HT Endocrine Flashcards
1
Q
What are the properties of peptide hormones? How do they work?
A
- Made from short-chain amino acids (size is anything from few AAs to small protein) - Pre-Made and stored in cell, released and dissolved into blood when needed - Large, hydrophilic, charged molecules - cannot diffuse through a plasma membrane - Bind to receptors on cell membranes, triggering a second messenger to be released within cell - very quick - Examples: Insulin, growth hormone, TSH, ADH
2
Q
What are the properties of steroid hormones? How do they work?
A
- Synthesised from cholesterol - Not stored in cell, released as soon as they are Made - Not water soluble - must be bound to transport proteins to travel in blood - Lipid soluble - can cross plasma membrane and Bind to receptor inside cell - slow response - Examples: Testosterone, oestrogen, cortisol
3
Q
Tell me about catecholamine hormones (amino acid derived)
A
- Synthesised from the amino acid tyrosine - Acts same way as peptide hormone - Large, hydrophilic, charged molecules - cannot diffuse through a plasma membrane, so released via exocytosis - Examples: Adrenaline, thyroxine
4
Q
Where is Broca’s area? What is its function?
A
- Left frontal lobe, Brodmann‘s area 44 and 45 - Language production
5
Q
Where is Wernicke’s area? What is its function?
A
- Left (usually) temporal lobe, Brodmann’s area 22- Perception of language
6
Q
What are the layers of brain covering?
A
- Skin - Bone - Dura mater - Arachnoid mater - (Subarachnoid space) - Pia mater
7
Q
What is the function of the proximal convoluted tubule?
A
Reabsorption of: - some water and Na+ - some other ions - all glucose and amino acids
8
Q
What is the function of the distal convoluted tubule?
A
- Regulating acid-base balance - By secreting H+ and absorbing HCO3- - Also regulates Na+ level
9
Q
What is the structure of the collecting duct in the kidney?
A
Principal cells: - Regulate Na+ reabsorption and K+ excretion - Respond to aldosterone and ADH Intercalated cells: - Exchange H+ for HCO3-
10
Q
What is the structure of urothelium?
A
- Complex stratified epithelium - Can stretch in 3 dimensions - Layer of umbrella cells - make it urine proof
11
Q
Describe the drug metabolism of aspirin
A
Phase I: - Hydrolysis reaction: Aspirin + H2O —> Salcylic acid + Ethanoic acid Phase II: - Conjugated with glycine or glucuronic acid - Forms a range of ionised products which can be excreted
12
Q
What is the metabolism reaction of alcohol
A
ADH alcohol dehydrogenase ALDH aldehyde dehydrogenase
13
Q
What is the innervation of bladder contraction?
A
- Autonomic parasympathetic (cholinergic) - S3-S5 nuclei - Drive detrusor contraction
14
Q
What is the innervation of bladder relaxation?
A
- Autonomic sympathetic (noradrenergic) - T10-L2 nuclei - Urethral contraction (smooth muscle component but remember the main part of the sphincter is skeletal muscle) - Inhibits detrusor contraction
15
Q
What is the innervation of A-δ fibres (bladder stretch) and C fibres (bladder pain)?
A
- Sensory Autonomic - S2-S4 nuclei
16
Q
What are the cell types and their functions within the islets of langerhans in the pancreas?
A
Alpha cells - produce glucagon Beta cells - produce insulin and amylin Delta/D cells - produce somatostatin PP cells - produce pancreatic polypeptide
17
Q
What are the classes of hormones?
A
- Steroids - Peptides - Thyroid hormones - Catecholamines
18
Q
Tell me about thyroid hormones üòé
A
- released via proteolysis - T3 triiodothyronine, T4 thyroxine - Take a day to act - in blood bound to thyroglobulin binding protein (produced By liver)
19
Q
What is the blood supply to the thyroid gland?
A
- Superior Thyroid artery - off thyrocervical trunk (subclavian) - Inferior Thyroid artery - off external carotid artery
20
Q
Where are the thyroid and parathyroid glands located?
A
- Thyroid gland sits at C5-T1 - Two lobes connected by an isthmus - Parathyroid is 4 glands on the posterior surface of thyroid glands
21
Q
What effect does parathyroid hormone have on the kidneys?
A
- Increased conversion of 25-hydroxyvitamin D (inactive) to 1,25-dihydroxyvitamin D(active) - At the DCT: Increased Ca2+ reuptake and PO43- excretion
22
Q
What effect does parathyroid hormone have on the gut?
A
Increased Ca2+ and PO43- absoroption
23
Q
What hormones does the adrenal gland produce?
A
Adrenal cortex: - Zona glomerulosa - mineralocorticoids (eg: aldosterone) - Zona fasciculata - glucocorticoids (eg: cortisol) - Zona reticularis - adrenal androgens Adrenal medulla: - Catecholamines (eg: adrenaline)
24
Q
Pathophysiology of T2DM
A
- Peripheral Insulin resistance with partial Insulin deficiency - Decreased GLUT4 expression - impaired Insulin secretion - Lipid and beta amyloid deposits in pancreas, progressive b cell damage
25
Epidemiology of T2DM
- Presents later on in life (usually 30+ years) - Males > females - People of Asian, African and Afro-Carribean ethnicity are 2-4x more likely to develop T2DM than white people
26
Clinical presentation of T2DM
- Obese hypertensive older patient - Polydipsia - Nocturia - Polyuria - Glycosuria - Recurrent thrush
27
Diagnosis of T2DM
- same as T1DM - Prediabetes exists this time
28
Risk factors for T2DM
- Genetic link (stronger than T1DM) - Obesity - Alcohol excess - Hypertension - Gestational diabetes - PCOS - Drugs: corticosteroids, thiazides
29
Last line of treatment for T2DM if all else fails
Insulin treatment
30
Treatment for T2DM
Initial: Biguanide (metformin) Second line: Carry on Metformin and add either: - DPP-4 inhibitor - Pioglitazone - Sulfonylurea - SGLT-2 inhibitor
31
Epidemiology of Diabetic Ketoacidosis
4% of T1DM patients develop each year
32
Risk factors for DKA
- Poorly managed/undiagnosed T1DM - Infection/illness - Characteristic in patients around 20 years old
33
Pathophysiology of DKA
- Absolute immune deficiency unrestrained lipolysis and gluconeogenesis and Decreased Peripheral glucose uptake - Not all glucose from gluconeogenesis is usable so converted to ketone bodies, which is acidic
34
Describe Kussmaul's breathing
Deep and rapid breathing in acidosis to expel acidic carbon dioxide
35
Signs of DKA
- Kussmaul's breathing - Pear drop breath - Reduced tissue turgar (hypotension + tachycardia)
36
How to investigate DKA
- Ketones > 3mmol/L - RPG > 11.1mmol/L (hyperglycemic) - pH < 7.3 or HCO3- < 15mmol - Urine dipstick glyosuria/ketonuria
37
What are common differentials of DKA?
