pathology Flashcards
(173 cards)
1
Q
What are neglected tropical diseases?
A
Diseases occurring in hot humid low-income places where little attention or research is put into them and there is poor sanitation, a lack of clean water and insufficient healthcare
2
Q
4 types of neglected tropical diseases?
A
Bacteria, protozoa, virus, helminths (parasitic worms)
3
Q
What is leprosy?
A
A chronic bacterial infection by Mycobacterium leprae caused by aerosol transmission and eating armadillos
4
Q
Pathogenesis of leprosy?
A
M. leprae multiplies slowly and causes skin sores, nerve damage and muscle weakness leading to permanent damage to skin, nerves, limbs and eyes
5
Q
How is leprosy detected?
A
Slit skin smear = small incision in the skin, stained for bacteria (will be pink and rod shaped)
6
Q
What are the two types of leprosy?
A
- Tuberculoid leprosy
- Lepromatous leprosy
7
Q
What is tuberculoid leprosy?
A
Leprosy fought with strong cell-mediated immunity to contain the infection, appears as dry hypo/hyperpigmented patches on skin, loss of sensation
8
Q
What is lepromatous leprosy?
A
Leprosy not fought due to weak cell-mediated immunity, bacteria multiply freely (high bacterial load), appears as poorly defined shiny nodules or plaques, does not always cause a loss of sensation
9
Q
How does the histology of tuberculoid vs lepromatous differ?
A
Tuberculoid = granulomas with many lymphocytes (local inflammation), few bacilli
Lepromatous = foamy macrophages packed with bacilli (more contagious), few lymphocytes, thickening of peripheral nerves
10
Q
What are the possible mechanisms of nerve damage in leprosy?
A
Ischaemia, apoptosis, demyelination
11
Q
What is leprosy sequelae?
A
Irreversible disability and disfigurement due to leprosy (e.g. loss of fingers and toes, blindness)
12
Q
What is the treatment of leprosy?
A
Multi-drug therapy using:
- Dapsone to inhibit bacterial synthesis of dihydrofolic acid used to synthesise dna bases
- Clofazimine that binds guanine bases of bacterial dna = no replication can occur
- Rifampicin that inhibits bacterial rna polymerase to prevent rna synthesis
13
Q
How does treatment vary between tuberculoid and lepromatous leprosy?
A
Tuberculoid needs 6 months of multi-drug therapy, lepromatous needs 12
14
Q
What is rabies?
A
Viral disease caused by lyssavirus that is transmitted through the saliva of animals
15
Q
7 steps of rabies pathogenesis?
A
- Virus inoculated
- Viral replication in muscle for 1-3 months
- Virus binds to nicotinic acetylcholine receptors at neuromuscular junctions
- Virus travels in axons of peripheral neurons via retrograde fast axonal transport
- Replication in motor neurons of the spinal cord and local dorsal root ganglia and rapid ascent to brain
- Infection of brain neurons with neuronal dysfunction
- Centrifugal spread along nerves to salivary glands, skin, cornea and other organs
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Q
Common sign of rabies in neurons in brain, salivary glands and tongue?
A
Inclusion bodies called Negri bodies (where viral transcription and replication occurs)
17
Q
2 types of rabies?
A
- Furious rabies (most cases)
- Paralytic rabies
18
Q
How is furious rabies present?
A
Hyperactivity and hydrophobia, death after a few days, function of anterior horn of spinal cord are disrupted
19
Q
How does paralytic rabies present?
A
Gradual muscle paralysis, slow coma development, death, peripheral nerves are demyelinated (muscle weakness)
20
Q
Why does rabies cause different presentations?
A
Unknown but could be due to type of animal vector, site of wound, incubation period or history of rabies vaccine
21
Q
Treatment of rabies?
A
Active immunisation of humans and dogs
Passive immunisation = immunoglobulins against lyssavirus used as an antidote
22
Q
What is chagas disease?
