Pathology, Immunology & Pharmacology Flashcards
what causes thrombus formation?
endothelial tissue damage - cells lift and expose collagen and platelets bind and aggregate
fibrin is formed and can entrap red blood cells
what is the definition of thrombosis?
solid mass of blood constituents formed within intact vascular system during life
what promotes thrombosis?
change in vessels wall
change in blood flow
change in blood constituents
why does smoking promotes thrombosis?
smoke/nicotine damage endothelial cells
what is laminar flow?
cells travel in the centre of arterial vessels and don’t touch the sides
what does asparin do?
inhibit platelet aggregation - can prevent thrombosis
what is an embolus?
mass of material in the vascular system able to become lodged within vessel and block it
what causes embolus?
thrombus most commonly
also air, cholesterol crystals, tumour, amniotic fluid, fat
what is ischemia?
reduction in blood flow
what is infarction?
reduction in blood flow with subsequent death of cells
what is the difference between resolution/repair of tissue
resolution - initiating factor removed. Tissue undamaged or able to regenerate
repair - –initiating factor still present. Tissue damaged and unable to regenerate
what cells regenerate?
- hepatocytes
- pneumocytes
- all blood cells
- gut epithelium
- skin epithelium
- osteocytes
what cells don’t regenerate?
*myocardial cells
* neurones
what happens during tissue repair?
replacement of damaged tissue by fibrous tissue
collagen produced by fibroblasts
how is inflammation classified?
acute/chronic
What cells are involved in inflammation?
*Neutrophil polymorphs
* Macrophages
* Lymphocytes
* Endothelial cells
* Fibroblasts
what is special about neutrophil polymorphs?
- polylobed nucleus
- contain lysosomes
- phagocytose
- first in acute inflammation, phagocytosed by macrophages
what is special about macrophages in inflammation?
- Phagocytic properties
- carry materials away to lymph nodes and lymphocytes
- different names in different areas, eg kupffer cells, osteoclasts, microglia
what are fibroblasts?
Produce collagenous connective tissue in scarring following
some types of inflammation
what cells are present in acute/chronic inflammation?
acute - neurophils & macrophages
chronic - macrophage & lymphocytes, then usually fibroblasts
what is an example of acute inflammation?
appedicitis
frostbite
burns
infection
allergy
what are some examples of chronic inflammation
fibromyalgia
lupus
autoimmune disease
rheumatoid arthritis
what are granulomas?
type of chronic inflammation with collections
of macrophages/histiocytes surrounded by lymphocytes
- may be due to myobacterial infection eg TB
- also seen in Crohn’s disease, sarcoidosis and around foreign material
what are the vascular and exudative components of inflammation?
dilation of vessels
vascular leakage of protein rich fluid
what are the outcomes of inflammation?
resolution
suppuration - pus formation
organisation
progression to chronic inflammation
what is atherosclerosis?
accumulation of fibrolipid plaques in systemic arteries, reducing blood flow
what are modifiable/non-modifiable risk factors for atherosclerosis?
Smoker
Lack of exercise
Weight
(Borderline) Diabetes (type 2)
HTN
High cholesterol
Age
Gender
Race
Family History
Diabetes (Type 1)
what explains the pathogenesis of atherosclerosis?
endothelial damage theory
- LDL/cholesterol can enter endothelial wall when damaged causing plaque build up
- macrophages take up LDL - causing foam cells - releases more LDL when they die
how can diabetes lead to atherosclerosis?
High glucose levels = Increased Free radicals = Increased oxidation of LDLs
- Loss of nitric oxide (NO) - normally allows relaxation of vessel +
increased flow - Promotes platelet aggregation
what are the 3 major stages of plaque formation?
1) the fatty streak, which represents the initiation
2) plaque progression, which represents adaption
3) plaque disruption, which represents the clinical complication of atherosclerosis
what are the 5 key stages of atherogenesis?