- HHS - Lactic acidosis - identical presentation, normal serum glucose and Ketones - Starvation ketosis - physiologically appropriate lipolysis
38
Treatment for DKA (in order)
- ABCDE - IV fluids FIRST 0.9% saline - IV insulin 0.1units/kg/hour - once glucose level <14mmol add 10% glucose - Restore electrolytes, eg: K+
39
Lateral corticospinal tract
- Supplies limbs - Fine motor movement - Decussates at medulla
40
Ventral corticospinal tracts
- Supplies trunk (proximal muscles) - Decussates at level of effector muscle - Also motor movement
41
Corticobulbar tract
Head and neck via cranial nerves
42
Symptoms of HHS
- Generalised weakness and leg cramps - Confusion, lethargy, hallucinations, headaches - Visual disturbance - Polyuria and Polydipsia - Nausea, vomiting and abdo pain (more common in DKA)
43
Epidemiology of HHS
- Less than 1% of diabetes admissions - 5-15% mortality Risk factors: - Infection - MI - Poor medication compliance
44
Pathophysiology of HHS
- Rise in counter-regulatory hormones (glucagon, Ad, cortisol, GH) - Causes hyperglycaemia ans hyperosmolality - Electrolytes in blood overflow into urine -> excessive loss of water and electrolytes
45
Characteristics of HHS
- Marked hyperglycaemia - hyperosmolality - Profound dehydration - Electrolyte abnormalities
46
Diagnosis of HHS
Diagnostic: - Hyperglycaemia ‚â•30mmol/L without a metabolic acidosis or significant ketonaemia - Hyperosmolality ‚â•320mOsmol/kg - Hypovolaemia Other tests: - Urine dipstick: heavy glycosuria - U+E: low total body K+, high serum K+
47
How can HHS be differentiated from Diabetic ketoacidosis?
DKA - T1DM - Patients younger and leaner - Ketoacidosis - Develops over hours to a day HHS - T2DM - No ketoacidosis - Significantly higher mortality rate - Develops over a longer time - days to a week
48
Treatment of HHS
- IV fluid 0.9% saline - IV insulin only if there is ketonaemia or IV fluids aren't working - LMWH to anticoagulate patient as they have thicker blood - Electrolyte loss (K+)
49
What are complications of HHS treatment with insulin?
- Insulin-related hypoglycaemia - Hypokalaemia
50
What structures are in the cavernous sinus?
(OTOMCAT) - Oculomotor nerve - Trochlear nerve - Ophthalmic division of trigeminal nerve - Maxillary division of trigeminal nerve - Carotid artery - Abducens nerve
51
DCML tract
- Ascending (sensory) - Dorsal root -> medulla, then decussates - Fine touch, vibration and proprioception
52
Spinothalamic tract
- Ascending (sensory) - Decussates at spine 1-2 levels above dorsal entry - Pain, temperature, crude touch - Anterior - trunk - Posterior - limbs
53
Brown sequard syndrome
- Ipsilateral DCML loss - decussate at medulla - Ipsilateral corticospinal loss - decussate at medulla - Contralateral spinothalamic loss - decussate at spinal cord (1-2 levels above)
54
Blood supply to the pituitary gland
- Anterior - Superior hypophyseal artery - Posterior - Inferior hypophyseal artery the hypothalamophyseal portal system is a branch of the internal carotid artery
55
Steps of acute inflammation
- Increased vessel calibre - inflammation cytokines (bradykinin, prostacyclin, NO) mediate vasodilation - fluid exudate - vessels become leaky, fluid forced out of vessel - Cellular exudate - abundant in neutrophils
56
5 cardinal signs of acute inflammation
- Rubor (redness due to dilation of small vessels) - Dolor (pain) - Calor (heat) - Tumor (swelling from oedema or a physical mass) - loss of function
57
Causes of acute inflammation
- Microbial infections - Hypersensitivity reactions - physical agents - Chemicals - Bacterial toxins - Tissue necrosis
58
Neutrophil action in acute inflammation
- Margination - migrate to edge of blood vessel (plasmatic zone) due to increase in plasma viscocity and slow flow - Adhesion - selectins Bind to neutrophil, cause rolling along the blood vessel margin - Emigration + diapedesis - movement out of blood vessel through or inbetween endothelium onto basal lamina and then vessel wall - Chemotaxis - site of inflammation
59
Neutrophil action at the site of inflammation
- Phagocytosis - Phagolysosome + Bacterial killing - Macrophages clear debris
60
Outcomes of acute inflammation
- Resolution - normal - Supporation - pus formation - Organisation - granulation tissue + fibrosis - Progression - excessive recurrent inflammation -> becomes chronic and fibrotic tissue
61
Chronic inflammation
- Subsequent and prolonged response to Tissue injury - Lymphocytes, Macrophages and plasma cells - Longer onset, long lasting effects - Autoimmune diseases
62
Causes of chronic inflammation
- resistance of infective agent - Endogenous + materials - Autoimmune conditions - Primary granulomatous diseases - Transplant rejection
63
Macroscopic appearance of chronic inflammation
- Chronic ulcer - Chronic abscess cavity - granulomatous inflammation - fibrosis
64
Microscopic appearance of chronic inflammation
- Lymphocytes, plasma cells and Macrophages - exudate is Not a common feature - Evidence of continuing destruction - Possible Tissue necrosis
65
Cellular cooperation in chronic inflammation
- B lymphocytes - transform into plasma cells and produce antibodies - T lymphocytes - responsible for cell-mediated immunity - Macrophages - respond to chemotactic stimuli, produce cytokines (interferon alpha and beta, IL1, IL6, IL8, TNF-alpha)
66
What are granulomas?