A
Parasitic protozoan trypansoma cruzi transmittd through triatomine bugs, blood transfusion, oral, congenital
23
Q
Steps of chagas disease in humans?
A
- Triatomine bug takes blood meals and passes parasite in faeces which either enters wound through rubbing or is rubbed into eyes
- Metacyclic trypomastigotes penetrate various cells at bite wound site and transform into amastigotes
- Amastigotes multiply by binary fission in cells of infected tissues
- Intracellular amastigotes transform into trypomastigotes that burst cell and enter bloodstream
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Q
2 phases of chagas disease?
A
- Acute phase = localised swelling at wound site
- Chronic phase = infection of other areas of the body like essential organs
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Phases of chagas disease in bug?
1. Triatomine bug takes blood meal and ingests parasite
2. Epimastigoles in midgut
3. Multiply in midgut
4. Metacyclic trypomastigotes in hindgut
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How is acute phase of chagas disease identified?
Early weeks/months, mild symptoms like fever, vomiting, rash, romana's sign (swollen eye), myocarditis or meningoencephalitis, heart and brain inflammation, most cases end here but some enter chronic phase
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How is chronic phase of chagas disease specified?
Life threatening heart, nervous and digestive systems dilations, cell death, inflammation, cellular lesions, fibrosis, cardiomyoopathy, megaoesophagus, megacolon
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Treatment of chagas disease?
Prevention through insecticides and bed nets
Early infections treated with anti-parasitic medication
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What is lymphatic filiasis?
Nematode worms (wuchereria bancrofti, brugia malayi, brugia timori) enter body via mosquitos and lodge in the lymphatic system to cause lymph flow blockages = lymphoedema (build up of interstitial fluid)
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How are filiarial worms identified?
Haematoxylin and eosin staining
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What can lymphatic filariasis present as?
Asymptomatic all the way to hugely swollen legs or genitals, also causes skin thickening due to increased risk of bacterial infection
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Treatment of lymphatic filariasis?
Prevention via mosquito nets and insecticide
Antimalarial drugs
Mass drug administration
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What is COVID-19?
SARS-CoV-2 virus that is transmitted through airborne droplets, bodily fluids and on surfaces
Children are most prominent contractors and asymptomatic individuals transmit it the least
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What is SARS-CoV-2 like?
Covered in spike glycoproteins (S1 and S2) mediate attachment to host cells (ACE2 receptor)
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Where does coronavirus attach?
S1 glycoprotein binds to angiotensin-converting enzyme 2 (ACE2) receptor on host cell, then a protease binds the S2 side leading to activation of S2 domain and fusion of membranes so viral DNA enters host cell
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How does SARS-CoV-2 effect cell?
Downregulates ACE2 and distrubs physiological balance of renin angiotensin aldosterone system (RAAS) = increased angiotensin ii = overactivation of RAAS = vasoconstriction, fluid retention, inflammation, cardiac stress, hypertension
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What does the pathogenesis of COVID-19 look like?
Dependent on where SARS-CoV-2 lands
--- if it goes to the lungs it cause immune cell overcrowding in alveoli which causes laboured breathing
--- increased angiotensin ii is bad for heart as it is cardiotoxic --- brain can be affected = strokes and confusion
--- causes issues with eyes, nose, liver, kidneys and intestines
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Treatment of COVID-19?
Anti-viral drugs, painkillers, neutralising monoclonal antibody, corticosteroids, vaccines
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What is ebola?
A filamentous virus that is transmitted via fruit bats or human-human bodily fluid transfer
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What does ebola cause?
Fever, fatigue, muscle pain, headache, sore throat
THEN vomiting, diarrhoea, impaired liver and kidney function, brain damage, internal bleeding, death
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What is the ebola virus like?
Long filamentous shape, ss negative sense RNA, glycoprotein spikes allow binding and infection of target cells
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What does the systemic spread (into the bloodstream) of ebola cause?
