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
what are uniporters?
use energy from ATP to pull molecules in
what are symporters?
use the movement in of one molecule to pull in another molecule against a concentration gradient
what are antiporters?
one substance moves against its gradient, using energy from the second substance (mostly Na+, K+ or H+) moving down its gradient
give examples of some ion channels
Epithelial (Sodium) – heart failure
Voltage-gated (Calcium, Sodium) – nerve, arrhythmia
Metabolic (Potassium) – diabetes
Receptor Activated (Chloride) - epilepsy
what are ENaC epithelial sodium channel blocked by?
high affinity diuretic amiloride (often used with Thaizide).
what does thaizide target?
Na+Cl− cotransporter
-reabsorbs Na and Cl from tubular fluid
what does amlodipine do?
angioselective
- blocks Ca channel & inhibits contraction eg. of heart and smooth muscle
- lowers BP
what drug blocks the transmission of an AP in voltage gated sodium channels?
lidocaine
how do Repaglinide, nateglinide and sulfonylureal lower blood glucose levels?
blocking K+ channels to stimulate insulin secretion
what do GABA A receptors do?
open Cl- channels - induce hyperpolarisation
what does Sodium Pump (Na/K ATP-ase) do?
pumps 3 Na out, 2 K in
requires ATP
what inhibits the Na+/K+ ATPase pump?
digoxin
when is digoxin used
to decrease HR
- lengthens cardiac AP
- increases intracellular Na and so Ca
what is the proton pump of the stomach?
The gastric hydrogen potassium ATPase or
H+/K+ ATPase
what does the Proton Pump (K/H ATP-ase) in Stomach do?
exchanges potassium from the intestinal
lumen with cytoplasmic hydronium
- acidification
what is the current legislation for control drugs?
misuse of drugs act 1971
what is the difference between tolerance and dependance?
tolerance - down regulation of receptors - need a higher dose
dependance -psychological, craving
what are the side effects of opiods
Respiratory Depression
Sedation
Nausea and Vomiting
Constipation
Itching
Immune Suppression
Endocrine Effects
what is codeine metabolised by, to?
CYP2D6, to morphine
what population has decreased activity of CYP2D6?
10-15% of caucasian population
what is morphine metabolised to and how does it compare?
morphine 6 glucuronide
- more potent than morphine but cleared quickly
when should morphine be prescribed with caution?
in renal failure
- may cause respiratory depression
what can be used instead of morphine if a patient has <30 renal function?
oxycodone
what does tramadol inhibit?
serotonin reuptake and noradrenaline
reuptake
what is tramadol metabolised to, to be active?
o-desmethyl tramadol
what is oral bioavailability for oral morphine?
50%
what is an antagonist for opioids?
naloxone
what is alpha-1 receptor in sympathetic nervous system responsible for?
vasconstriction
what is alpha-2 receptor in sympathetic nervous system responsible for?
negative feedback - suppresses noradrenaline release
what is beta-1 receptor in sympathetic nervous system responsible for?
increases HR and contractibility
what is beta-2 receptor in sympathetic nervous system responsible for?
bronchodilation
what do beta blockers do?
block effect of sympathetic nervous system on the heart
- decrease HR and contractibility and workload
what do alpha 2 agonists do?
reduce amount of noradrenaline released
- They work as antihypertensives, sedatives and analgesics
what is the most commonly used alpha 2 agonist?
clonidine
how does adrenaline work?
stimulates all sympathetic receptors
- short duration
what are antagonists for both sympathetic alpha receptors?
phenoxybenzamine
phentolamine
what are antagonists for both sympathetic beta receptors?
propranolol
carvedilol
what are antagonists for sympathetic alpha-1 receptors?
prazosin
doxazosin
what are antagonists for sympathetic beta-1 receptors?
metoprolol
atenolol
what are agonists for both sympathetic alpha receptors?
adrenaline (noradrenaline precuser)
what are agonists for sympathetic alpha-1 receptors?
phenylephrine
metaraminol
what are agonists for sympathetic alpha-2 receptors?
clonidine
dexmedetomidine
what are agonists for sympathetic beta-1 receptors?
dobutamine
what are agonists for sympathetic beta-2 receptors?
salbutamol
as prescribers, in terms of drug interactions we need to…
- Avoid co-prescribing drugs with clinically significant interactions
- Appropriately monitor patients taking interacting drugs
- Recognise drug interactions and take appropriate action
what is pharmacodynamic drug interaction?
Occur when drugs have an effect on the same target or physiological system
what is pharmacokinetic drug interaction?
Occur when a drug affects the pharmacokinetics (absorption, distribution, metabolism or excretion) of another drug
what are the 2 types of pharmacodynamic interactions?
synergistic or antagonistic
how may Pharmacokinetic drug interactions affect absorption?
Drugs which alter pH of GI tract (ionised/unionised drugs)
Formation of insoluble drug complexes
P-glycoprotein induction/inhibition (P-gp transport toxic substances out)
give an example of a drug that upregulates P-gp?
carbamazepine
how do Pharmacokinetic drug interactions affect distribution?
when drugs compete for albumin binding in plasma
- eg warfarin has high protein binding - need to monitor INR
how do Pharmacokinetic drug interactions affect metabolism?
drugs can work as cytochrome enzyme inducers (increase metabolism of enzyme substrate) or inhibitors (decrease metabolism of enzyme substrate and can cause toxicity)
how do Pharmacokinetic drug interactions affect elimination?
drug Competition for renal tubular secretion
by OAT or OCT
what foods interact with drugs?
grapefruit - CYP3A4 inhibitor
Milk - affects absorption due to insoluble complex formed with Ca
Vitamin k - apposes warfarin
cranberry juice - CYP2C9 inhibitor
what is the definition of an adverse drug reaction?