- An aggregate of epithelioid histocytes (macrophages) - Granuloma + eosinophil -> parasite - Secrete ACE as a blood marker
67
Types of granulomas
- Central necrosis - TB (identified by Ziel-Neelsen stain) - No central necrosis - sarcoidosis, leprosy, vasculitis, Crohn's disease
68
What is thrombosis?
Solidification of blood constituents (mostly platelets) forming in vessels
69
Platelets
- NO nucleus, arise from megakaryocytes - Contain alpha granules (Adhesion) and dense granules (aggregation) - Contain lysosomes - Activated, releasing their granules when they come into contact with collagen - Activation forms thrombus in intact vessels
70
Thrombosis formation (primary platelet plug)
- Platelet aggregation, starts the coagulation cascade - Positive feedback loops
71
Causes of thrombosis (Virchow's triangle, typically 2 out of these 3)
- Endothelial injury (trauma, surgery, MI, smoking) - Hypercoagulability (sepsis, atherosclerosis, COCP, preggomalignancy) - Decreased blood flow (AF, immobility)
72
Arterial thrombosis
- By atherogenesis and plaque rupture - High pressure, low pulse - Thin cool Skin, intermittent claudication - Mainly Made of platelets - so treat with antiplatelet (aspirin)
73
Venous thrombosis
- Caused By venous stasis - low pressure, High pulse - Rubor, tumour and pain - Mainly fibrin - so treated By anticoagulants (DOACs, warfarin)
74
Fate of thrombi
- Resolution (dissolves and clears, normal/best case scenario) - Organisation (leaves scar tissue, slight narrowing of vessel lumen) - Recanalisation (intimal cells may proliferate, capillaries may grow into the thrombus and fuse to form larger vessels) -
75
Formation of the secondary platelet plug (coagulation cascade)
Prothrombin -> thrombin Fibrinogen -> fibrin
76
What is an embolism
A mass of material in the vascular system able to block in a vessel and block its lumen
77
Arterial vs venous embolism
Arterial - Lodges in systemic circulation (from left heart) - eg: AF thrombus lodges in carotid artery -> ischaemic stroke Venous - Lodges in pulmonary circulation (from right heart) - eg: DVT thrombus embolises and lodges in pulmonary artery -> pulmonary embolism
78
Ischaemia
- the reduction in blood flow to a Tissue or part of the body Caused By constriction or blockage of the blood vessels supplying it - effects can be reversible - Brief attack - Cardiomyocytes and cerebral neurons are most vulnerable
79
Infarction
- the necrosis of part of the whole of an organ that occurs when the artery supplying it becomes obstructed- usually macroscopic - Reperfusion injury damage to Tissue during reoxygenation
80
What organs are susceptible to infarcts?
- most organs as they only have a single artery supplying them - liver, brain and lungs are Less susceptible as they have a dual supply
81
What is atherosclerosis?
- Fibrolipid plaques forming in the intima and media of systemic arteries - more in High pressure arteries, eg: aorta and bifurcations
82
What is in an atherosclerotic plaque?
- Lipids (cholesterol) - Smooth muscle - Macrophages (+foam cells) - Platelets - Fibroblasts
83
What are foam cells?
Macrophages that phagocytose LDLs
84
Atherosclerosis formation
#NAME?
85
Risk factors for atherosclerosis
- Smoking - High bp - Hyperlipidemia - Increasing age - Male - Poorly controlled diabetes mellitus (all risk factors for MI!!)
86
Complications of atherosclerosis
- cerebral infarction - carotid atheroma, leading to TIAs and cerebral infarcts - MI - Aortic aneurysm - Peripheral vascular disease - Gangrene - Cardiac failure - Ischaemic collitis in colon
87
Preventative measures for atherosclerosis
- smoking cessation - blood pressure control - Weight reduction - low dose aspirin - Statins - control diabetes
88
What is apoptosis?
- Non-inflammatory, controlled cell death in single cells - cells shrink, organelles retained, CSM intact - Chromatin unaltered, fragmented for easy Phagocytosis
89
What is necrosis?
- Induces inflammation and repair, traumatic cell death - cells burst, organelles splurge, CSM damaged - Chromatin altered, cell is f*cked
90
Intrinsic apoptosis mechanism
- Bax is a protein, inhibited by BCl-2 - It acts on mitochondrial membrane to promote cytochrome C reusase - This activates caspases
91
Extrinsic apoptosis mechanism
Fas-L or TNF-L binds to CSM receptors which activate caspases
92
Cytotoxic apopstosis mechanism
- CD8+ binding releases Granzyme B from CD8+ cells - Granzyme B -> Perforin -> Caspases
93
Types of necrosis
Coagulative, liquifactive, caseous and gangrene
94
Coagulative necrosis
- most common type - can occur in most organs - Caused By ischaemia
95
Liquefactive necrosis
Occurs in the brain due to its lack of substantial supporting stroma
96
Caseous necrosis
- Causes a cheese pattern - eg: TB
97
Gangrene
- necrosis from rotting of the Tissue - Affected Tissue appears black due to deposition of iron sulphide from degraded haemoglobin
98
What is inflammation?
Acute/chronic tissue injury response
99
What are polymorphs?
- What neutrophils are referred to as sometimes - Because they have a varying number of lobulated nuclei
100
What is hypertrophy?
- increase in cell size without cell division - eg: skeletal muscle
101
What is hyperplasia?
- increase in cell number By mitosis - eg: Bone marrow at High alititudes, prostate at older age
102
What is atrophy?
- Decrease in tissue/organ size caused by a decrease in the number or size of constituent cells - eg: brain in Alzheimer's, muscular atrophy in ALS
103
What is metaplasia?
- The change in differentiation of a cell from one fully-differentiated cell type to another - eg: GORD (squamous -> columnar epithelia)
104
What is dysplasia?
Morphological changes seen in cells in the progression to becoming cancer
105
What is carcinogenesis?