1) endothelial dysfunction
2) formation of lipid layer or fatty streak within the intima
3) migration of leukocytes and smooth muscle cells into the vessel wall
4) foam cell formation
5) degradation of extracellular matrix
what is the difference between apoptosis vs necrosis?
apoptosis - programmed cell death
necrosis - cell death by damage/ external factors
why can hypertension lead to atherosclerosis?
Increased pressure causes increased damage of the endothelial cell wall
what are some complications of atherosclerosis?
blocked arteries
- can lead to infarction and embolism
what are some primary/secondary preventative measures for atherosclerosis?
primary
● Exercise more
● Eat more healthily -Less salt + sat fats, Less sugar- diabetes risk
● Stop smoking
secondary
● Statin
● Antihypertensives
● DM control: carbs, meds
● Social prescribing - Weight loss groups, Gym vouchers
what is the difference between apoptosis vs necrosis?
apoptosis - programmed cell death
necrosis - cell death by damage/ external factors
what protein detects DNA damage?
p53
why is apoptosis important?
- development
- cell turnover eg. intestinal villi
name 2 diseases where apoptosis is abnormal
cancer - cells in tumours don’t apoptose - mutated p53
HIV - virus induces apoptosis in CD4 helper cells
what is hypertrophy?
increased size of tissue due to increased size of cells
what is hyperplasia?
increassed size of tissue due to increased number of cells
where does hypertophy/hyperplasia occur?
hypertrophy - in organs where cells cannot divide eg. skeletal muscles
hyperplasia - in organs where cells can divide eg. benign prostatic hyperplasia, endometrial hyperplasia
where/when does mixed hypertrophy and hyperplasia occur?
smooth muscle cells of uterus during pregnancy
what is atrophy?
decrease in size of tissue due to decreased number of cells or their size
what is metaplasia?
change in differentiation of a cell
give an example where metaplasia occurs?
bronchial epithelium
- from ciliated columnar epithelium to squamous epithelium due to smoking
what is dysplasia?
abnormal organization of cells within a specific tissue
- can lead to cancer
why is there a limit on how many times cells can divide?
telomeres get shorter each time until they’re too short for a cell to divide - hayflicks limit
what are some effects of ageing on the body?
- dermal elastosis
- osteoporosis
- cataracts
- dementia
- sarcopaenia - loss of muscle mass
- deafness
Do basal cell carcinoma of skin spread?
No! only invades locally
what is the definiton of carciogenesis
The transformation of normal cells to neoplastic cells though permanent genetic alterations or mutations
what cancers most commonly spread to bone?
breast, prostate, lung, thyroid and kidney
what is oncogenesis?
formation of benign/malignant tumours
what are the classes of carcinogens?
chemical
viral
radiation
Hormones, parasites and mycotoxins
Miscellaneous
what are some examples of chemical carcinogens and what can they cause?
polycyclic aromatic hydrocarbons -smoking/minerals -lung/skin cancer
aromatic amines - rubber/dye - bladder cancer
nitrosamines - animals - gut cancer
alkylating agents - leukaemia
what are some examples of DNA virus carcinogens?
HHV8 - kaposi sarcoma
EBV (Epstein Barr) - lyphoma, nasopharyngeal
HBV - hepatocellular carcinoma
HPV - squamous cell carcinomas
MCV - merkle cell carcinoma
what are some exaples of RNA virus carcinogens?
HTLV-1 - t-cell leukemia
HCV - hepatocellular
what do anabolic steroids increase the risk of?
hepatocellular carcinoma
what is a myotoxin that causes hepatocellular carcinoma?
