficacy
what is an allosteric modulator
a drug which binds to a separate site other than the active site, and increases or decreases normal ligand binding
what is an example of an allosteric modulator
benzodiazepine
what is a selective drug
a drug that only binds to a specific receptor type in a family - only binding B1
what is an example of a non selective drug
propranolol - non selective beta blocker
what is a non selective drug
a drug that binds to all receptors within a family
what is an example of a selective drug
verapamil - selective beta blocker (only B1)
what is an example of an enzyme targeting drug
Cox-1 - NSAIDs
ACE-i - Inhibits conversion of angiotensin 1 to 2
What is an example of transporter targeting drugs
Proton pump inhibitors
Diuretics - loop - Furosemide inhibits NKCC2 and Thiazides inhibits NaCl cotransporter
What is an example of an ion channel targeting drug
calcium channel blockers - amlodipine, diltiazem
Local anesthetics - lidocaine
what is a specific drug
when a drug acts on a certain target
what is a selective drug
when a drug acts on a subtype of a target
what is bioavailability of a drug
how fast and to what extent a drug reaches systemic circulation
what type of drug administration gives 100% bioavailability
intravenous drugs
what are the mechanisms of drug administration
the route taken and the entry into the body
what are the mechanisms of drug distribution
drugs can be distributed in the plasma according to chemical properties and size, they may be taken up by organs and tissues.
- protein binding will affect how much drug is available and the strength it will act at
what are the mechanisms of drug metabolism
drugs are metabolised in the kidneys or liver (CYP450)
- kidneys metabolise mostly small water soluble drugs
- liver hydrophobic molecules: phase 1 and phase 2 reactions
what are the mechanisms of drug excretion
through urine (mostly) or feces
- renal will be pH dependent
what are some drug interactions to be aware of
Warfarin - lots of interactions causing enzyme induction (increased activity so warfarin has bigger effect quicker)
Acute kidney injury - NSAIDs and ACEi
what drugs work at the neuromuscular junction
Botulinum toxin - Ach release inhibited
Curare - nAch receptor antagonist
Ach-ase inhibitors - decreases Ach degradation
what happens when there is overstimulation of Ach at the neuromuscular junction
you go into cholinergic crisis
what are the symptoms of cholinergic crisis
Salivation
Lacrimation
Urination
Defecation
GI distress
Emesis
where are M1, M2 and M3 receptors found in the body
M1 = Brain
M2 = Heart
M3 = Lungs
what is the definition of a drug
a medicine or other substance which has a physiological effect when ingested or otherwise introduced into the body
what are different types of receptors found in the body
ligand gated ion channels e.g nicotinic Ach receptor
G - protein couples receptors
Kinase - linked receptors e.g growth factors
Cytosolic/nuclear receptors e.g steroid receptors
what is tolerance to a drug
where there is reduction in the drug effect over time. This comes from continuous repeated use at high concentrations
what is drug desensitisation
this is rapid and comes when either the receptor is uncouples, internalised or degraded
what does afferent mean
takes signals toward the brain/spinal cord
what does efferent mean
takes signals away from the brain/spinal cord
what does adrenergic mean
relating to adrenaline or noradrenaline and either receptors
what does cholinergic mean
relating to acetylcholine and its receptor
what is the somatic nervous system
- there are single neurons between the CNS and skeletal muscle 2. innervates skeletal muscle
- leads to muscle excitation
what is the autonomic nervous system
- a two neuron chain
- smooth muscle, cardiac muscle, glands and GI
- leads to excitation or inhibition
what separates the two peripheral neurons of the ANS
an autonomic ganglion
which branch of the autonomic nervous system (Para or sym) has a longer presynaptic neuron - before ganglion
parasympathetic
which branch of the autonomic nervous system (para or symp) has a longer post synaptic neuron - after ganglion
sympathetic
what are the two main neurotransmitters of the ANS
acetylcholine and noradrenaline
what types of preganglionic receptors does acetylcholine act on
nicotinic receptors
what type of postganglionic receptors does acetylcholine act on
muscarinic (PS)
what type of postganglionic receptors does noradrenaline act on
alpha and beta receptors (s)
in what part of the body is acetylcholine released at sympathetic postganglionic termini