Transformation of normal cells to neoplastic (malignant) cells through permanent genetic alterations or mutations
106
What is a neoplasm?
An autonomous, abnormal and persistent growth
107
What is a tumour?
Any abnormal swelling; neoplasm, inflammation, hypertrophy, hyperplasm
108
What can a neoplasm arise from?
- Nucleated cells - So can't arise from erythrocytes but can arise from their precursor
109
Properties of benign tumours
- Non-invasive - Localised - slow growth rate, low mitotic activity - Close resemblance to normal Tissue - Well circumscribed - Rare necrosis and ulceration - growth on mucosal surfaces - Often exophytic (outward growth)
110
Properties of malignant tumours
- invasive - Rapid growth rate, High mitotic activity - Poorly defined + irregular border - Hyperchromatic and pleomorphic nuclei - common necrosis and ulceration - growth on mucosal surfaces and Skin - Often endophytic (inward growth)
111
Complications of benign tumours
- Hormone secreting (eg: prolactinoma) - Pressure on local structures (eg: pituitary -> optic chiasm) - Obstruct flow - Transformation to malignant neoplasm - Anxiety
112
Complications of malignant tumours
- all of the issues of benign tumours + - Destroy surrounding Tissue - Metastasise (spread around the body) - blood loss from ulcers - pain - Paraneoplastic (eg: SCLC, SIADH) - form Secondary tumours
113
Benign epithelial neoplasms
- Papilloma - Non-glandular, Non-secretory, eg: squamous cell Papilloma - Adenoma - glandular, secretory, eg: colonic Adenoma
114
Malignant epithelial neoplasms (carcinomas)
eg: urothelial carcinoma glandular epithelium -> adenocarcinoma
115
Benign connective tissue neoplasm
- Lipoma - adipocytes - Chondroma - cartilage - Osteoma - Bone - Angioma - vascular - Rhabdomyoma - striated muscle (Rare) - Leiomyoma - smooth muscle (more common) - Neuroma - nerves
116
Malignant connective tissue neoplasms
Same as benign ones, but followed by 'sarcoma' instead of 'myoma'
117
What is a tumour called where the cell origin is unknown?
Anaplastic
118
Lymphoid tumours (always malignant)
- Leukemia, lymphoma - Need to be treated By systemic chemotherapy
119
Other tumours
- Melanoma (melanocyte malignancy) - Mesothelioma (mesothelial malignancy - typically pleural) - Teratoma - cancer of all 3 embryonic germ layers - Blastoma - embryonal tumours
120
Eponymously named tumours
- Burkitt's lymphoma (B cell malignany cause by EBV) - Kaposi sarcoma (vascular endothelial malignancy, HIV associated) - Ewing's sarcoma (bone malignancy)
121
Tumour differentiation grading
- Graded based on similarity to parent cell 1. >75% cells resemble parent - well differentiated 2. 10-75% 3. <10% cells resemble parent - poorly differentiated
122
Characteristics of the neoplastic cell
- Autocrine growth stimulation (overexpression of GF and mutation of tumour suppressor genes, eg: P53, and underexpression of growth inhibitors) - Evasion of apoptosis - Telomerase - prevents shortening of telomeres with each replication
123
Classes of carcinogens
- Chemical - eg: paints, dyes, rubber, soot - Viruses - eg: EBV, HPV - Ionising and Non-Ionising radiation - eg: UVA and UVB, Ionising radiation - hormones, parasites, mycotoxics - eg: High oestrogen, anabolic Steroids - Misc - eg: asbestos, arsenic
124
Host factors for cancer
- Race - Diet - age - Gender - Inheritance - Premalignant lesions - Transplacental exposure
125
Metastasis pathway
1. Detachment of tumour cell 2. Invasion of surrounding connective tissue 3. Intravasation into blood vessels 4. Evasion of host defence mechanisms 5. Adherance to endothelium at a remote location 6. Extravasation to distant site 7. Angiogenesis - growth of own blood supply
126
Methods of cancer spread
- Haematogenous - via blood, Bone, breast, lung, liver - Lymphatic - Secondary formation in lymph nodes - Transcolemic - via exudative fluid accumulation, spread through pleural, pericardial, peritoneal effusions
127
Method of spread for sarcomas
Mostly haematogenous
128
Method of spread for carcinomas
- Mostly Lymphatic - Exceptions: follicular Thyroid, choriocarcinoma, RCC, HCC
129
Tumour staging
- spread determined By histopthological and clinical examination - TNM: Primary tumour, lymph node, metastases - Different for leukemias, lymphomas and CNS cancers
130
Screening in the UK
- Cervical cancer (Cervical swab test) - breast cancer (mammogram) - Colorectal cancer (fecal occult) - Heel prick test at birth for sickle cell, CF and hypothyroid
131
Mutation involved in colorectal cancer
- FAP (familial adenamatous polyposis) - HNPCC (lynch syndrome)
132
FAP
- Autosomal dominant - Mutated APC (adenomatous polyposis coli) gene, millions of colorectal adenomas inevitable - Adenocarcinoma by 35 years old - Overexpression of x-MYC and point mutation in KRAS
133
HNPCC
- Autosomal dominant - Mutated MSH gene - Involved in DNA mismatch repair
134
Which tumours are most likely to metastasise via bone?
Breast Lung/lymphoma Thyroid Kidney Prostate …and multiple myeloma
135
Primary lymphoid organs
- Bone marrow - origin of all immune cells, b cell maturation site - Thymus - T cell maturation site, thymic tolerance
136
Secondary lymphoid organs
- lymph nodes - site of DC, b and T cell interactions - Spleen - RBC recycling, encapsulated Bacterial cell killing
137
Tertiary lymphoid organs
- Pathological - Germinal centres of rapidly proliferating Lymphocytes
138
Innate immunity
- Non-specific - Rapid - Already active (little Activation needed) - NO memory - short duration - killing usually via complement Activation - mediated By neutrophils and Macrophages
139
Adaptive immunity
- specific - slow - Needs Activation - have memory - killing usually antibody mediated - main cells are T, b and plasma cells - long lasting
140
Examples of physical barriers
- Skin - Mucus - Cilia
141
Examples of chemical barriers
- Lysozyme in tears - Stomach acid
142
Compliment pathways
- Classical - Lectin - Alternate
143
Compliment system destroys foreign bodies by...