Enters body and infects macrophages at site ---> infected immune cells travel to lymph nodes then bloodstream (viremia) ---> spreads to major organs and triggers massive cell death
This then causes dysregulated host immune response, coagulation abnormalities, impairment of vascular system, hypotension
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Treatment of ebola?
2 treatments and there are some vaccines for some strains
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What is zika?
A flavivirus from aedes mosquitoes, sexual transmission, mother-to-child or blood transfusion
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What is the pathogenesis of zika?
Mild symptoms for 2-7 days but infection during pregnancy can cause microcephaly
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What is the zika virus like?
Enclosed in capsid membrane, ss positive sense RNA, envelope glycoprotein allows attachment of viral particle to host cell receptor
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What is antibody-dependent enhancement and how does it link to zika?
When non-neutralising antibodies from a dengue infection bind zika as they are very similar, it helps it infect immune cells and cause a more severe case (can increase risk of microcephaly)
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What is microcephaly?
Small head of baby, dwarfism, sloping forehead, seizures, delays in speech and movement
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How does zika virus cause cell death?
Massive vacuole formation in cells = implosive cell death
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What is a direct target of zika virus?
Human neural progenitor cells --- disturbs proliferation, increases apoptosis and impacts human brain development (causing microcephaly)
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Treatment of zika?
No treatment so you can only prevent it via insect repellent and nets etc
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What is diabetes mellitus?
Complex group of chronic metabolic diseases usually caused by a defect in insulin secretion or in insulin action
Characterised by abnormally high blood levels of glucose (hyperglycaemia)
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3 common forms of diabetes?
Type 1 diabetes (10%) --- antibodies against beta cells in pancreas so insulin cannot be made
Type 2 diabetes (90%) --- peripheral tissue insulin resistance = hypoglycaemia
Gestational diabetes --- detected during pregnancy
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3 rare forms of diabetes?
Maturity onset diabetes of the young (MODY) (1-5%) --- mostly inherited, strong genetic risk factor
Neonatal diabetes --- can be transient or permanent
Diabetes related to mitochondrial DNA mutations as the maternally inherited diabetes or deafness (MIDD)
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What is type 1 like?
Insulin-dependent, autoimmune disease that destroys pancreatic cells, lack of insulin production, requires insulin to treat, develops at young age, fast onset
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What is type 2 like?
Non-insulin dependent, develops to an inability to produce enough insulin, may require insulin, more predominant in older adults, slow onset
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What is gestational diabetes like?
Diagnosed in second or third trimester, body cannot respond to increasing insulin demand, can damage both mother and foetus, driven by obesity, physical inactivity and rising maternal age
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What causes type 1 diabetes?
Beta cell destruction by body's immune system due to genetic predisposition or environmental factors like viral infection (mimicry) or infant feeding practices
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Causes of type 2 diabetes?
Genetic predisposition and environmental factors like obesity, lack of exercise, high bp and high cholesterol
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3 phases of type 2 diabetes?
Phase I -- pre diabetes = obesity, normal glucose levels, compensatory hyperinsulinemia
Phase II -- non-insulin dependent phase = strong insulin resistance with hyperglycemia, compensatory hyperinsulinemia
Phase III -- insulin-dependent phase = hyperglycemia with insulin resistance, hypoinsulinemia with gradual loss of function of beta cells
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Symptoms of type 1 diabetes?
Increased thirst, frequent urination, weight loss, fatigue, nausea, vomiting, coma, ketonuria (ketones in urine)
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Symptoms of type 2 diabetes?
Increased thirst and urination, increased appetite, obesity, fatigue, blurred vision, slow healing, impotence
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3 ways diabetes is diagnosed?