sweat glands
in blood vessels what can be released from parasympathetic postganglionic termini
nitric oxide
where are the five types of muscarinic receptor found
M1: Brain
M2: Heart
M3: all organs with ps function - most notably the Lungs
M4: Mainly CNS
M5: Mainly CNS
what type of receptor are Muscarinic receptors
G coupled protein receptors
what does activation of M2 receptors in SAN cause
decrease in heart rate
what does activation of M2 receptors in AVN cause
- decrease in conduction velocity
- Induces an AV node block (increases PR)
What does M3 receptors stimulation in the respiratory system cause
- mucus production
- smooth muscle contraction (bronchoconstriction)
what does M3 receptor stimulation in the GIT cause
- increased saliva production
- increased gut production
- stimulates biliary secretion
what does M3 receptor stimulation in the skin cause
sweating
where is the only place in the body where the sympathetic system releases Ach
the skin
what does M3 receptor activation of the urinary system cause
- Contraction of the detrusor muscle
- relaxation of the internal urethral sphincter (in males)
what does muscarinic receptor activation in the eyes cause
- increases myosis
- increases drainage of aqueous humour
- secretion of tears
what are pilocarpine eye drops
they are M3 agonists - induce tear secretion and increases drainage of aqueous humour
what is atropine used for
used intravenously to increase heart rate, treat bradyarrythmias and AV node block
what type of drug is Hyoscine
it is a predominant M3 antagonist
what is hyoscine action
it is used in palliative care to treat respiratory secretions and symptoms of bowel obstruction
what are examples of inhales antimuscarinics
tiotropium, glycopyrronium, umeclidinium, aclidinium
why would you inhale an antimuscarinic
can cause bronchodilation
what are side effects of inhaled antimuscarinics
they can cause dry mouth, urinary retention, can worsen existing glaucoma
what is solifenacin
a treatment for an overactive bladder
how does solifancacin work
blocks M3 receptors in the bladder and inhibits smooth muscle contraction
what is mebeverine
a treatment for irritable bowel syndrome
how does mebeverine work
it blocks M3 receptors in the gut to slow contractility
why might anticholinergics (antimuscarinics) cause memory problems
because Ach is used in CNS as well and implicated in memory
what can be used to prevent Ach release in the somatic nervous system
Botulinum toxin
what are examples of muscle relaxants given during surgery
Rocuronium, suxamethonium, pancuronium
what is the mode of action for rocuronium, suxamethonium and pancuronium
they block nicotinic (N1) receptors to inhibit Ach activity in the somatic nervous system
what happens during myaesthenia gravis
there is Ach receptor antibodies which prevents Ach binding to post synaptic neurons. This leads to skeletal muscle weakness with the most notable weakness being on repeated attempts at a movement
what is a treatment for myaesthenia gravis
the treatment includes anti-cholinesterase to increase Ach availability at the neuromuscular junction
what is the precursor of noradrenaline
dopamine
what are the features of alpha 1 receptors
- Agonist is noradrenaline over adrenaline
- mechanism of action is increasing intracellular calcium via Gq signalling
- its activation causes contraction of smooth muscle - mainly in the skin and abdomen
what are the features of alpha 2 receptors
- Agonists are both noradrenaline and adrenaline
- Mechanism of action is acting through Gi singalling to inhibit cAMP generation
- causes mixed effects on smooth muscle
what are the features of beta 1 receptors
- agonists are both noradrenaline and adrenaline
- acts through Gs to raise cAMP
- causes chronotropic and inotropic effects on the heart
what are the features of beta 2 receptors
- agonist is adrenaline over noradrenaline
- acts through Gs to raise cAMP
- relaxes smooth muscles
What are the features of beta 3 receptors
- agonist is noradrenaline over adrenaline
- acts through Gs to raise cAMP
- enhances lipolysis and relaxes the bladder detrusor muscle
what is given in ITU for shock
IV noradrenaline
what is xylometazoline used for
a nasal decongestant - topical alpha activation
what is clonidine and what is it used for
it is an alpha 2 agonist and it is used in ADHD to help concentration
what is the action of alpha 2 stimulation in blood vessels
it reduces vascular tone and blood pressure
what are some examples of alpha 1 blockers
- doxazosin used to lower blood pressure