- Direct lysis - Membrane attack complex formation - Opsonisation - Increased phagocytosis via protein C3b - Inflammation - Macrophage chemotaxis via proteins C3a and C5a
144
Innate cells - neutrophils
- Key mediator of acute inflammation - IL8 chemokine - 70% of all leukocytes - Act in hours-days - Express CD66 receptor (common for all granulocytes)
145
Innate cells - macrophages
- Act over months-years (typically chronic) - Phagocytosis, antigen presenting and cytokine secreting (TNF-a, IL1 and IL12) - Express CD14+ and CD40+ - Can be circulating or resident (eg: Kuppfer cells, alveolar macrophages) - Clear apoptotic debris
146
Innate cells: eosinophils
- Release major basic protein - Seen in parasitic infections
147
Innate cells: basophils
- Circulate mast cells - Secrete serotonin and heparin - Important in asthma, anaphylaxis, atopic dermatitis and hay fever
148
Innate cells: mast cells
- Important in parastic infections and allergic reactions - Activate type 1 hypersensitivity: IgE crosslinking -> degranulation -> histamine release - Fixed at tissues at mucosal surfaces
149
Innate cells: natural killer cells
- In blood and tissues - Express CD16+ - Antibody-dependent cellular cytotoxicity - Recognise self and non-self by the presence of MHC-I on cell surfaces - Activation -> degranulation -> perforin -> perforates viral infected cells
150
Non-cellular components of innate immunity
Physical and chemical barriers
151
Receptors on innate cells
- Toll like receptors (TLRs) and nod like receptors - respond to PAMPs and DAMPs
152
Which TLRs are intracellular?
3, 7, 8, 9 (rest are extracellular)
153
What are antigen presenting cells?
- the interface between innate and adaptive immunity - all present exogenous antigens in the presence of MHCII - best cells for this are dendritic cells - (Macrophages and b-cells Also do this)
154
What do dendritic cells do?
- Present foreign antigens to T helper cells - Stimulates further T helper proliferation - Stimulates B cell production -> antibodies
155
What is formed when a dendritic cell and T helper cell communicate?
Immune synapse
156
3 conditions that must be met for antigen presenting cells to function
- receptor binding - Co-stimulation (other molecules Bind after Primary receptor binding) - cytokine Release
157
Adaptive cells: T cells
- Mature in the Thymus - thymic tolerance selects best T cells - T cell never encountering antigen (Not matured in Thymus yet) naïve T cell
158
Process of thymic tolerance
- Positive selection - T cells tested to see if they recognise major histocompatability complexes 1 and 2 (selected FOR) - Negative selection - T cells tested to see if they produce an immunological response against MHCs (selected AGAINST) - Allocation
159
Allocation in thymic tolerance
- If interact with MHC1 -> CD8+ cells (cytotoxic, kill) - If interact with MHC2 -> CD4+ cells (helper, increase immunity response by activating cells)
160
Adaptive cells: B cells
- maturation and production in the Bone marrow - Any b cells with autoimmunity apoptose
161
Activation of B cells
- APC and interactions between MHC-II activates T helper 2 cells - T helper 2 cell releases IL4 (B cell proliferation) and IL5 (B cell differentiation into plasma cell -> immunoglobulins) - IGs act against specific pathogen present - Somatic hypermutation
162
What do IL4 and IL5 promote class switching to?
IL4 - IgA IL5 - IgE
163
IgG
- Most abundant in blood - Highly specific - Key in secondary response - 4 subtypes - Can cross the placenta
164
IgA
- most abundant in total body - Found on mucosal linings, colostrum and breast milk (a dimer)
165
IgM
- FIRST Ig released in adaptive response - b cell mediated - a pentamer
166
IgE
- Least abundant in body - Activates mast cell + basophil degranulation in type 1 hypersensitivity (anaphylaxis)
167
IgD
Unknown function, irrelevant
168
Major histocompatability complex
- Also known as human leukocyte antigen (HLA) - On chromosome 6 - Interact with T cells - Confer susceptibility to inherited autoimmune diseases
169
Type 1 hypersensitivity
- Anaphylactic - antigen reacts with IgE bound to mast cells - vasodilation, Increased permeability, bronchoconstriction, facial flush, puritis, swollen tongue and face - eg: atopy: asthma, eczema, hay fever
170
Type 2 hypersensitivity
- Antibody-antigen complex formation üë¥üèª Goodpasture's Rheumatic fever AHA Myasthenia gravis Pernicious anaemia Anti-TSH (Graves')
171
Type 3 hypersensitivity
- Antibody-antigen complex deposition üíÉüèª Haemolytic uraemic syndrome and hypersensitivity pneumonitis IgA nephropathy Post-strep glomerulonephritis SLE
172
Type 4 hypersensitivity
- Delayed - T-cell mediated and activated by antigen presenting cells GBS MS üê± Contact dermatitis + coeliac Allopurinol drug reaction Tuberculin skin test and T1DM
173
Assessing vitals in anaphylaxis
A - airways - hoarse voice, stridor B - breathing - SpO2 < 94% C - circulation - are they pale, cold, clammy? low BP D - disability - confused, comatose, movemet E - exposure
174
What is immune tolerance?
- Physiological - Central - thymic tolerance - Peripheral - If T/B faulty cell evade central tolerance, they're dealt with in secondary lymphoid organs
175
What is autoimmunity?
- Phathological response vs self - faulty immune tolerance - Molecularmimickery
176
Organ specific autoimmunity
- T1DM - endocrine pancrease b cells - MS - oligodendrocytes of CNS - Pernicious anaemia - parietal cells of Stomach - Myesthemia gravis
177
Non-organ specific autoimmunity
- Affects DNA, eg: SLE - Affects cell antigens - RBCs -> autoimmune haemolytic anaemia - Platelets - > immune thrombocytopenic purpura - Rheumatoid arthritis
178
Immunodeficiency can be...