1. Fasting glucose = blood glucose levels after an overnight fast
2. Oral glucose tolerance test = measure fasting glucose and then ingest 75g of glucose and measure glucose levels 2h later
3. A1C levels = measure of blood glucose in past 2/3 months by showing amount of glucose that irreverisbly binds to haemoglobin in RBCs to form glycalated haemoglobin --- good indicator of hyperglycaemia
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What is C peptide and how does it determine the type of diabetes?
C peptide is cleaved when insulin is produced, but insulin is degraded in the liver and C peptide is not so it is a better indicator of blood insulin
Blood C peptide indicates insulin ---if the levels are low, impaired beta cell function is likely
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What test can determine if diabetes is type 1?
Auto-antibody test that targets glutamic acid decarboxylase 65, islet cells, insulin, zinc transporter
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Treatment of type 1 diabetes?
Insulin injection
Tight dietary controls
Pancreas transplant (extreme)
Immunotherapies to prevent T lymphoctyes attacking and destroying pancreas
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Treatment of type 2 diabetes?
Dietary changes
Exercise
Glucose lowering oral drugs if there is damage to beta cells
Insulin injections
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What are insulin analogues and how do they relate to diabetes?
Genetically engineered types of insulin with improved properties that better mimic body's insulin --- can be rapid- or long-acting
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3 categories of complications from diabetes?
1. Metabolic complications -- due to low blood glucose levels and high blood glucose levels
2. Microvascular complications -- damage to small blood vessels leading to damage of retina, kidneys and nerves
3. Macrovascular complications -- damage to larger arteries leading to damage of brain (stroke), heart (CVD) and legs and feet
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What causes hypoglycaemia in diabetes and how can it be treated?
Not eating enough sugar, taking too much insulin, too much exercise without adjusted insulin injections
---- higher risk for people with T1D at night (lower metabolic demand = lower hepatic gluconeogenesis)
--- can lead to coma
Glucagon injection or sugary drinks can fix it
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Causes of hyperglycaemia and its consequences?
Eating too much sugar/drinking alcohol, no insulin therapy, no exercise
------------
- Diabetic ketoacidosis in type 1 diabetes and diabetic coma (build up of ketone products from increased fatty acid metabolism combined with loss of fluid due to hyperglycaemia)
- Advance glycation end products -- nonenzymatic glycosylation of proteins
- Osmotic dehydration -- glucose spill over in urine that depletes organs of fluids, decreases blood flow and o2 supply to peripheral organs
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Explain diabetic ketoacidosis (mostly in type 1)?
Complete lack of insulin causes unrestrained lipolysis, free fatty acids are converted to ketones (causing ketoacidosis), glucose cannot be used to so body metabolises fat = dehydration, acidosis and coma
Insulin deficiency leads to shift of potassium from cells into extracellular fluid --- kidney compensates by excreting fluids = osmotic diuresis = loss of water, electrolytes and glucose
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Explain hyperglycaemia hyperosmolar state (mostly in type 2)?
Partial insulin deficiency = prevented fat breakdown and ketone production (so no ketoacidosis), glucose levels are very high causing hyperosmolarity = severe dehydration, confusion and coma
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What are advanced glycation end products?
Harmful compounds formed when sugars react with proteins, lipids or nucleic acids (glycation) --- accelerated in diabetes due to hyperglycemia
These cause inflammation, oxidative stress, stiffening of proteins like collagen (decreased vessel elasticity)
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How does chronic hyperglycaemia cause high blood pressure?
Causes water to be extracted from cells to decrease blood glucose concentration
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What can the high blood pressure combined with increased free fatty acids and low density lipoproteins cause?
Damage to small vessels and atheroclerosis in larger vessels
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What is retinopathy and how does diabetes cause it?
Increased glucose in the blood causes damage to capillaries in the eye = vision problems and blindness (not curable)
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What is diabetic nephropathy?
High bp and hyperglycaemic metabolic complications cause gradual damage to kidney microvessels = increased protein leakage in urine and decreased rate of glomerular filtration
Can cause end stage chronic kidney disease and even kidney failure
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How is diabetic nephropathy treated?