2 phenoxybenzamine used in treating a catecholamine secreting tumour - tamsulosin used to block alpha 1 receptors in the the prostate during benign prostatic hypertrophy
where are beta 1 receptors mainly found
in the heart, kidney and fat cells
what does an activation of B1 receptors lead to
- tachycardia
- increased stroke volume
- renin release
- lipolysis and hyperglycaemia
what do beta 1 blockers cause
reduced heart rate, reduced stroke volume, reduced myocardial oxygen demand
what are some examples of beta blockers
carvedilol, bisoprolol, atenolol
what does beta 2 receptor activation in the bronchi cause
bronchodilation
what does beta 2 receptor activation in the bladder wall cause
inhibition of micturition
what does beta 2 receptor activation in the uterus cause
inhibition of labour
what does beta 2 receptor activation in skeletal muscle cause
increased contraction speed (induces a tremor)
what does beta 2 receptor activation in the pancreas cause
insulin and glucagon secretion
what are beta 2 receptor agonist drugs used for
asthma i.e salbutamol, and chronic obstructive pulmonary disease
what are the steps Ach goes through at the neuromuscular junction
- synthesis
- vesicle storage
- release
- breakdown
- reuptake
what effects does Ach stimulation have in the parasympathetic nervous system
- rest and digest
- pupil constriction
- decreased HR
- bronchoconstriction
- increased gut motility and secretion
- bladder contraction - detrusor muscles
- penis erect
what effects does noradrenaline stimulation have in the sympathetic nervous system
- fight or flight
- pupil dilation
- increased heart rate
- bronchodilation
- decreased gut motility
- detrusor muscle relaxation
- ejaculation
what is the noradrenergic synthesis pathway
tyrosine - DOPA - dopamine - Noradrenaline - Adrenaline
what drug is given in cardiogenic shock
B1 agonist dobutamine
what are the two types of Nad receptors
alpha and beta receptors
what are dopamine agonists used for
prolactinoma (pituitary tumour), acromegaly, and early in Parkinson’s
give an example of a dopamine agonist
bromocriptine
what are dopamine antagonists used for
they are often used in psychiatric disorders and for nausea and vomiting
what are some examples of dopamine antagonists
- metoclopramide: antiemetic
- halopemide
what are GABA agonists used for
anxiety, sleep disorders, alcohol withdrawal and states epilepticus
what is an example of a GABA agonist
benzodiazepines (lorazepam and diazepam)
what are histamine H1 antagonists used for
for allergy (T1 IgE anaphylaxis)
what is an example of H1 histamine antagonist
loratadine
what are H2 histamine antagonists used for
these are second line treatments for GORD or an increased gastric acid after proton pump inhibitors
what are examples of a histamine H2 receptor antagonist
ranitidine (main)
Cimetidine
what is an irreversible inhibitor
they react with an enzyme and change it chemically (via covalent bond formation)
what is a reversible inhibitor
they bind non-covalently and different types of inhibition a produced dependent on whether the inhibitors binds to the enzyme, the enzyme substrate complex or both
what are the 4 types of ion channels
- epithelial - sodium
- voltage gated - calcium and sodium
- metabolic - potassium
- receptor activated - chloride
what is the oral bioavailability of opioids
at most about 50%
why is oral bioavailability of opioids quite low
due to first pass metabolism in the liver
what class of drugs are opioids
class A drugs
what are the practical issues with prescribing opioids in hospital
they are stored in locked containers and you must have two people sign them out
what is the action of codeine in the body
it is converted into morphine and then acts on the body
why must you not proscribe codeine to new mothers or infants
because 5-10% of people have an overactive enzyme which converts codeine to morphine - can lead to respiratory arrect in children (through breast milk)
what is the most common form of morphine found in hospitals
oromorph - taken orally
what does parenteral drug administration mean
IV administration
what does enteral drug administration mean
non-IV
how longs does it take an IV drugs, a sub-cutaneous drug and a drug taken orally to go through the body (roughly)
- IV - minutes
- Sub-cutaneous - about half an hour
- Orally - about 1-2 hours
what is the difference between morphine and diamorphine
diamorphine is more potent and faster acting
how do opioids work
they attach to the opioids receptors in the brain/spinal cord and dampen pain reception.