Aflatoxin B1
what parasites are carcinogenic
Chlonorchis sinensis → cholangiocarcinoma
Shistosoma → bladder cancer
what are some examples of miscellaneous carcinogens?
asbestos
metals
what is micro-invasive carcinoma?
cancer has only invaded partially past basement membrane
what is the difference between innate and adaptive immunity?
innate - non-specific, doesn’t require lymphocytes
adaptive - acquired/learned, requires lymphocytes
what are Polymorphonuclear
leukocytes?
neurophils, eosiphils, basophils
what are Mononuclear
leukocytes?
monocytes (macrophages), t-cells, b-cells
what other cells (apart from white blood cells) make up immune system?
mast cells, natural killer cells, dendritic cells, kupffer cells, langerhans cells
what are complement soluble factors?
group of 20 proteins made by liver that need to be activated.
Action - lysis, attract leukocytes, coat invading organisms
what are the 5 classes of antibodies?
igG(1-4), igA(1&2), igM, igD, igE
what is the most predominant Ig in human serum?
IgG
what is IgM responsible for?
primary immune response
where is IgA found?
mucous secretions
where is IgD found?
mature B cells
where is IgE found?
basophils and mast cells - allergic response
what specific region on antigen bind to antibodies?
epitope
what are some examples of cytokines?
interferons - limit viral infections
interleukins - IL1-pro-inflam, IL10-anti-inflam
colony stimulating factors
tumour necrosis factors - TNFalpha
what are chemokines?
direct movement of leukocytes - different for different cells
what is inflammation?
A series of reactions that brings cells and molecules of the immune system to sites of infection or damage
what are the hallmarks of inflammation?
increased blood supply
increased vascular permeability
Increased leukocyte transendothelial migration ‘extravasation
what are Pattern Recognition Receptors?
located on cells, recognise bacteria/pathogens
what are Pathogen-Associated Molecular Patterns?
found on microbes
how are complement serum factors activated?
Ab binds to microbe
alternative pathway - C’ binds to microbes
lectin pathway - mannose binding lectin bound to microbe
what does C3b do?
activated complement factor 3
- marks cells for phagocytosis
- amplifies complement response
what do C3a and C5a do?
chemotaxs - attract macrophages
what is E-selectin?
endothelial cell surface molecule makes endothelium ‘sticky’ - binds to CD15 on neutrophils
what are the 2 pathways to kill pathogens?
O2 dependent - ROIs (reactive oxygen intermediates)
O2 independant - enzymes, proteins, pH
what does cell-mediated immunity require?
MHCs - major histocompatibility complexs
intrinsic antigens
extrinsic antigens
what is T cell selection?
T cells that recognise self are killed in foetal thymus
what is the difference between MHC1 and MHC2?
MHC1 - on all cells - present foreign protein antigen to cytotoxic t cells (CD8+)
MHC2 - on APC - present foreign protein antigens to helper t cells (CD4+)
what do Th1 and Th2 cells produce?
1 - IFN-gamma helps kill intracellular pathogens
2 - antibodies
what do CD8 T cells do?
Kill Intracellular pathogens directly
what activates CD4 Th1 cells?
high levels of IL-12
how do T cells help B cells?
Th2 cells bind to B cells presenting Ag.
Th2 cell then secrete cytokines
causing B cell clonal expansion - plasma cells (secrete Ab) and B memory cells
where do activated B cells go for clonal expansion?
lymph nodes
what do Th1 and Th2 activate
macrophages
b cells
what are DAMPs?
Damage associated molecular patterns - molecules created to alert the host to tissue injury and initiate repair.
give some examples of Secreted and circulating PRRs (pattern recognision receptors?
pentraxins - proteins like CRP (c reactive protein)
lectins and collectins - eg. Surfactant proteins A and D - bind to oligosaccharide structure or lipids that are on the surface of microorganisms
what are TLRs (toll-like repectors)?
cell-associated PRRs
what do TLRs do?
bind to ligand and activate a tailored signalling cascade in response to pathogen
what are mannose receptors?
PRRs on macrophages
what is dectrin-1?