A response to a medicinal product, or combination of medicinal products, which is noxious and unintended
how are ADRs classified?
a - augmented
b - bizarre
c - chronic
d- delayed
e- end of use/withdrawal
f - failure of treatment
g -genetic
what are augmented ADRs?
- most common
- Exaggerated effect of drugs pharmacology at a therapeutic dose
Dose dependent and reversible upon withdrawing the drug
what are chronic/continuing ADRs?
continue after the drug has been stopped
what are delayed ADRs?
ADRs that become apparent some time after stopping the drug
what is another way ADRs can be classified?
D - dose-related
T - timing
S - susceptibility
what are dose-related ADRs?
Hypersusceptibility - subtheraputic doses eg anaphylaxis with penicillin
Collateral effects (side effects)
Toxic effects
what is meant by susceptibility in ADRs?
Certain patient groups/populations may have a specific susceptibility to ADRs from a drug
how are ADRs identified?
pre-clinical - eg. animal testing
clinical trial data
post marketing surveillance
pharmacovigilance
what are muscarinic receptors M2?
cardiac
what are muscarinic receptors for exocrine glands and smooth muscles?
M3
what are muscarinic receptors M4 and M5?
CNS
what are muscarinic receptors M1?
CNS and higher cognative
what are nicotinic signs of acetylcholinesterase inhibitor toxicity?
Monday = Mydriasis
Tuesday = Tachycardia
Wednesday = Weakness
Thursday = Hypertension
Friday = Fasciculations.
what are the muscarinic effects of organophosphate poisoning?
D = Defecation/diaphoresis
U = Urination
M = Miosis
B = Bronchospasm/bronchorrhea
E = Emesis
L = Lacrimation
S = Salivation
what are the physiological manifestations of atropine overdose
“hot as a hare, blind as a bat, dry as a bone, red as a beet, and mad as a hatter”
what does atropine block and when is it used?
blocks parasympathetic action
- eg in life threatening bradycardia
what are nicotinic repectors in parasympathetic system for?
vasodilation
what are antagonists and agonists for nicotinic receptors?
antagonist - trimethaphan (rarely used)
agnostic - nicotine & Ach
neostigmine and organophosphates - Ach Esterase inhibitors
what are pilocarpine agonists for?
M1, M2, M3
what are some antagonists for muscarinic receptors?
atropine - (crosses BBB) treat poisoning by muscarinic agents eg organophosphates
glycopyrrolate - inhibit salivary gland and respiratory secretions eg peptic ulcers
hyoscine - treats stomach spasms
ipratopium - for bronchospasms
how does botox work?
has an irreversible effect on exocytosis of ACh in the pre-synaptic neurone
what are the opioid receptors?
Mu
delta
kappa
nociceptin (NOP)
what receptors do the opioid agonists morphine and fentanyl act on?
mu-opioid receptors
what can kappa agonists cause?
respiratory depression
what do allergic reactions to drugs require to happen?
subsequent re-exposure
what is drug allergy often mistaken for?
Drug intolerance
- have to ask patient about symptoms
what is immediate vs delayed hypersensitivity?
immediate <1hr
delayed >1hr
what Ig mediates anaphylactic reactions?
IgE
re-exposure causes mast cell degranulation and histamine release
what 2 reactions come under the term anaphylaxis?
anaphylactic reactions - categorized as IgE-mediated responses
anaphylactoid reactions - categorized as IgE-independent events
what causes type 2 hypersensitivity in drugs?
- drug/metabolite combines with protein - treated as foreign body, IgG and IgM form
what are type 3 reactions?
Antigen and antibody form large complexes and activate complement factors
what are type 4 reaction?
lymphocyte mediated
- Antigen specific receptors develop on T-lymphocytes
what is Non immune anaphylaxis?
Anaphylactoid reactions
- Due to direct mast cell degranulation
- caused by some drugs
what is the definition of anaphylaxis?
a severe, life-threatening, generalised or systemic hypersensitivity reaction which is likely when both of the following criteria are met:
Sudden onset and rapid progression of symptoms.
Life-threatening airway and/or breathing and/or circulation problems usually associated with skin and
mucosal changes
what blood test can used to clarify an anaphylaxis diagnosis?
Serum mast-cell tryptase- (peak at one hour after an anaphylacticreaction, remaining elevated for approximately six hours)
- elevated levels show massive mast-cell degranulation or a condition called mastocytosis
- not in every case - sensitivity/specificity is 95%.
what are the signs/symptoms of anaphylaxis?