- Inherited (defects in T cells), eg: IgA deficiency (north Europe), SCID (death within 2 years) - Acquired, eg: HIV
179
Patterns of immunodeficiency
- Decrease in T helper cells in HIV, PCP pneumonia - B cell deficiency - Complement deficiency (SLE) - Hyposplenism - lack of/decreased function of the spleen ->
180
What are the Pfizer and Biotech Moderna COVID-19 vaccines made from?
mRNA
181
What are vaccinations?
A form of active immunity
182
Forms of vaccines
- Live attenuated (genetically modified) organism, eg: MMR, BCG, Polio - DNA antigens - Subunit/toxoid vaccines, eg: tetanus, diphteria, cholera - Recombinant vector, eg: Hep b - whole inactivated pathogen, eg: influenza
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Active immunity natural vs artificial
Natural - Body encounters pathogen + produces memory cell after infection Artificial - Vaccine mimics encountering pathogen + stimulates Ig production
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Passive immunity natural vs artificial
Natural - Maternal Igs passed onto feeding baby in breast milk/colostrum Artificial - Antivenom, injection of Ig from another organism
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Advantages and disadvantages of live attentuated pathogens
Advantages: - Full natural immune response - Prolonged protection - Often only single immunisation Disadvantages: - Immunocompromised patients may become infected - Can have outbreak in places with poor sanitation
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Advantages and disadvantages of whole inactivated pathogens
Advantages: - No risk of infection - Storage less critical - Good immune response Disadvantages: - Just activates humoral response (not T cells) - Not full transient infection - Boosters required
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Advantages and disadvantages of subunit/toxoid vaccines
Advantages: - Safe (only parts of pathogen are used) - No risk of infection - Easier to store and preserve Disadvantages: - Less powerful immune response - Repeated vaccinations and edjuvants - Consider genetic heterogeneity of population and choice of antigen
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Advantages and disadvantages of DNA antigen vaccine
Advantages: - Safe, even in immunocompromised patients - No complex storage or transport - Simple drug delivery Disadvantages: - Mild response during boosting - No transient infection
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Advantages and disadvantages of recombinant vector vaccines
Advantages: - Ideal stimulus to immune system - Immunological memory - Flexible Disadvantages: - Can cause illness in compromised individuals - Immune response can regate effectiveness - Requires refridgeration for transport
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Types of drug administration
Systemic - Enteral (GI tract: PO and PR) - Par-enteral (non-GI tract) Local
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Examples of parenteral drug administration (not via GI tract)
- Intravenous - Intramuscular - Subcutaneous - Inhalers - Sublingual
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Examples of local drug administration
- Topical - Intranasal - Eye drops - Inhalation - Transdermal
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What is pharmacodynamics?
Action of the drug on the body
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What is pharmacokinetics?
Action of the body on the drug
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What is an agonist?
- Full affinity - Full efficacy - Mimics endogenous substance eg: Salbutamol is a beta 2 agonist
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What is an antagonist?
- Full affinity - NO efficacy - Therefore Decrease the Activation of the receptor - can be reversible or irreversible (if covalent bond forms) eg: propanolol is a beta blocker
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Types of receptor ligands
- Agonists (including partial) - Antagonists - Allosteric modulators
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What is bioavailability?
- How much of a drug reaches systemic circulation unaltered - IV drugs have a 100% bioavailability as they go straight into systemic circulation
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What does a competitive antagonist do?
- Binds to the active site - Decreases efficacy reversibly - affinity is unchanged - Ligand concentration is rate limiting eg: naloxone
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What does a non-competitive antagonist do?
- Binds away from the active site, changing its shape - Decreases efficacy irreversibly - affinity is reduced - Ligand concentration is Not the rate limiting step eg: ketamine
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Ways drugs cross membranes
- Passive diffusion - Facilitated diffusion - active transport - Endocytosis
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Factors of pharmacokinetics
- Absorption - Distribution - Metabolism - Elimination
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First pass metabolism
- The gut and liver metabolise drugs given orally before reaching circulation - Phase 1 and 2 detoxification by the liver - Aims to slightly increase hydrophilicity - By microsomal enzymes, eg: CYP450
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What does drug distribution depend on?
#NAME?
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What drugs can the kidney excrete?
- water soluble Drugs - Not Lipid soluble Drugs
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How does the liver metabolise drugs to help the kidney?
- Phase 1: Mildly increases hydrophilicity via microsomal enzyme cytochrome p450 - Phase 2: Majorly increases hydrophilicity by conjugation, making the drug polar, eg: acetylation, glucoronidation - Drug becomes water soluble
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What are inducer drugs
- increase cytochrome P450 activity and speed up Metabolism of other Drugs - May result in sub-therapeutic dose
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What are inhibitor drugs?
- Decrease cytochrome P450 activity, reduce Metabolism of other Drugs - May result in toxicity - eg: erythromycin, grape juice
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Examples of inducers
PCARBS Phenytoin Carbamazepine Alcohol (chronic use) Rifampicin Barbiturates (St John's Wort) Sulfonylureas and smoking
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Examples of inhibitors
ODEVICES Omeprazole Disulfiram Erythromycin Valproate Isoniazid Ciprofloxacin Ethanol (acute use) Sulphonamides and SSRIs
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First order elimination of drugs
- Catalysed By enzymes - rate of Metabolism directly proportional to drug concentration
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Zero order elimination of drugs
- enzymes saturated By High drug doses - rate of Metabolism is constant - eg: ethanol, phenytoin
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Allosteric modulators
- increase/Decrease normal Ligand binding - eg: benzodiazepine
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Non-selective vs selective beta blockers
- Non-selective binds to every single beta adrenergic receptor (1 and 2) - CONTRAINDICATIONS - Selective binds only to a specific subtype of beta adrenergic receptor (eg: cardioselective) - Usually we just say more or less selective rather than categoris
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Enzymes as drug targets
NSAIDS - Inhibit Cox-1 - Prevent arachidonic acid - Decrease prostaglandin production - Risk of GI bleeds due to ulcers as prostaglandins maintain stomach mucosa ACE inhibitors - Inhibit conversion of Angiotensin I -> II - Antihypertensive - Many side effects including hyperkalemia and dry cough
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Transporters as drug targets
- Mostly ATP dependent - Proton pump inhibitors (eg: omeprazole) cause irreversible inhibition of H+, K+ and ATPase pumps, decreasing pH - Diuretics - Selective serotonin reuptake inhibitors - Tricyclic/tetracyclic antidepressants
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How does local anaesthesia work
Blocks Na+ voltage gated channels
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Specific vs selective drugs
- specific - act on certain targets - selective - act on subtype of target
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Neurotransmitter in between synapses in cholinergic pharmacology
Always acetylcholine acting on nicotine
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Ach binding at the nmj
- Autonomic sympathetic nervous system: Noradrenaline working on noradrenergic receptors - Autonomic parasympathetic nervous system: Muscarinic acetylcholine receptors - Somatic nervous system: Acetylcholinergic nicotinic receptors
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Drugs at the neuromuscular junction
- Botolinum toxin (botox) - Curare (nAch-R antagonist) - Ach-ase inhibitors
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How does botox work?