PRRs on various phagocytes/myeloids
what are RIG-I-like Receptors (RLRs)?
detect viral RNA in cytoplasm
what are NOD-like Receptors (NLRs)?
detect cytoplasmic bacteria
22 NLRs in humans
what are NOD1&2 activated by?
specific motifs (mostly muropeptides) present in bacterial peptidoglycan
1 - sense meso-DAp mainly in gram -ve
2 - sense MDP (Muramyl dipeptide in both gram-ve/+ve)
what is the definition of allergy?
type 1 hypersensitivity via IgE
what does der p 1 (found in dust mites) cause when affecting protease activity?
type1 hypersensitivity reaction using IgE
what are the 4 pharmacokinetic processes?
absorption
distribution
metabolism
excretion
what are the 3 ways drugs permeate membranes?
Passive diffusion through hydrophobic membrane - most common
Passive diffusion aqueous pores
Carrier mediated transport
what are the 2 factors affecting drug absorption?
lipid solubility
drug ionisation
- ionised drugs have poor lipid solubility - poorly absorbed
where are weak acid and weak bases best absorbed?
acids - stomach
bases - intestine
what factors affect oral drug absorption in stomach?
Gastric enzymes - drug molecule may be digested (peptides, proteins)
Eg. insulin and biologicals
Low pH - molecule may be degraded (benzylpenicillin)
Food (full stomach will generally slow absorption)
Gastric motility (altered by drugs and disease state)
Previous surgery (eg gastrectomy)
what factors affect oral drug absorption in intestine?
drug structure - size, solubility
medicine formulation - capsule/tablet effects rate of release
P-glycoprotein - substrates moved back into lumen
what is first pass metabolism?
metabolism of drugs preventing them reaching systemic circulation
what is bioavailability (F) in drugs?
Proportion of administered drug which reaches the systemic circulation
what is bioavailability not affected by?
rate of absorption
what is bioavailability dependent on?
extent of drug absorption from GI tract and extent of first pass metabolism
what are transdermal drugs only suitable for?
lipid soluble drugs
what affects a drugs ability to distribute around body?
molecule size
lipid solubility
protein binding
what is volume distribution (Vd)
Theoretical volume a drug will be distributed in the body
Volume of plasma required to contain the total administered dose
what does a high and low Vd show?
high Vd - drug’s well distributed ( small & lipophyllic)
low Vd - poorly distributed
what are 3 ways for drugs to reach CNS and cross BBB?
high lipid solubility
Intrathecal administration
inflammation - cases BBB to be leaky
how does Vd change as you get older?
smaller Vd of water soluble drugs - higher plasma conc
what is phase 1 in drug metabolism?
Oxidation/reduction/hydrolysis to introduce reactive group to chemical structure
what is phase 2 drug metabolism
Conjugation of endogenous functional group (glycine, sulfate, glucuronic acid) to produce hydrophilic, inert molecule.
Hydrophyllic metabolite can then be renally excreted.
what enzyme is responsible for most phase 1 metabolism?
Cytochrome P450
what is paracetamol toxicity treated with?
IV N-acetylcisteine (NAC)
how are drug molecules transported out in kidneys?
glomerular filtration
carrier system - organic anion/cation transporters
passive reabsorption
what is first order kinetics?
Rate of elimination is proportional to the plasma drug concentration
- most drugs
A constant % of the plasma drug is eliminated over a unit of time
what is zero order kinetics
Rate of elimination is NOT proportional to the plasma drug concentration
A constant amount of the plasma drug is eliminated over a unit of time
what is half-life dependant on?
clearance of drug
volume of distribution - A drug with large Vd will be cleared more slowly than a drug with a small Vd
what is IV bioavailability?
100%
why is a short half life significant?
- requires more frequent dosing
- increases risk of withdrawal
how does reduced clearance affect half life and what does it mean?
increases half life
time to Css increases
reduced dosing required
what are Drugs with a narrow therapeutic window?