what type of receptor is the opioid receptor
a G protein coupled receptor
how do naturally occurring opioids work (ones the body makes)
they inhibit pain transmission at the spinal cord/midbrain and they change the emotional perception of pain. They are part of the bodies fight or flight response and they have short term activity
how quicky does opioid tolerance occur
after a couple of days of medication
- receptors lost
what are the types of opioid receptor
MOP, KOP, DOP. NOP
what is tolerance
the down regulation of the receptors with a prolonged use. You need a higher dose to achieve the same effect
what is dependence
the psychological effect - craving, euphoria
what is opioid withdrawal
when you stop someones opioid medication - there will be withdrawal within 24 hours and it lasts about 72 hours
need to be careful with this as severe withdrawal symptoms can lead to death
why do you get opioid side effects
because you have opioid receptor outside the pain system - in the digestive tract, respiratory control centre etc
what are the side effects of opioid use
- respiratory depression
- sedation
- nausea and vomiting
- constipation
- itching
- immune suppression
- endocrine effects
how are opioids metabolised in the body
morphine is metabolised to morphine 6 glucuronide which is more potent than morphine and is renally excreted. With normal renal function this is cleared quickly
what is the antidote for morphine
naloxone
what are the relative potencies of diamorphine, morphine and pethidine (in an average human)
- diamorphine - 5mg
- morphine - 10mg
- Pethidine - 100mg
how do you treat opioid induced respiratory depression
- ABC; airway, breathing, circulation
- Give them IV naloxone (slowly - titrate)
what is the advice on prescribing opioids in chronic, non-cancer pain
- before prescribing discuss the risks and features of opioid tolerance, dependence and addiction
- agree a treatment strategy and when it will end
- at the end, taper off the medication to help with withdrawal
what is the common antibiotic given for community acquired pneumonia
- Amoxicillin
- clarithromycin
what is the common antibiotic given for COPD
- Amoxicillin
- clarithromycin
what is the common antibiotic given for TB
RIPE
1. Rifampicin
2. Isoniazid
3. Pyrazinamide
4. Ethambutol
what is the common antibiotic given for hospital acquired pneumonia
- co-amoxiclav 3X daily 500mg or 125mg for 5days
what are the side effects of rifampicin
red pee/tears
what are the side effects of isoniazid
peripheral neuropathy
what are the side effects of Pyrazinamide
can cause hepatitis
what are the side effects of ethambutol
can cause optic neuropathy
what is the common antibiotic given for cellulitis
flucloxacillin
- if MRSA give vancomycin
what is the common antibiotic given for a UTI
Trimethoprim or nitrofurantoin (Give nitrofurantoin)
(if pregnant give folate as well as can be teratogenic - nitrofurantoin preferred)
what is the common antibiotic given for pyelonephritis
cefalexin or co-amoxiclav
what is the common antibiotic given for chlamydia trachomatis
azithromycin or doxycycline
what is the common antibiotic given for Neisseria gonorrhoea
IM ceftriaxone and azithromycin (one off)
what is the common antibiotic given for syphilis
benzathine penicillin or benzylpenicillin
what is the common antibiotic given for H.Pylori
CAP for 7 days
1. clarithromycin
2. Amoxicillin
3. PPI
what is the common antibiotic given for gastroenteritis
campylobacter = clarithromycin
salmonella and shigella = ciprofloxacin
what is the common antibiotic given for infective endocarditis
s.aureus = vancomycin and rifampicin
s.vindans = benzylpenicillin and gentamycin
what is the common antibiotic given for bacterial meningitis
ceftriaxone in hospital, amoxicillin of listeria suspected and steroids
in the community = benzylpenicillin if meningococcal suspected
what is the common antibiotic for C.Difficile
vancomycin - 125mg for 4 times a day for 10 days
what neurotransmitter does the parasympathetic system release (commonly)
Ach which acts on muscarinic receptors