Glycaemic control
Angiotensin converting enzyme (ACE) inhibitors to lower bp
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What is diabetic neuropathy?
Damage to nerves causes by damage to blood vessels by hyperglycaemia = poor blood supply = decreased oxygen supply to nerves
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What is peripheral diabetic neuropathy?
Nerves supplying extremities affected --- results in loss of sensation and numbness/acute pain sensation
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When are macrovascular complications most common?
Type 1
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What do macrovascular complications cause?
High blood glucose and damage to vessels = strokes, CVD (leading to myocardial infarction) and peripheral vascular disease leading to amputations
83
What is diabetic foot disease?
Neuropathy and vascular disease can cause tissue damage in legs and feet which increases sepsis and slow healing adds to issues of neuropathy and ischemia
Must be regularly inspected to ensure this isnt happening
84
What is age-related macular degeneration (AMD)?
Progressive retinal disease affecting the macula that is caused by age, genetics, environment and lifestyle factors
85
Risk factors of age-related macular degeneration (AMD)?
Age
Smoking
Genetics --- genes like chromosome 1q31 and ARMS2/HTRA1 relate to inflammation and complement system dysfunction
Diet and exercise
Heritability (45-70%)
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2 types of AMD?
Dry (atrophic) AMD
Wet (neovascular) AMD
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How is dry AMD characterised?
Most common (80-90%), drusen (yellow-white spots under retina), geographic atrophy (progressive death of retinal pigment epithelium, loss of photoreceptors and choriocapillaris), slow progression
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How is wet AMD characterised?
Less common, rapid onset, abnormal blood vessel growth under retina (choroidal neovascularisation), leakage, bleeding, scarring
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How can AMD be prevented?
Diet -- eating leafy greens, fruits and omega-3s
AREDS2 supplements (if intermediate/advanced)
Stop smoking
Regular exercise
UV protections
90
What is early AMD like?
Small and sparse drusen, minimal pigment change, often asymptomatic, often picked up during routine check ups
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How is intermediate AMD characterised?
Medium/large and more numerous drusen, hyper/hypopigmentation of retinal pigment epithelium, difficulty reading or in dim light, migrating retinal pigment epithelium cells, subretinal drusenoid deposits
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How is advanced AMD characterised?
Can be dry or wet
Dry geographic --- atrophy of retinal pigment epithelium, no neovascularisation or leakage, causes centre of vision loss
Wet neovascular --- new fragile blood vessels grow under retina = leakage of fluid/blood = macular oedema, haemorrhages and scarring
93
How does retina change as you age?
Choriocapillaris rarefication or loss
Lipid/lipoprotein depostion in
Bruch's membrane and retinal pigment epithelium
Basal laminar deposit deposition
Oxidative or metabolic stress = retinal cell damage
Oxidative stress = ""
Parainflammation
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What are drusen?
Focal deposits of extra-cellular debris (lipid) that appear as yellow-white mound-like elevations under retinal pigment epithelium
95
Treatment of wet AMD?
Anti-VEGF therapy that shrink blood vessels that have grown abnormally, fluid goes and vision improves, requires frequent injection
96
Is there a cure for geographic atrophy in dry AMD?
No but treatments are available to slow the progression -- target complement system (part of immune response that is dysregulated in AMD)
97
What factors indicate greater geographic atrophy rate?
Larger baseline lesion, multifocal (spread out) lesion, perilesional FAF pattern (banded, diffuse-trickling FAF phenotypes), nonfoveal location
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What does advancing geographic atrophy manifest as?
Struggling with everyday activities, progressive vision loss
99
What is the key thing with treating any type of AMD?
CATCH IT EARLY
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What is the complement system?
Important innate immunological network that helps with detection and removal of pathogens, regulates and coordinates innate and adaptive immune response to provide an integrated host defense response
101
Why does complement system dysregulation cause dry AMD?