- Occurs within minutes and lasts 1-2 hours
- Vasodilation
- Increased vascular permeability
- Bronchoconstriction
- Urticaria (hives)
- Angio-oedema (rapid, oedema, or swelling, of the area beneath the skin or mucosa)
how is anaphylaxis managed?
basic life support - ABCDE (disability and exposure)
adrenaline IM 500mg
high flow O2
IV fluids
antihistamines - skin symptoms
what are risk factors for hypersensitivity?
medication
females more common
EBC, HIV infected patients
uncontrolled asthma
genetic factors - eg. certain HLA groups
what is Refractory anaphylaxis?
when there is no improvement in cardiovascular or respiratory symptoms after 2 doses
what is a commensal?
Organism which colonises the host but causes no disease in normal circumstances
what is a opportunistic pathogen?
Microbe that only causes disease if host defences are compromised
what is virulence/pathogenicity?
The degree to which a given organism is pathogenic
what is asymptomatic carriage?
When a pathogen is carried harmlessly at a tissue site where it causes no disease
what is the differnece between coccus and bacillus bacteria?
coccus - spherical
bacillus - rod
what are the main features of a bacteria cell?
cell wall, cell membrane, inner membrane
Chromosome of circular double stranded DNA
pili
capsule - around bacteria
what bacteria has lipopolysaccharide and what is it made up of?
gram -ve (component of outer membrane)
made of: terminal sugar, o antigen, lipid A
what bacteria contains lipoteichoic acid?
gram +ve
what is the difference between endotoxins and exotoxins from bacteria?
endotoxins - Component of the outer membrane of bacteria - LPS in gram -ve, non-specific, stable, weak
exotoxins - Secreted proteins in gram +ve and -ve, strong, specific
how is variation created in bacterial genetics?
mutations:
- base substitution
- deletion
- insertion
Gene transfer
what are the significant genes in a plasmid?
transfer promotion genes
Plasmid maintenance genes
Antibiotic or virulence determinant genes
how are genes transferred in bacteria?
transformation - via plasmid
transduction - via phage
conjugation - via sex pilus
what are some examples of obligate intracellular bacteria?
chlamydia
coxiella
rickettsia
what are bacteria with no cell wall called?
mollicutes
- eg mycoplasma pneuomoniae
what bacteria with a cell wall grow as filaments?
actinomyces
nocardia
streptomyces
what bacteria are spirochaetes?
leptospira
treponema
borrelia
what group of bacteria do staphylococcus and streptococcus belong to?
aerobic gram +ve
give an example of anerobic gram +ve bacteria (coccus)
PEPTOSTREP-TOCOCCUS
how is streptococcus bacteria further classified?
BETA-HAEMOLYTIC then lancfield grouping
ALPHA-HAEMOLYTIC then optochin test (sensitive vs resistant)
NON-HAEMOLYTIC
what bacteria is ZIEHL-NEELSEN
STAIN POSITIVE?
mycobacteria
eg M.tuberculosis
M.leprae
give some examples of aerobic and anerobic gram +ve rod bacteria
anaerobic
- clostridium
- propionibacterium
anerobic
- corynebacterium
- listeria
- bacillus
give some examples of gram -ve bacteria
anaerobic
- bacteroides
aerobic
- coliforms - salmonella, shigella, citrobacter
- vibro - campylobacter, helicobacter
what is coagulase +ve staphylococci bacteria?
enzymes produced that clot blood plasma - fibrin clot may protect from phagocytosis
- S.aureus
what is the diffeerence between streptococcus and staphylococcus?
strep - chain coccus
staph - clusters coccus
how is streptococcus bacteria sub-divided?
haemolysis - beta/alpha
beta - antigenic group - A, B, C, G
alpha - optochin test - sensitive = S.pneumoniae. Resistant = viridans strep
what are staphylococcus aureus virulence factors?
pore-forming toxins - a - haemolysin & Panton-Valentine Leucocidin
proteases - exfoliatin
toxic shock syndrome toxin
protein A - binds to Ig in wrong orientation
what group does staphylococcus aureus bacteria belong to?
spherical gram +ve
what diseases does Staphylococcus aureus
cause?
wound infections/abscesses
impetigo
septcaemia
osteomyelitis
pneumonia
endocarditis
what are 2 examples of Coagulase-negative Staphylococci and what do they cause?
S.epidermidis (forms persistant biofilms) - causes infectious endocarditis
S.saprophyticus ( has haemagglutinin for adhesion andurease)
- causes UTIs
what are the surface carbohydrate antigens (lancefield grouping) on beta haemolytic streptococcal cells?
A-H and K-V
most important…
A (C and G) - s.pyogenes
B - S.agalactiae (neonatal infections)
D - UTIs - enterococci
what is the difference in alpha vs beta haemolysis in bacteria?
alpha - hydrogen peroxide produced -reacts with haemoglobin - makes green met-haemoglobin (damage of RBCs)
beta - production of two pore-forming toxins – streptolysin O and S. (clear, lysis of RBCs)
gamma - no-lysis
give an example of alpha and beta haemolytic bacteria (gram +ve)
alpha - s.intermedius
beta - s.pyogenes
what are the virulence factors of S.pyogenes?
hyaluronidase - spreading
streptokinase - breaks clots
C5a peptidase - reduces chemotaxis
toxins - streptolysins O&S (binds cholesterol) and SPeA (exaggerates response)
hyaluronic capsule layer - non-antigenic
M protein - antiphagocytic protein
what infections are caused by S.pyogenes?
most commonly tonsillitis and pharyngitis
- also, scarlet fever, impentigo, wound infections
what are the virulence factors of S.pneumoniae?
capsule - antiphagocytic
Inflammatory wall constituents - teichoic acid (choline) & peptidoglycan
cytotoxin - pneumolysin - pore-forming
what is viridan factors streptococci?