Drugs with a narrow window between MEC (Minimum effective concentration) and MSC (maximum safe concentration)
is conventional chemotherapy better used in fast dividing or slow dividing tumours?
fast dividing
what is different about growth factor A receptors in cancer?
- more receptors
- receptors constantly activated
how can monoclonal antibodies effect growth factor A?
bind to recepters so less activation
what gene is amplified in 20-30% of breast cancers?
HER-2
what is PD1?
programmed cell death protein 1
- involved in immune response
what is a tumour?
any abnormal swelling
- can be neoplasm, inflammation, hypertrophy, hyperplasia
what are neoplasms?
a lesion resulting from autonomous abnormal growth of cells which persists after taking away initial stimulus
what is the structure of neoplasms?
neoplastic cells surrounded by a stroma that supports growth
what does central necrosis signify in a tumour?
that the tumour is growing faster and larger than the blood supply
is neoplasia benign or malignant?
both
what is angiogenesis?
forming new blood vessels
what are characteristics of benign neoplasms?
- localised, slow growth rate
- low mitotic activity
- non-invasive
- resembles normal tissue
- circumscribed or encapsulated
- growth on mucosal tissue is exophytic
how can benign neoplasms cause damage?
- pressure on tissue
- obstruct flow
- produce hormones autonomosly
- transform to malignant neoplasm
- cause anxiety for patient
what are the features of malignant neoplasms?
- invasive (defining feature)
- metastases - spread
- rapid growth rate
- poorly defined/irregular border
-hyperchromatic, pleomorphic nuclei - growth is endophytic
- necrosis and ulceration is more common
what affects do malignat neoplasms have on the body?
- destruction of tissue
- metastases
- blood loss from ulcers
- obstruct flow - by narrowing lumen
- paraneoplastic effects
- produce hormones
what is the behavioural classification of neoplasms?
benign or malignant
what is the histogenetic classification of neoplasms?
the specific cell of origin of neoplasm
what cell types can neoplasms originate from?
epithelial cells
connective tissue
lymphoid/haematopoietic
what suffix is used for neoplasm
‘oma’
what is a papilloma?
benign neoplasm of non-glandular non-secretory epithelium
what is an adenoma?
benign neoplasm of glandular/secretory epithelium
what is a benign cartilage neoplasm called?
chondroma
what are benign skeletal muscle neoplasms called?
rhabdomyoma
what are benign smooth muscle neoplasms called?
leiomyoma (more common than skeletal)
what are nerve benign neoplasms called?
neuroma
what is sarcoma?
malignant connective tissue neoplasm
what are anaplastic neoplasms?
neoplasms where the cell of origin can’t be identified
what is carcinoma?
malignant epithelial cells neoplasm
what are the exeptions to neoplasms that don’t contain carcinoma/sarcoma in name but are malignant?
- melanoma
- mesothelioma
- lymphoma
what is the difference between TSAs and TAAs?
tumour specific - only on tumours
tumour associated - on both normal and tumour cells but overexpressed in cancer
what is tumour escape?
when the immune responses change tumours so they’re no longer seen
what is tumour evasion?
tumours change the immune response by promoting immune suppressor cells
Give examples of active immunotherapy in cancer
killed tumour vaccine
purified tumour antigens
APC based vaccines
DNA vaccines
cytokine vaccines
Give examples of passive immunotherapy in cancer
adaptive cellular therapy - T cells
anti-tumour antibodies - HER-2
what is cell-based therapy?
they activate patients immune system to attack cancer
what cells are used in therapy for cancer?
dendritic cells - APC
T cells - killer cells
natural killer cells, stem cells, tumour cells
why does tumour hypoxia decrease patient prognosis?
- stimulates new vessel growth
- suppresses immune system
- resistant to radio/chemotherapy - increases tumour hypoxia
what is passive immunisation?
administration of pre-formed immunity
what are the adv/disadv of passive immunisation?