what neurotransmitter does the sympathetic nervous system release (commonly)
noradrenaline which activates adrenergic receptors (alpha/beta receptors)
what do both sympathetic and parasympathetic fibers release pre-ganglionically
Ach which acts on nicotinic receptors
what are side effects of anti-cholinergics
worsening or memory and cause confusion. Constipation, drying of the mouth, blurring of vision and worsening of glaucoma
what are the different routes of drug administration
- oral
- intravenous
- intra-arterial
- intramuscular
- subcutaneous
- inhalational
- topical
- sublingual
- rectal
- intrathecal
what are the four major metabolic barriers oral drugs must pass through
- intestinal lumen
- intestinal wall
- liver
- lungs
what are the features of intradermal and subcutaneous absorption
- it avoids the barrier of the striatum corneum
- it is mainly limited by blood flow
- only small volume can be given
- this is used for local effect or to limit the rate of absorption
what are the different types of pain
Acute, Cancer, Neuropathic, Chronic non cancer
What is the cause of acute pain
nociceptor signaling (Ab, Ad and C fibres) to the thalamus
what is the gate control theory
Pain modulated by:
heat - rubbing the site of pain - decreased pain impulses via the ascending tract
medication acting on the same pathway - NSAIDs, Opioids, anesthesia
What are the features of adverse drug reactions
ABCDEs
Augmented - is it predictable
Bizarre - is it because of allergy
Chronic - has the drug been used for a long time
Delayed - has the drug been used in the past
End of use - is it because there is withdrawal of drug
what are patient factors which must be considered with drug interactions
- Age
- Polypharmacy
- Genetics
- Hepatitis/renal disease
what are the pharmacokinetic influences in drug absorption
acidity, motility and solubility
what are the pharmacokinetic influences in drug distribution
influenced by protein binding
what are the pharmacokinetic influences in drug metabolism
CYP450 induction and inhibition
what are the pharmacokinetic influences of drug excretion
affected by urine pH
- acids cleared faster if urine is weakly basic
- bases cleared faster if urine is weakly acidic
what are the antiplatelet drug used in practice
aspirin - COX inhibition
Clopidogrel - P2Y12 inhibition
what are the anticoagulant drugs used in practice
Heparin - activates antithrombin 3 and inhibits factor 10
Warfarin - anti vitamin K
DOACs - anti factor Xa
Thrombolytics
what is the action of NSAIDs
inhibit COX1 and 2 and prevent prostaglandin production
- needs to be given with PPI now (aspirin)
what is the common side effect of NSAIDs
Peptic Ulcer disease
What is the common side effect of ACE inhibitors
increased bradykinin accumulation and causes a dry cough
reduces GFR and can cause acute kidney injury
what are common side effects of PPIs
prolonged use can increase fracture risk
what are common side effects of opioids
respiratory diseases
tolerance and dependence
nausea and vomiting
what are common side effects of loop diuretics and thiazides
hypokalemia and dehydration
what are common side effects of spironolactone
hyperkalemia
what is the common loop diuretic and its action
Furosemide
inhibits the NKCC2 channels in the ascending loop of henle
it increases Cl-, K+ and Na+ and water excretion
what is is the common thiazide used and what is its action
Bendroflumethiazide
they inhibit NaCl- channels in the distal convoluted tubule and therefore increase Cl- Na+ and water excretion
what is spironolactone and what is its action
it is a diuretic and it inhibits ENaC channels (aldosterone antagonist as well) and therefore increases sodium potassium and water excretion
what are the common steroid side effects
Cataracts Increased infection risk
Ulcers Necrosis of bone
Striae Growth restriction
Osteoporosis Increased ICP
DMT2 Myopathy
Adipose hypertrophy Pancreatitis
what does intramuscular absorption depend on
blood flow and water solubility with an increase in either enhancing removal of drug from injection site.