Causes inflammation and cell death (normally stops immune system attacking host cells)
102
What does the future of AMD treatment look like?
Stem cell therapies (iPSC derived) to replenish retinal pigment epithelium cells and cone photoreceptors
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Adverse effects of COX inhibitors?
GI bleedng
Hypersensitivity/bronchospasm
112
How do P2Y12 receptor antagonists act as antiplatelet drugs?
Inhibit platelet activation and aggregation by preventing ADP binding which normally activates platelets
113
Mechanism of action of P2Y12 antagonists?
Primary drug metabolised to active form with thiol group --- thiol forms disulphide bond with cysteine residues in receptor = irreversible inhibition
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Adverse effecs of P2y12 antagonists?
Dysepsia
Diarrhoea
Rashes
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Cons of first generation p2y12 antagonists and pros of second gen?
Cons = longer onset of action, complex drug interactions
Pros = less dependence on metabolism, quicker
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Why do glycoprotein iib/iia receptor inhibitors work?
When the receptors are activated by platelet agonists, fibrinogen can create cross-linked bridges between the receptors to induce platelet aggregation
SOOOO blocking them prevent aggregation
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Adverse effect of glycoprotein iib/iia receptor inhibitors?
Thrombocytopenia
118
How do phosphodiesterase inhibitors act as anti-platelet drugs?
Inhibit PDE so cAMP/cGMP increase = inhibited platelet activation and prolonged cAMP and cGMP mediated vasodilation in smooth muscle cells
Also block adenosine uptake into platelets and endothelial cells = increasing extracellular adenosine concentration = vasodilation
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Adverse effects of phosphodiesterase inhibitors?
GI disturbances
Headaches
Dizziness angina pectoris
Rashes
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Treatment of stable angina and primary prevention of acute coronary syndrome?
Aspirin low dose or P2Y12 antagonist
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Treatment of unstable angina (NSTEMI) and myocardial infarction (STEMI)?
Aspirin
Aspirin + P2Y12 antagonist + more
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Secondary prevention of myocardial infarction treatment?
Low dose aspirin and P2Y12 antagonist (12 months)
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Treatment in percutaneous coronary intervention (angioplasty)?
Short term = aspirin + iib/iia inhibitor + heparin
In prep for PCI = low dose aspirin and p2y12 antagonist
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What is thrombotic thrombocytopenic purpura?
Formation of small blood clots in blood vessels that appear as small purple bruises below the skin due to low platelet count
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2 main types of thrombotic thrombocytopenic purpura?
1. Inherited = mutations in ADAMTS12 gene or immunodeficiency in ADAMTS13 enzyme that breaks down von William factor
2. Acquired = drug induced or diseases or pregnancy
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Key aspects of the clotting cascade i must know?
Endothelial damage activates FX
FX activates thrombin
Thrombin activates fibrinogen to for fibrin clot
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Endogenous anticoagulants?
Anti-thrombin III and heparins
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What do anticoagulants do?
Inhibit factor X (FX)
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How do heparins work?
Can be unfractionated (UFH) and low molecular weight (LMwH)
--- both bind antithrombin III and enhance its bind to factor Xa (inhibits)
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Negative of using heparins?
Hyperkalemia (aldosterone suppression)
Osteoporosis
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What do heparins need to do to inhibit thrombin as well as factor Xa?
Bind antithrombin III AND factor IIa (thrombin)
---- but most LMWHs are too short to bind to exosite 2 of thrombin so they only inhibit factor Xa
---- UFH can do it
SOOO activity decreases when molecular weight does
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Antidote that UFH has to reverse bleeding?
Protamine sulfate (a positively charged protein) --- binds to negatively charged UFH forming stable inactive ion pairs
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Cons of protamine sulfate as an antidote to reverse bleeding?