- eg S.sanguinis and S.oralis - cause infective endocarditis. Milleri - cause abscesses in deep organs
what are some examples of gram +ve bacilli?
C.tetani
C.botulinum
C.difficle
how do gram +ve and gram -ve bacteria stain?
+ve - purple, stain binds to peptidoglycan
-ve - pink
why do gram -ve have penicilin resistance
thin peptidoglycan - covered by outer membrane
what is important in gram -ve bacteria
LPS - lipid A released when broken down - toxic - can cause sepsis
what shapes do gram -ve bacteria have?
rods
cocci
spriochaetes
what are coliforms bacteria?
- rod shaped gram -ve bacteria
- have flagella - very motile
- facultatively anaerobic
- colonise intestinal tract (can be good or bad)
how are enterobacteriaceae (coliform) differentiated?
appearance on MacConkey plate - CLED or XLD - lactose fermentation (acid produced- yellow turns red)
do - Escherichia coli and Klebsiella sp.
don’t - salmonella and shigella
followed by oxidative test
what does salmonella reduce that turns black?
thiosulphate
what are serovars?
specific coding for identifying specific bacteria
what infections are caused by e.coli?
UTIs
wound infections
gastroenteritis
meningitis(infants)
what does shigellosis most commonly cause?
severe bloody diarrhoea
what are features of shigella pathogenesis?
entry through M cells in gut
acid-tolerant - low infective dose
self-limiting
shiga toxin inhibits protein synthesis - haemolytic uraemic syndrome - kidney failure
what are the 2 salmonella species?
s.enterica - common
s.bongori - rare
what are the 3 forms of salmonellosis?
gastroenteritis/entercolitis - localised
enteric fever - where poor sanitation/water quality
bacteraemia
what is the pathogenesis of enteric fever?
spread through macrophages and released into blood
what is the pathogenesis of salmonella gastroenteritis?
interleukin-8 released - causes neutrophil recruitment - tissue injury - fluid and electrolyte loss
what is distinctive about Klebsiella pneumoniae?
thick capsule
- environmental, opportunistic
what is Pseudomonas aeruginosa bacteria?
gram -ve rods shaped
- environmental - many antibiotic resistance
- motile
what kind of people does P. aeruginosa infect, causing most problems?
CF patients, mucoid version secretes thick coating
what group does vibrio cholera bacteria belong to?
gram -ve rods, facultative anaerobic
what is the pathogenesis of cholera?
sits on intestinal wall, secretes cholera toxin causing pathogenesis
- can be treated with ORT
what bacteria is the most common cause of food poising and what does it look like?
campylobacter
- spiral rods, unipolar/bipolar flagella
what does helicobacter pylori cause?
gastritis, peptic ulcer disease
what are the features of haemophilus influenzae?
nasopharyngeal carriage
opportunistic infection (smokers & children)
causes: meningitis, brochpneumonia,
non-motile
fastidious - requires factor X and factor Y
what are th virulence determinants of H.influenzae?
capsule - penetrates nasopharyngeal epithelium, resistance to phagocytosis and complement system
Hi b strain main cause of meningitis
LPS- inflammation, complement resistance
what are the features and virulence factors of bordetella pertussis?
short rods (coccobacilli)
pertussis - whooping cough
highly contagious - aerosol transmission
toxins: pertussis toxin, CyaA - hypersynthesis of Camp - supresses macrophage phagocytosis
where can legionella pneumophila replicate?
alveolar macrophages
what is the main feature of bacteroides (gram -ve rods) and name one example
anaerobes
(non-motile)
b.fragilis
what are common gram negative rod bacteria?
bacteroids - anaerobic
vibro.cholerae
camplyobacter
helicobacter
haemophilus
bordetella
coliforms - salmonella, e.coli, klebsiella, shigella
pseudomonas
what are gram negative cocci bacteria?
anaerobic - veillonella
aerobic - neisseria
what are the 2 most common species of neiseria?
n.meningitidis (meningococcus
n.gonorrhoeae (gonococcus, non-capsulated)
what are the 3 common groups of spirochaetes bacteria?
leptospira - due to infected rats proximal to water source
treponema (t.pallidum) - syphilis
borrelia (b.burgdorferi - lyme disease - bulls-eye rash, flu-like
what are features of spirochaetes?
long, slender, helical, highly flexible
most are free-living, non-pathogenic
what are the features of the 3 stages of syphilis?
primary - localised genital infection. highly transmissible
secondary - systemic. skin rash, swollen lymph, aches/pains, fever (1-3 months post infection)
tertiary - granulomas in bone and soft tissue, cariovascular syphilis, neurosyphilis (several years post infection)
all stages can be treated with antibiotics
what are the 3 most common subgroups of obligate intracellular bacteria?
chlamydia
rickettsia
coxiella
what are the 2 growth cycles of chlamydia?
elementary bodies - infectious, enter cell through endocytosis, prevent phagosome-lysosome fusion
reticulate bodies - fragile, replicative, nutrients from host cell
what are the 3 important species of chlamydia?
c. trachomatis…
- trachoma biovar serotype A-C- eye to eye transmission
- genital tract biovar serotype D-K - STD, infects mucous membrane of urethra (can ascend), conjuctivitis - hand-to-eye transmission
- lympho granuloma venereum LGV biovar serotype L1-L3 - STD, endepic to tropics
c.pneumoniae
c.psittaci - zoonotic infection
what group of bacteria does TB belong to?
mycobacteria
what shape are mycobacteria?
beaded bacillia
why is Ziehl-Neelsen stain used to stain mycobacteria?