what are the features of inhalational absorption
there is a larger surface area and blood flow but it is limited by the risks of toxicity to the alveoli
it is largely limited to volatiles such as anesthetics and locally acting drugs
what is the most common protein drugs bind to in blood
albumin (reversibly)
what happens during phase 1 metabolism of drugs
transforming the drugs to more polar metabolites
- unmasking or adding functional groups
- oxidation reactions catalyzed by CYP450
what happens during phase 2 drug metabolism
formation of covalent bonds between the drug and endogenous substrates
- glucuronidation
what is first order kinetics
- pharmacokinetics
when an IV drug is given and rapidly distributed into the tissues, the decline in plasma concentration will be exponential
(constant fraction of the drug is eliminated per unit of time)
what is zero order kinetics
- pharmacokinetics
if an enzyme that removes a drug is saturated, the rate of removal of the drug is constant and unaffected by any increase in the concentration
what are the most common drugs to have allergy to
Antibiotics and NSAIDs
what percentage of adverse drug reactions are allergy
5-10%
what is the definition of 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 and non immunologic mechanisms
what are examples of delayed drug hypersensitivity
rashes, hepatitis and cytopenia’s
what is a urticarial rash
a fast forming, intensely itchy rash
what are the features of anaphylaxis
it occurs within minutes and causes vasodilation, increased vascular permeability, bronchoconstriction, urticaria and angio-oedema, swelling of the lips, face, wheeze.
what is the most common cause of anaphylaxis
insect venom, followed by medications
what is a biphasic anaphylactic shock
where you have the initial reaction, you are treated for it, and you get the response again (without another stimulus) soon after treatment
what percentage of anaphylaxis is biphasic
1-20% of responses
what drugs are commonly implicated in hypersensitivity reactions
Aspirin, Penicillin, sulfonamides, antituberculosis drugs, nitrofurans, anticonvulsants, anesthetics, antiarrhythmia agents, antisera and vaccines, heavy metals, antibiotics, phenolphthalein
what is non immune anaphylaxis
this is where you need no prior exposure to the allergen, but you still get mast cell degranulation. looks exactly the same as immune mediated anaphylaxis
what is the management of anaphylaxis
Common basic life support: ABC
Adrenaline IM 500 micrograms and high flow oxygen
IV fluids and antihistamines
what are the actions of adrenaline in anaphylaxis
causes vasoconstriction increasing PVR and BP via alpha 1 receptors
stimulation of Beta 1 receptors causes positive ionotropic and chronotropic effects on the heart
bronchodilation via beta 2 receptors
stops further mast cell and basophil degranulation via cAMP increase
what are risk factors of hypersensitivity
medicine factors: protein or polysaccharide based molecules
Host factors: Female, having EBV or HIV, Being in the extremes of life, uncontrolled asthma, previous drug reactions
Genetic factors: certain HLA groups, acetylator status
what are the clinical criteria for allergy to drug
- dont correlate with pharmacological properties of the drug
- no linear reaction with dose
- reaction similar to those with other allergens
- induction period of primary exposure
- disappearance on cessation
- re-appears on re-exposure
- occurs in minority of patients on the drug
what are the impacts of adverse drug reactions in healthcare
- adversely affects patients quality of life
- increases the cost of care
- precludes the use of a drug in most patients
- may mimic disease
- very common cause of death
what is an adverse drug reaction
it is unwanted or harmful reaction following the administration of a drug or combination of drugs under normal conditions of use and suspected to be related to the drug
- has to be noxious and unintended
are adverse drug reactions the same as side effects
they can be however not all the time as side affects can be beneficial, but adverse drug reactions are never beneficial
what is a toxic affect - adverse drug reaction
when the drug concentration is beyond the therapeutic range
what is a collateral effect - adverse drug reactions
when the drug concentration is within the therapeutic range
what is a hyper-sensitivity effect - adverse drug reactions
when the drug concentration is below the therapeutic range
what are examples of toxic drug effects when the drug concentration is too high
Gentamicin: causes nephropathy or ototoxicity at high concentrations