- Binds to presynaptic vesicles - Ach Release inhibited - Paralysis
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How do Ach-ase inhibitors work?
- Inhibit the breakdown of Ach - Increased concentration at the neuromuscular juntion
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Overstimulation of Ach at the neurmuscular junction
Cholinergic crisis Salivation Lacrimation Urination Defacation GI distress Emesis Anything that understimulates Ach does the opposite
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Parasympathetic (Ach) responses
- Rest + digest - Pupil constricts - Lower heart rate - Bronchoconstritction - Increased GI motility and secretion - detrusor muscle contracts - Penis points (erect)
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Sympathetic (NAd) response
- Fight or flight - Pupil dilates - Increased heart rate - Bronchodilation - Decreased GI motility and secretion - detrusor muscle relaxes - Penis shoots (ejaculation)
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Adrenaline formation
Tyrosine -> DOPA -> Dopamine -> Noradrenaline -> Adrenaline
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NAd alpha 1 and 2 receptors
- Vessels + sphincters - Agonism causes: - Vasoconstriction - Bladder contraction - Pupil dilation - (eg: tamsulosin alpha blocker for benign prostatic hyperplasia)
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NAd beta 1 receptors
- heart - Agonism Causes Increased force of heart contraction - Higher blood pressure - Renin Release
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NAd beta 2 receptors
- lungs - Agonism Causes Bronchodilation
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Agonism and antagonism in beta 2 receptors
Agonists: Short and long acting beta 2 agonists for asthma Antagonists: Non-selective beta blockers
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Drug for community acquired pneumonia
Antibiotics such as amoxicillin/clarythromycin
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Drug for HAP
Co-amoxiclav (3x daily, 500 or 125mg for 5 days)
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Drugs for TB (ripe) and their side effects
Rifampicin - 6 months - red urine and tears, hep, drug interactions Isoniazid - 6 months - hep, peripheral neuropathy Pyramizinamide - 2 months - hep, arthralgia, rash Ethambutol - 2 months - optic neuritis Give first 2 for 12 months if in CNS
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What should you take with isoniazid
Pyramidine to prevent: - B6 deficiency - Siderobastic anaemia - Peripheral neuropathy
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Drug for cellulitis
High dose oral antibiotic If MRSA, give vancomycin
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Side effect of trimthoprim
Can cause birth defects in the first trimester of pregnancy
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Treatment for pyelonephritis
- Analgesia: Paracetamol - Antibiotics: Ciprofloxacin or Co-amoxiclav (if pregnant, give cefalexin) - Refer to hospital if there are signs of sepsis
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Treatment for chlamydia
- FIRST line: doxycycline - if CI or Not tolerated: azithromycin - if CI: erythromycin...or ofloxacin but this is CI in pregnancy - Sexual intercourse should be avoided until treatment is complete - Partner must Also be treated
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Treatment for gonnorrhoea
- IM ceftriaxone 1g - Refer to GUM clinic
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Treatment for early syphilis
- Single deep intramuscular dose of benzathine benzylpenicillin - Refer to GUM clinic - Notify all partners in the last 3 months
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Drug for H.Pyloriüߢ
Clarythromycin Amoxicillin PPI For 7 days
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Drug for gastroenteritis
- Campylobacter -> clarythromycin - Amoebiasis -> metronidazole and diloxanide - Giardiasis -> tinidazole
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Drug for C.Difficile
- Vancomycin - 125mg - 4x a day - for 10 days
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Drug for bacterial meningitis in hospital
- Ceftriaxone (3rd gen cephalosporin) - Cefuroxime if prgenant or under 3 months old - Amoxicillin if listeria suspected - Steroids simultaneously (dexamethasone) within 12 hrs
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Drug for bacterial meningitis in community
Parenteral benzylpenicillin (IV or IM) and then refer to hospital urgently Dosage: - Children < 1: 300mg - Children 1-9: 600mg - Adults and children 10+: 1200mg
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Drug for infective endocarditis
Antibiotics
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Types of pain
- Acute (nociceptive) - Cancer - Neuropathic (nerve pain) - Chronic non-cancer (3+ months)
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Possible categories for adverse drug reaction reporting:
Augmented - is the pain predictable/common? Bizarre - is there a chance of allergy? Chronic - has patient been using the drug for a long time? Delayed - has patient used drug in the past? End of use - is the patient withdrawing from the drug?
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Things that affect drug absorption
- Acidity (eg: PPI), ionised drugs can’t cross phospholipid bilayer - Motility (eg: erythromycin) - Solubility
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Types of opioids
- Naturally ocurring from the poppy - morphine + codeine - Modification - diamorphine (heroin), oxycodone, dihydrocodeine - Synthetic opioids - eg: pethidine
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What do opioids act on?
- CNS + GI tract receptors - Resp centres of the brain (pontine)
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Side effects of opioids
- Addiction - Constipation - Nausea and vomiting - Respiratory distress/depression
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Tolerance vs dependance
- tolerance - Physiological, body has gotten used to a certain amount of drug, desensitisation - Dependance - Physcological, craving euphora
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Treatment for opioid induced respiratory depression
- naloxone (competitive opioid inhibitor) - IV is fastest route
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Types of anticoagulants
- warfarin - Direct oral anticoagulation - Thrombolytics - LMWH (low molecular Weight heparin)- Antiplatelets (aspirin, clopidogrel)
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What to give a patient bleeding on Warfarin?