High lipid content with mycolic acids in cell wall makes Mycobacteria resistant to Gram stain
what are the microbiology features of mycobacteria?
weakly gram +ve or colourless
thick lipid cell wall
aerobic, non motile, non-spore forming
slow growth
Mycolic acids
Lipoarabinomannan
what are the 3 stages of TB?
primary Tb - initial contact - taken in by lymphatics to hilar lymph
latent TB - T cells detected but no disease
pulmonary TB - granulomas form, less blood supply - forms primary complex - necrosis
what can TB cause after spreading?
genito unrinary TB
bone/joints TB
meningitis TB
miliary TB
plearal TB
what cells protect against mycobacteria eg TB?
macrophages - phagocytsosis & phagolysosomes
CD4 T-cells - generate interferon gamma
when do granulomas (from mycobacteria) become unstable?
due to CD4 depletion - eg HIV patients
due to TNF-alpha depletion
what cells synthesise INF-y and TNF-a, and what does it do?
macrophages
type 1 helper T lymphocytes
- stabalise granuloma
why do granulomas form?
mycobacteria at centre, when in dormant stage, surrounded by cells
why is nucleic acid detection advantageous when testing for bacteria?
rapid results to detect mycobacteria
detects rifampicin resistance
what is the standaard therapy for TB?
isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA) and ethambutol (ETH) x 2 months followed by isoniazid and rifampicin for further 4 months
what does Mtb (mycobacterium tuberculosis) produce that interacts with drugs?
beta-lactamase
what TB is resistant to most commonly used drugs?
XDR-TB
how is XDR-TB treated?
BPaL regimen:
Bedaquiline
Pretomanid
Linezolid
All oral treatments for 6 months
- can fail too in total drug resistance
what is a virus?
obligate intracellular parasite, Comprising genetic material
(DNA or RNA) surrounded by a protein coat and/or a membrane
what are the different structures/shapes of viruses
enveloped/non-enveloped
shape - helical, icosahedral, complex
what do viruses exist as when not in a cell?
virions
- genetic material
- protein coat
how do viruses replicate?
- attach to a specific receptor on a cell (they then infect that cell)
- cell entry - only nucleic acid and proteins enter
- host cell interaction and replication - migration of genome to cell nucleus, transcription to mRNA using host cell materials
- assembly of viron (happens in different location of cells)
- release of new virus - bursts out and cell death or by exocytosis
what do HIV drugs traget?
NRTIs and NNRTIs (neuclotide Reverse-transcriptase inhibitors) that are involved in transcription of the viral RNA to viral DNA
how do viruses cause disease?
- Direct destruction of host cells
- Modification of host cell
- “Over-reactivity” of immune system
- Damage through cell proliferation - eg HPV
- Evasion of host defences
how does rotavirus cause disease?
modifies host cell - atrophies villi and flattens epithelial cells
- also resistant to acidic pH
how do viruses evade the immune system?
cellular level
- by celll-cell spread
- latency
molecular level
- antigenic variability
- prevention of host cell apoptosis - so virus continues to replicate
- Downregulation of interferon and other intracellular host defence proteins
- Interference with host cell antigen processing pathways
what are the causes of meningitis?
bacteria eg meningococcus, pneumococcus
viruses eg mumps, herpes
funig, protozoa (rarely)
non-infectious causes:
- medications eg antibiotics
- cancers eg melanoma
- autoimmune disease eg lupus
what bacteria causes meningococcal disease?
gram -ve diplococci
what are the 2 main manifestations of meningococcal disease?
Meningitis: a localised infection of the meninges
Septicaemia : a systemic infection with widespread signs, and generalised organ damage
what 6 serogroups are responsible for most of the cases of meningitis?
A
B
C
W
X
Y
what is the tansmission of meningitis?
aerosol, direct contact with secretions of URT
frequent/prolonged contact
what are some risk factors of meningitis?
sickle cell disease
cranial anatomical defects
cochlear implants
overcrowed household
travellers to high risk areas
cancer - eg leukaemia
immunocompromised
what are Meningococcal meningitis symptoms?
fever
stiff neck
headache
confusion
increased sensitivity to light
naesea/vomiting
babies - poor feeding, slow/inactive, irritable, bulging anterior fontanelle
what are Meningococcal septicaemia symptoms?
fever/chills
fatigue
vomiting
cold hands/feet
severe aches in muscles/joints
rapid breathing
diarrhoea
pinpoint/non blanching rash - petechiae - later stages is dark purple rash purpura
what is important about the onset of meningitis?
acute onset, sudden and escalates quickly - can be fatal
what specimens should be taken when infected with meningitis?
blood sample for culture
CSF for culture and PCR
throat swabs for culture
swabbing family members etc.
who do you need to notify if treating meningitis?
regional UKHSA health protection team of
Meningitis (any cause)
Meningococcal septicaemia
and notify public health on suspicion
- legal responsibility
what is given to carriers/close contact of meningitis and what does it do?
chemoprophylaxis or rifampicin - single dose to eradicate throat carriage - not infection (need antibiotics if infected)
how long is chemoprophylaxis offered for to housecold contacts of meningitis?