why can toxic drug affects occur
when you have too high drug concentration, you cant excrete the drug correctly, or there are interactions with other drugs
what is an example of collateral adverse drug reaction effects
beta blockers causing bronchoconstriction
antibiotics causing clostridium difficile
what is an example of hypersensitivity adverse drug reaction
anaphylaxis and penicillin
what can the severity of adverse drug reactions be
can range from mild (nausea or drowsiness) to severe (respiratory depression, hemorrhage, anaphylaxis)
what are risk factors of adverse drug reactions
Patient risk: female, elderly, neonates, polypharmacy, genetics, hypersensitivity or allergies, hepatic or renal impairment
Drug risk: steep dose response curve, low therapeutic index, commonly causes ADRs
Prescriber risk: human error
what are causes for ADRs
- pharmaceutical variation
- receptor abnormality
- abnormal biological system unmasked by drugs
- abnormal drug metabolism
- immunological
- drug-drug interactions
- multifactorial
what is an augmented ADR
it is an extension of the primary effect or the drug (such as propranolol and bradycardia) and has a high morbidity with a low mortality (excludes overdose)
what is a bizarre ADR
It is non predictable or related to the pharmacology of the drug and is not dose dependent. It is less common but more serious with low morbidity and high mortality
what is idiosyncrasy
where there is an inherent abnormal response to a drug
- enzyme abnormality, deficiency or abnormal receptor activity
what are continuous ADRs
it is related to cumulative dose on dose responses to a drug and it occurs over time. It is uncommon
- steroids and osteopetrosis
what are delayed ADRs
where the ADR shows itself after the use of the drug. They are uncommon and normally dose related
- Carcinogens
what are ending of drug use ADRs
where the ADR occurs once a drug has been withdrawn. they are uncommon
- example is opioid withdrawal
what is a failure ADR
This is often caused by drug interactions causing failure of the drug, it is common and dose related
- failure of oral contraceptive and enzyme inducers
when do you suspect ADR
- symptoms occur soon after new drug starts
- Symptoms appear after increased dose
- symptoms disappear when drug is stopped
- symptoms appear when drug is restarted
when do you suspect ADR
- symptoms occur soon after new drug starts
- Symptoms appear after increased dose
- symptoms disappear when drug is stopped
- symptoms appear when drug is restarted
what do you do if there is an ADR
- assess if urgent action is required
- take history
- review medication history
- review adverse effect profile of suspected drug
- modify dose, stop or swap
- report
what drugs commonly have ADRs
antibiotics, NSAIDs, Cardiovascular drugs, hypoglycemics, CNS drugs
what are common ADRs
confusion, Nausea, balance problems, diarrhea, constipation, hypotension
how do you gather information on ADRs
pre-clinical trials, post marketing surveillance and yellow card reporting
what are the MHRA responsible for
approving medicines for use and watching over them and take actions to protect the public if there is an issue
what is the yellow card scheme
it is a ADR reporting scheme which collects spontaneous reports as well as suspected adverse drug reactions - voluntary
why would you report an ADR
- patient safety
- identify ADRs not seen in clinical trial
- identify new ADRs quickly
- compare drugs within the same class
- identify ADRs in at risk groups
what is a black triangle drug
one that is undergoing additional monitoring
what are pharmacokinetic issues with immunotherapy
- immunoglobulins cant be filtered by the kidney: too big
- FcRn receptor - systemic receptors which absorb IgG into cells protecting them from metabolism dont recognise mouse antibodies resulting in a shorter half life
how is insulin currently made
Recombinant Human Insulin
- insulin gene inserted into a plasmid which is transfected into bacteria. The bacteria will then produce insulin during fermentation which can then be purified and used
what are examples of recombinant proteins in clinical use
- insulin
- EPO
- growth hormone
- interleukin 2
- gamma interferon
what are the clinical uses of glucocorticoids (steroids)
asthma, allergic reaction, hives, eczema, COPD, lupus, IBD, MS
what is rational drug design
the process of finding new medications based on the knowledge of a biological target
- complementary
what is drug re-purposing
a technique where existing drugs are used to treat emerging and challenging diseases
what is the monoclonal antibody against TNF alpha
Infliximab