+ve immediate protection
-ve short-lived, possible transfer of pathogens
give examples of passive immunisations against diseases
human tetanus
human rabies specific Ig
human hep B Ig
varicella zoster
what are 3 whole-microbe approach of vaccines?
- inactivated vaccine
- live-attenuated vaccine
- viral vector
what are disadvantages of whole killed vaccines?
can cause excessive reactions
need more than 2 shots usually
what are live attenuated vaccines?
The organisms replicate within the host and induce an immune response which is protective against the wild-type organism but does not cause disease
what are advantages of live-attenuated vaccines?
immune response more closely mimics real infection
lower does required and fewer
can be oral administration
what are disadvantages of live-attenuated vaccines?
in immunocompromised hosts vaccine may not be so attenuated
- Often impossible to balance attenuation and immunogenicity
- Reversion to virulence
- Transmissibility
what proteins do most drugs target?
receptors
enzymes
transporters
ion channels
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
give 4 examples of receptors
Ligand-gated ion channels
G protein coupled receptors
Kinase-linked receptors
Cytosolic/nuclear receptors
how are g protein coupled receptors regulated?
By factors that control abilitty to bind/hydrolyse GTP to GDP
what catalyse the exchange of GDP to GTP
GPCRs
what are kinase enzymes responsible for?
catalyze the transfer of phosphate groups between proteins - phosphorylation
how do nuclear receptors work?
modify gene transcription
ie by zinc fingers
give an example of a nuclear receptor
steroid hormone receptors
- tamoxifen - SERN
give an examle where there is increase/decrease of receptors
Mastocytosis (Mast cells); increased c-kit receptor
myasthenia gravis; loss of ACh receptors
what is an agonist?
a compound that binds to a receptor and activates it
what is an antagonist?
a compound that reduces the effect of an agonist
what is the two state model of receptor activation?
describes how drugs activate receptors by inducing or supporting a conformational change in the receptor from “off” to “on”.
what is the EC50 of a drug?
the concentration that gives half the maximal response
what is the intrinsic activity of a drug?
the ability of a drug-receptor complex to produce a maximum functional response
how do antagonists effect receptors?
they don’t activate them
- they only reverse agonists
what are non-competitive antagonist?
Binds to an allosteric (non-agonist) site on the receptor to prevent activation of the receptor
what are the two categories of cholinergic receptors?
nicotinic (n) and muscarinic(m)
what are the antagonists to nicotinic (n) and muscarinic(m) receptors?
atropine
curare - muscle relaxant
what factors affect drug action
Receptor-related
affinity
efficacy
Tissue-related
receptor number
signal amplification
what is affinity?
Describes how well a ligand binds to the receptor
what is efficacy?
Describes how well a ligand activates the receptor
what is the efficacy of antagonists?
zero
what is a irreversible antagonist?
binds to a receptor so that the receptor becomes inactive
what is reverse agonism?
When a drug that binds to the same receptor as anagonist but induces a pharmacological response opposite to that of the agonist
what is drug tolerance?
slow onset
reduction in agonist effect over time
due to continuous, high-dose use
what is drug desensitisation?
- induces tolerance to drug
rapid onset, uncoupled, internalized, degraded
what are statins also know as?
HMG-CoA reductase inhibitors
how do statins work?
Block the rate limiting step in the Cholesterol pathway
give an example of a peripheral DDC inhibitor ( that make dopamine)
carbidopa
what does the Peripheral COMT Inhibitor do?
prevents breakdown of L-DOPA to 3-methyl dopa
(in periphery)
- treat parkinsons
what do central COMT inhibitors do?
Function within the CNS to keep Dopamine levels up
what do Mono Amine Oxidase B (MAO-B) Inhibitors do?
Prevents Dopamine breakdown and increases availability
treat depression
what do Central Dopamine Receptor Agonists do?
Antagonise dopamine receptors (not enzyme inhibitors) in CNS
what are the 3 main types of protein ports?
uniports
symporters
antiporters