Vitamin K
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How to NSAIDs decrease inflammation?
By inhibiting Cox2
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Side effects of ACE inhibitors
- High bradykinin accumulation in lungs Causes dry caugh (switch to ARB) - Dilutes afferent arteriole/glomerulus, can cause AKI due to low GFR
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Side effects of PPIs
Prolonged use can increase fracture risk
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Dopamine agonists and antagonists
- Agonists, used in prolactinoma, acromegaly and early in Parkinson's - Antagonists often for nausea and vomiting (eg: metoclopramide, antiemetic) + for psychiatric disorders (eg: haloperidol)
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Where are DA receptors mostly found?
Nucleus accumbens in brain
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GABA
- Main inhibitory CNS neurotransmitter - Agonists - benzodiazepines (eg: lorazepan and diazepan) - Anxiety, sleep disorders, alcohol withdrawal, status epilepticus,
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H1 and H2 antagonists
- H1: For allergy (T1 IgE anaphylaxis), eg: loratidine - H2: 2nd line for GORD/high acid reflux after PPI, eg: ranitidine, cimetidine
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Glutamate
Main excitatory CNS neurotransmittor
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Drug factors that influence drug interactions
- Solubility - Narrow therapeutic index:
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Factors that affect drug excretion
- acids cleared faster if urine is weakly basic - Bases clear faster if urine is weakly acidic
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Side effects of beta blockers
- low blood pressure - slow HR - Symptoms of shock
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What can ankle swelling be caused by?
Calcium channel blockers (eg: amlodipine) OR heart failure
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Steroid side effects (glucocorticoids)
CUSHINGOID MAP Cataracts/glaucoma Ulcers Striae Hypertension Infection risk increase Necrosis of bone Growth restriction Osteoporosis ICP high DMT2 Myopathy Adipose hypertrophy Pancreatitis Sleep problems
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Thiazides
- eg: bendroflumethiazide and indapemide - Inhibits Na-Cl channel cotransporter in distal convoluted tubule - Increased Cl-, Na+ and water excreted
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Spironolactone
- Inhibits ENaC channel in collecting duct (aldosterone antagonist) - Increased Na+ and water excreted - Increased K+ retention
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Mechanism of warfarin
Antivitamin K because in inhibits Vitamin K epoxide reductase
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Thrombolytics
- "Clot buster" - eg: alteplase, Activated Tissue plasminogen, activates plasmin to degrade fibrin
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Hospital autopsy
- Less than 10% in the UK - Requires medical certificate of cause of death (MCCD) - Used for audit, teaching, research and governance
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Medico-legal autopsy
- >90% in the UK - Coronial autopsy - death is not due to unlawful action - Forensic autopsy - unlawful (eg: murder)
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What percentage of deaths are referred to the coroner?
- About 40% - But they only choose to investigate about 10%
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Deaths referred to coroner
- Presumed natural - Presumed iatrogenic - Presumed unnatural
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Presumed natural death
- Not seen by a doctor in the last 14 days - Unknown cause
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Presumed iatrogenic death
- Peri/postoperative deaths - Anaesthetic deaths - Abortions - Complications of therapy
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Presumed unnatural death
- Accidents - Industrial death - Suicide - Unlawful killing - Neglect - Custody deaths
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Who carries out an autopsy?
A doctor (pathologist)
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Who can refer to autopsy
- Doctors - Registrar of BDM (statuatory duty to Refer) - Relatives - Police - Anatomical pathology technicians
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What 4 questions do coronial autopsies aim to answer?
- Who was the deceased? - when did they die? - Where did they die? - How did they come About their death?
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Steps of autopsy
- external examination - Evisceration - internal examination
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Autopsy external examination
- Identification: formal identifiers, Gender, age, body habitus, jewellery, body modifications, clothing - disease and treatment - Injuries
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Autopsy evisceration
- Y-shaped incision - Open all body cavities - Examine all organs in situ - Remove thoracic and abdominal organs - Remove brain
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Autopsy internal examination
- heart and great vessels - lungs trachea, bronchi - liver, gallbladder, pancreas - Spleen, Thymus and lymph nodes - Genitourinaty tract - endocrine organs - CNS
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Lifespan of neutrophil polymorphs
2-3 days
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Cellular sequence of acute inflammation
- injury or Infection - neutrophils arrive and phagocytose and Release enzymes - Marophages arrive and phagocytose - Either Resolution with clearance of inflammation or Progression to Chronic inflammation
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Examples of acute inflammation
- acute appendicitis - Frostbite - Streptococcal sore throat - Lobar pneumonia
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Treating inflammation
- Ice/cold - Antihistamines - aspirin/ibuprofen - Inhibit prostaglandins - corticosteroids - upregulate inhibitors of inflammation and downregulate Chemical mediators of inflammation
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What is the acute mediator of inflammation?
Histamine
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Ischaemia vs infarction
Ischaemia - reduction in blood flow Infarction - reduction in blood flow with subsequent cell death
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Endothelial damage theory for atherosclerosis
- Endothelial cells are delicate - Easily damaged By cigarette smoke, shesring forces as arterial divisions, Hyperlipidemia, glycosylation products
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When does apoptosis take place?
- Development - removal of cells during Development, eg: interdigital webs - cell turnover - removal of cells during normal turnover, eg: cells in the intestinal villi at the tips are replaces By cells from below
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Apoptosis in HIV
- can induce apoptosis in CD4 helper cells - Reduces their numbers enormously to produce an immunodeficient state
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Examples of necrosis
- infarction due to lack of blood supply - Frostbite - Toxic venom from reptiles and insects - Pancreatitis - Avascular necrosis of Bone- cuts off blood supply
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Why do we get deafer as we get older?
Hair cells in cochlea can’t divide
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Basal cell carcinoma
- the Skin only invades locally - can be cured By complete local excision
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What is adjuvant therapy?
Extra treatment given after surgical excision Eg: radiotherapy in breast cancer
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Example of chronic inflammatory process from the start
Infectous mononucleosis