- Hypersensitivity and anaphylactic reaction
- Less effective against LMWHs
- Can cause immune thrombocytopenia (reduced platelets)
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What is fondaparinux?
An anticoagulant that mimics the binding sequence of heparin to antithrombin iii to enhance interactions of ATIII with factor Xa active site without causing thrombocytopenia
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Con of fondaparinux?
No antidote
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How do direct oral anticoagulants work?
Directly inhibit factor Xa to block conversion of prothrombin to thrombin
---- lasts 8-10 hours and has an antidote
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What are hirudin peptide analogues?
Bind and inhibit the free form of active thrombin --- lepirudin is an irreversible thrombin inhibitor, bivalrudin can be cleaved and displaced by fibrinogen
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What is dabigatran?
Oral anticoagulant that is taking in an inactive form and hydrolysed to active form
Rapid and reversible thrombin inhibitor that inhibits both free and fibrin bound forms of thrombin as well as thrombin-idnuced platelet aggregation
Has an antidote
Success depends on metabolism
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How does warfarin act as an anticoagulant?
Inhibits vitamin K epoxide reductase to prevent vitamin k reduction so the factors involved in clotting cannot be carboxylated (activated) so they cannot bind to platelets
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How is warfarin activated?
Drugs that unbind it from albumin in the plasma (inactive when bound)
Antidote is vitamin K
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Cons of warfarin?
Narrow therapeutic window
Teratogenic
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5 things that increase action of warfarin?
1. Alcohol excess (decreased liver function)
2. Liver disease
3. Plasma protein binding displacement (NSAIDs)
4. CYP polymorphisms/inhibitors
5. VKORC polymorphisms (type a)
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4 things that decrease warfarin activity?
1. Chronic alcoholism (increases CYP activity)
2. Diet (vitamin K rich foods)
3. CYP enzyme inducers
4. VKORC polymorphisms (type b)
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What are the therapeutic applications of anticoagulants?
- Unstable angina and prevention of STEMI
- Prophylaxis (prevent) of stroke in TIA (transient ischemic heart attack)
- Prophylaxis and treatment of deep-vein thrombosis and pulmonary embolism
- Thromboprophylaxis (prevent blood clots)
- Warfarin is used in haemodialysis patients
- Heparins are used after hip/knee replacements
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What is tranexamic acid and what is it used for?
A fibrinolytic agent that competively inhibits plasminogen activators by blocking lysine binding sites on plasminogen and it can block plasmin noncompetitively at high concentrations
(inhibits fibrinolytic pathway)
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Therapeutic uses of tranexamic acid?
Haemorrhage complications
Prophylaxis and treatment in patients at high risk of pre and post operative haemorrhage
Periods
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Therapeutic uses of fibrinolytics?
In acute myocardial infarction to dissolve thrombus and prevent further ischaemic damage
Acute thrombotic stroke
Life-threatening thromboembolisms
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What do fibrinolytics do?
Decrease bleeding by inhibiting fibrinolytic pathway
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Define heart failure
When the heart is incapable of maintaining a cardiac output adequate to accommodate metabolic requirements and the venous return
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Why has the incidence of heart failure increased?
Treatment of disease is better so the risk of getting heart failure is greater as it increases with age
This is causing a heavy burden on the NHS
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Potential causes of heart failure?
- Ischaemic heart disease and MI
- Cardiomyopathy (dilated or hypertrophic) --- reduces ability to pump blood
- Systemic hypertension
- Diabetes and obesity
- Arrhythmias
- Congenital heart defects like family history of enlarged heart, damage to heart valves or history of heart murmur
- Inflammatory cardiomyopathy (myocarditis)
- Pulmonary hypertension, COPD = right ventricle failure
- Drugs and toxins (alcohol, cocaine, cytotoxic agents)
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4 types of heart failure?
1. High output heart failure
2. Low output heart failure
3. Systolic heart failure
4. Diastolic heart failure
2-4 are congestive
3 and 4 can be left or right sided
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What is high output heart failure?