4 weeks
what diseases are not notifiable?
STDs
what do notifiable diseases have in common?
- very infectious
- most have vaccines
- very unpleasant symptoms/death
- some have specific control measures - eg food poisoning needs investigation of source
what do anifungals target?
cell wall - B1, glucan and B1,6 glucan and chitin
cell membrane - ergosterol
DNA/RNA synthesis
what targets fungi cell membrane?
Polyenes e.g. amphotericin
Azoles
Allylamines e.g. terbinafine
what targets fungi cell wall
Echinocandins
what targets fungi DNA/RNA synthesis/protein synthesis?
Flucytosine
Griseofulvin
what do dermatophytes cause?
many nail/skin fungal diseases
what are the 3 main species of dermatophytes?
Trichophyton
Microsporum
Epidermophyton
what fungal disease is common and can cause significant morbidity?
Mucosal candidiasis
what is the difference between yeasts and moulds?
yeasts - single celled, divide by budding
moulds - multicellular hyphae and spores
(some fungi exist as both - diamorphic fungi)
what are Coccidioides fungi?
diamorphic fungi that grow in warmer temperatures
- commonly asymtopatic, later manifestations include Cavitatory lung disease
what causes Invasive candidiasis (fungi)?
most commonly due to infection of prosthetic devices or intra-abdominal disease
what can cryptococcus (yeast) cause in people with reduced cell mediated immunity?
acute/chronic meningitis
what diamorphic fungi can cause meningitis?
Histoplasma, Coccidioides, Blastomyces
what biomarkers are used to identify fungi?
Beta-D-glucan galactomannan
- both not very specific
CrAg LFT - cryptococcal LFT
what does Invasive aspergillosis fungi cause?
respiratory failure
what are Mucoraceous moulds?
start in sinuses and spread to brain etc.
eg. Rhinocerebral mucormycosis
- need aggressive antifungal therapy
what is Pneumocystis jirovecii?
causes pneumonitis with severe hypoxia in the immunocompromised
BDG test +ve
what are the 5 groups of protazoa?
flagellates
sporozoa
amoebae
cilliates
microsporida
what is African Trypanosomiasis and American Trypanosomiasi?
sleeping disease
chagas disease - flu like
protozoa, flagellate
what is Trichomonas vaginalis?
STD
protazoa, flagellate
what is Amoebiasis?
protazoa - amoeba
Faeco-oral spread
causes: Dysentry, Colitis, Liver and lung abscesses
what test is done to diagnose malaria?
blood film, thick and thin
thin - shows parasite count and species
what is the most signficant symptom of maleria?
fever
also, chills, headache diarrhoea etc.
what can maleria cause if left untreated?
Anaemia
Jaundice
Hepatosplenomegaly
what is P. falciparum?
complecated maleria due to vascular occulsion
- cerebral maleria
- ARDS
- renal failure
- sepsis
- bleeding/anaemia
what is used to treat malaria?
IV artesunate
chloroquine
what species of maleria cause hypnoizites in the liver and cause relapse of maleria?
P. ovale and vivax
primiquine used as treatment - have to check G6PD levels
what does aciclovir treat?
herpes simplex virus type 1 & 2 and VZV infection
how does aciclovir work?
Pro-drug, activated to a monophosphate by the viral thymidine kinase only in herpesvirus infected cells
- then added second and third phosphate group
- triphosphate inhibits DNA polymerase
where does chickenpox lie dormant to later cause shingles?
dorsal root or
cerebral ganglion
what is Shingles: Herpes Zoster spectrum red flags?
Multiple dermatomes
Haemorrhagic change
Occular involvement
Peripheral/unusual dermatomes affected
what does IV acyclovir treat?
herpes
shingles
eczema herpeticum
what is ganciclovir treat and hoe does it work?
CMV infection
- inhibits most herpesvirus, and DNA polymerase
Valganciclovir: L-Valyl ester of ganciclovir
what drug is secendaryly used for herpes/CMV
foscarnet
what is ribvirin used for?
hep E
(not hep C as in past)
what are symptoms of measels?
high fever
morbilliform rash
koplik spots
coryza
cough
diarrhoea
cojuctivitis
how are antibiotic classified?
by the binding site on bacterium
what group of antibiotics inhibit cell wall synthesis?
beta lactams - eg penicillins, cephalosporins, carbapenems and monobactams
glycopeptides - eg vancomycin and teicoplanin
how do beta lactams work?
disrupt peptidoglycan production & cause lysis - must diffuse cell wall first
- gram +ve are more susceptible
- gram -ve have lipopolysaccharide layer - harder to penetrate
why is penicillins ineffective in the treatment of intracellular pathogens.?
poorly penetrate mammalian cells
what antibiotics affect nucleic acid synthesis?
DNA gyrase - quinolones
RNA polymerase - rifampin
what do antibiotics target when affecting protein synthesis?
50s subunits
30s subunits
what antibiotic affect folate synthesis?