Increased cardiac output DUE TO peripheral vasodilation (e.g. in anaemia, sepsis or hyperthyroidism) OR systemic arterio-venous shunting OR arterio-venous fistulae OR insufficiency of vitamin B1
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What is arteriovenous shunting?
Direct passage of blood from an artery to a vein (bypassing capillary network)
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Direct passage of blood from an artery to a vein (
Abnormal connection or passageway between an artery or vein (bypassing capillaries)
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What causes low output heart failure?
Reduced cardiac output
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Heart fails to contract properly = heart failure with reduced ejection fraction (HFREF)
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What is diastolic heart failure?
Heart fails to relax and fill properly during diastole = HF with preserved ejection fraction (HFPEF)
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Symptoms of right sided low output heart failure?
Fluid build up in abdomen (ascites) and swelling in legs and feet (pitting oedema)
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Symptoms of left sided low output heart failure?
Fluid build up in the lungs = shortness of breath, dyspnoea, cough
Low tissue perfusion = fatigue, tiredness and exercise intolerance
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How does congestive heart failure progress?
Normal (no symptoms, normal exercise, normal left ventricle function)
-----> Asymptomatic left ventricle dysfunction (no symptoms, normal exercise, abnormal left ventricle function)
-----> Compensated congestive heart failure (no symptoms, reduced exercise, abnormal left ventricle function)
-----> Decompensated congestive heart failure (symptomatic, further reduced exercise, abnormal left ventricle function)
-----> Refractory congestive heart failure (symptoms cannot be controlled with treatment)
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Classification levels of heart failure?
Class I (mild) --- no limitations
Class II (mild) --- slight limitation of physical activity causing fatigue, palpitation or dyspnoea
Class III (moderate) --- marked limitation of physical activity
Class IV (severe) --- cannot carry out physical activity without discomfort, issues at rest
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Symptoms of heart failure?
Fatigue
Exercise intolerance
Abdominal and peripheral oedema
Breathing difficulties on exertion or at rest in sleep
Cough
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4 pathogenesis factors of heart failure?
1. Impaired cardiac contractility and reduced cardiac output --- normally body could respond, but CHF means it is inefficient and only weakens heart further
2. Increased sympathetic activity (due to reduced cardiac output and activation of baroreceptors)
3. Activation of RAAS
4. Fluid and salt retention
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5 therapies for heart failure?
1. Positive inotropes = enhance cardiac output
2. Beta blockers = decrease cardiotoxicity of catecholamines (reduce sympathetic activity)
3. ACE inhibitors/Angiotensin ii receptor blockers = reduce RAAS activation
4. Diuretic = reduce fluid retention and oedema
5. Vasodilators = decrease total peripheral resistance and central venous pressure
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What is the first line treatment for congestive heart failure?
ACEI or ARB + beta blocker + diuretic
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Potential benefits of beta blockers in congestive heart failure treatment?
Inhibition of cardiotoxicity of catecholamines via increase in the density of beta1 adrenoceptors (increased contractility), anti-hypertensive, anti-anginal, anti-arrhythmic, antioxidant, antiproliferative
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What drugs may be added to first line therapy of congestive HF?
Aldosterone antagonists and/or hydralazine + nitrate vasodilators
If the HF is associated with angina then a calcium channel blocker may be effective
+positive inotropic agent
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Examples of positive inotropes used in the treatment of CHF?
- Catecholamines (beta1 adrenoceptor agonist) --- used in acute decompensated HF
- PDE3 inhibitors --- used in short term treatment of acute decompensated HF (long term use = mortality)
- Cardiac sensitisers --- used in acute decompensated HF
- Cardiac glycosides --- used in worsening/severe HF
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How do catecholamines treat heart failure?
Stimulate beta1-adrenergic receptors = increased cAMP = calcium influx = stronger and faster contractions
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How