Sulphonamides - Sulphamethoxazole
Trimethoprim - Co-trimoxazole
what antibiotics affect cell membrane of bacteria?
polymyxins
what is the difference between bactericidal antibiotics and Bacteriostatic Antibiotics?
kill bacteria
prevent bacteria growth - reduced toxin production
what are the 2 major determinants of anti bacterial effects of an antibitic?
Concentration & time of antibiotic at binding site on bacteria
what antibiotic no longer works on MRSA?
flucloxacillin - unable to bind to PBP of staphylococci
how are penicillins and cephalosproins inactivated by bacteria?
beta lactam ring hyrolysed by beta lactamase - unable to bind to PBP
when can Vancomycin and Teicoplanin be used?
gram +ve bacteria resistant to beta-lactams eg. mrsa
penicillin allergy
what are aminoglycosides antibiotics?
eg. gentamicin
- affects protein synthesis
- used against gram -ve and staphs
- for UTIs and infective endocarditis
what does CRE stand for in terms of bacteria?
Carbapenem Resistant Enterobacteriaceae
(gram -ve bacteria)
what are some gram -ve and gram +ve resistant bacteria?
+ve - MRSA, VRE (Methicillin resistant Staphylococcus aureus, vancomycin-resistant enterococci)
-ve - ESBL, CRE, AmpC
(extended spectrum beta lactamase)
how do ESBL resistant bacteria work?
hydrolise oxyimino side chain of antibiotics - (cephalosporins: cefotaxime,ceftriaxone, andceftazidime and monobactams: aztreonam)
what are the 4 ways bacteria become resistant to antibiotics?
- change antibiotic target binding site
- antibiotic is destroyed or inactivated
- prevent antibiotic access - porin channels on bacteria are modified
- remove antibiotic from bacteria - protein in bacterial membrane act as efflux pump
what does MIC stand for?
Minimum Bactericidal Concentration
give some examples of beta-lactams
Penicillin V
Benzylpenicillin
Flucloxacillin
Amoxicillin
Amoxicillin-clavulanate
Piperacillin-tazobactam
Meropenem
cephalosporins:
Cephalexin
Cefuroxime
Ceftriaxone
Cefotaxime
what kind of bacteria do beta-lactams work on?
gram +ve
what are macrolides antibiotics and what are they used for?
Clarithromycin and erythromycin
for gram +ve bacteria
- penicillin allergy
- severe pneumonia
what are examples of glyopeptide antibiotic and what are they used for?
vancomycin and teicoplanin
- gram +ve ONLY - especiallythose resistant to beta-lactams eg MRSA, or peniclllin allergy
what are lincosamides antibiotics? give an example, and when are they used?
eg. clindamycin
- affect protein synthesis of bacteria, destroys toxins
- used for gram +ve bacteria eg. S.aureus, beta strep
in cellulitis if penacillin allergy, necrotising fasciitis
what are tetracyclines antibiotics?
eg. doxycycline
- used for broad spectrum, mainly gram +ve
eg for cellulitis or pneumonia
what is ciprofloxacin antibiotic for?
gram -ve more than gram +ve
- affects DNA synthesis of bacteria
- used if penicillin allergy, UTIs, itra-abdominal infections
how does trimethoprin antibiotic work?
- folate antagonist - affects metabolism of bacteria
- mainly used for gram -ve
eg UTIs
what are CPEs?
carbapenemase producing enterobacteriacease
- bacteria producing enzyme that inactivates carbapenem antibiotics
-enterobacteriacease - colonise large bowl, skin below waist. Most common cause of UTIs and intra-abdominal infections
- eg. e.coli, klebsiella
what are some examples of pathegens that need to be controlled through infection control?
CPEs
MRSA
Norovirus
Clostridium difficile
Endogenous infections
what are sterile parts of the body?
blood
CSF
pleural fluid
peritoneal cavity
joints
urinary tract
lower respiratory tract
what are non-sterile parts of the body with flora?
mouth
skin
vagina
urethra
large intestine
what is the 90/90/90 UNAIDS goal?
90% of people living with HIV being diagnosed
-90% diagnosed on ART (antiretroviral therapy)
-90% viral suppression for those on ART by 2020
what is the fast-track cities partnership for HIV?
political leadersof affected areas and service providers work together to accelerate response to HIV
what are the transmission routes for HIV?
sexual
vertical
blood
what can be taken before sex if effected with HIV?
Pre-exposure prophylaxis of HIV (PreP)
what drug is taken after sex if affected with HIV, with 72 hours?
PEP - Post-exposure prophylaxis
how is HIV most preferably screened for?
venous blood sample
- 4th generation HIV tests include p24 antigen and will detect the vast majority of infections at 4 weeks
what are HIV POCT (point of care tests)?
Finger prick blood
Immediate result
Lower sensitivity and specificity
False positive and negative results
Longer incubation period
what kind of virus is HIV?
retrovirus, small RNA virus - expresses 10 genes
- uses reverse transcriptase to make DNA copy and insert itself into cell DNA
lentivirus - long incubation time
describe the basic pathology of how HIV infects a cell
- glycoprotein gP160 (made of gP120 and gP41)on HIV dock and fuse onto the CD4 and CCR5 receptors
- viral capsid enters cell, enzymes and nucleic acid released
- reverse transcriptase converts viral RNA to double stranded DNA
- viral DNA integrated into cell DNA by integrase enzyme
- viral proteins are made
- budding immature virus pushes out of cell with some cell membrane
- ## maturation protein chains of freed virus cut by protease that combine to form working virus
what does pol proetin in HIV do?
encodes the enzymes: reverse transcriptase, integrase and protease
what does tat do in HIV?
contributes to viral replication. Enhances production of host transcription factors e.g NF-kB
what does rev do in HIV?
binds to viral RNA and allows export from nucleus and also regulates RNA splicing
what does gag do in HIV?
encodes structural proteins.
Made as a polyprotein and cleaved by HIV protease
what are the receprors on the cells that HIV binds to?
primary - CD4
co-receptors CCR5 (early) and CXCR4 (later)
what do antiretroviral therapies target in the HIV replication cycle?
integrase inhibitors
protease inhibitors
reverse transcriptase inhibitors
fusion/entry inhibitors
what is the genetic resistance to HIV-1?
homozygous 32bp deletion in CCR% gene
- seen in 1% caucasions
- onlt one copy = infected but slow progression
why does HIV-1 mutate rapidly?
- error prone replication of reverse transcriptase - 1 error per replication
- rapid viral replication
- large population size
- recombination between subtypes
what are the symptoms of acute retroviral syndrome?
Glandular fever”-like illness
Fever, lymphadenopathy
Sore throat, oral ulcers
Skin rash (upper trunk)
May include neurological features
what is signicicant about the immune response during acute HIV infection?
deterime Long-term viral control and Disease progression
what cells does HIV affect?
range of CD4 + immune cells
- helper T-cells, (including regulatory T-cells, T follicular helper cells, dendritic cells, macrophages and thymocytes)
what ultimately happens with immune system when fighting against HIV?
immune exhaustion
why are antibodies not effective against HIV for mosst people?
HIV-1 envelope spike is heavily glycosylated - sugars resemble human type - difficult for antibodies to bind
- envelope protein can change and evolve quickly
what are the main targets for broadly neutralising antibodies against HIV-1?
CD4 binding site
Membrane-proximal region
V2V3 conformational epitope
Envelope glycans
what T cell recognise cells expressing foreign material presented as HLA class 1 molecules?
CD8+ cytotoxic T-cells
what is released when CD8+ cytotoxic T-cells recognistion is triggered?
Cytokines – soluble anti-viral factors
CC- chemokines
(compete with HIV for
the receptor CCR5)
Cytotoxic factors
– kill the cell
how does HIV-1 evade T cell recognistion?
- The HIV-1 nef protein reduces cell-surface expression of HLA class I molecules
- upregulates Fas molecules to kill Cytotoxic T-lymphocytes (CTL)
what are Long-term non-progressors (LTNPs) of HIV?
survivors with HIV-1 infection for >7-10 years, no therapy, no symptoms and stable CD4+ T-cell count
what are elite controllers of HIV
HIV-1 infected individuals with plasma VL <50 copies/ml for over one year without ART: VERY RARE
where population is HIV concentrated?
sex workers and their clients
gay men and other MSM
people who inject drugs
transgender people
prisoners
what age group is most at risk of HIV?
15-24 year olds
how does transmission occur from mother to child?
In utero: transplacental, mostly during the third trimester
Intra partum: exposure to maternal blood and genital secretions during delivery
Breast milk: ingestion of large amounts of contaminated milk
what are the 2 markers used to monitor HIV infection?
CD4 cell count
HIV viral load
what are most common symptoms of acute HIV?
most common:
Fever
Sore throat
Myalgia
Rash
Vomiting + diarrhoea
Headache
Lymphadenopathy
Weight loss
what symptoms would prompt you to ask out sexual history and HIV seroconversion?
fever, rash and non-specific symptoms
what is clinical latency of HIV?
CD4 cell population increases, and the viral load temporarily decreases
then, CD4 declines, causing immunosupression and symptoms
what symptoms can be present when HIV is not treated, after clinical latency?
shingles
candida - thrush
Oral hairy leucoplakia
Molluscum contagiosum - spots
other bacterial/funal/viral infections
you should think about testing for HIV when a patient has a common problem that…
is an unexpected patient
That is recurring
That has no clear underlying cause
what is CD4 level in AIDS?
<200
what is the most common AIDS defining illness?
Pneumocystis Pneumonia
- fever, dry cough
what is the most common oppertunistic infection?
what are some AIDS defining illnesses?
Persistent HSV
Kaposi’s sarcoma
CMV colitis
Candidiasis - oesophageal
HSV oesophagitis
Wasting syndrome
Recurrent salmonella sepsis
Cervical cancer
Primary CNS Lymphoma
Cryptococcal meningitis
CMV retinitis
Recurrent pneumonia
PCP
TB
what do all TB patient require to be tested for?
HIV
how is HIV treated?
HAART (Highly Active Anti-Retroviral Therapy
- 3 antiretroviral drugs
what are NRTIs?
Nucleoside reverse transcriptase inhibitors
- part of HAART regime
what sgould be considered in seropositive person with a headache?
lumbar puncture
why does HIV develop drug resistance?
- Non-adherence
- Drug-Drug interactions
what are 2 classes of drugs that act as entry/fusion inhibitors to HIV and when are they used?
maraviroc
enfuvirtide
- used with resistant viral strains
