ICS Flashcards

Question

What is a risk in an advanced stage of atherosclerosis?

Answer 1

- Unstable atheroma (plaque) The fibrous cap covering the plaque may weaken or rupture. If it ruptures, exposing the plaque's contents, it will trigger platelet activation which leads to platelet aggregation at the site of the plaque disruption --> leading to the formation of clots within the arterial lumen --> impedes blood flow --> can lead to acute cardiovascular events (MI, stroke)

Answer 2

Smoking, diabetes, hypertension, obesity, hyperlipidemia increased age, males (Also risk factors for MI)

Answer 3

ENDOTHELIAL DAMAGE THEORY Endothelial cells are delicate and can be damaged by cigarette smoke (free radicals released), shearing forces at arterial divisions, hyperlipidemia (lipids taken up by macrophages, forming foam cells which lead to plaque forming) and glycosylation products (Where blood flow is turbulent or low at arterial branch points, that area is more susceptible to plaque buildup)

Answer 4

If an atherosclerotic plaque completely blocks an artery (which can be due to a rupturing of the plaque leading to the formation of a thrombus), then no blood will flow to the organ supplied by that artery and unless there is second arterial supply e.g. the brain, the organ will infarct (die).

Answer 5

- Cerebral infarction - Myocardial infarction - Emboli (when pieces of the atherosclerotic plaque break off and travel downstream to smaller vessels) --> can cause transient ischemic attacks or cerebral infarcts if in the carotid artery (carotid atheroma) - Aortic aneurysm (if atherosclerosis occurs in the aorta, it can weaken the wall of the aorta causing it to be less elastic and causing turbulent blood flow. - Gangrene (lack of blood flow and lack of oxygen to extremities can lead to necrosis)- body tissue dies (usually starts in the toes) - Intermitted claudication (muscle pain due to lack of oxygen)

Answer 6

Apoptosis --> Non inflammatory, programmed cell death Necrosis --> Inflammatory, traumatic cell death (due to injury, disease initiated, etc) Apoptosis --> Cell membrane remains intact Necrosis --> Disrupted cell membrane (loss of membrane integrity) Apoptosis --> Cell shrinks (nucleus condenses) Necrosis --> Cell swells (and bursts) Apoptosis --> Chromoatin is unaltered. Pyknosis (condensation of chromatin) and Karyorrhexis (fragmentation of the nucleus) Necrosis --> Chromatin is altered - degrades and fragments(could mutate). Pyknosis, karyorrhexis and karyolysis occurs (dissolution of cytoplasm) Apoptosis --> Energy dependent process (and therefore controlled) Necrosis --> Energy independent

Answer 7

The cell triggers a series of proteins which lead to the release of enzymes like caspases which autodigest the cell. Cascade of activated enzymes.

Answer 8

The inheritance of a trait (e.g. height, skin colour) influenced by more than one gene.

Answer 9

- Via the amount of DNA damage within the cell. p53 is a protein that can detect DNA damage and can then trigger apoptosis. - In cancer cells, there is a mutation of the p53 protein so it can no longer detect DNA damage and induce apoptosis. - In HIV, the HIV virus can induce apoptosis in CD4 helper cells which reduce their numbers, resulting in an immunodeficient state.

Answer 10

- Single stranded break - Double stranded break - Base alteration - Cross linkage (other forms of damage to cellular systems --> accumulation of toxic by-products of metabolism, telomere shortening, damage to mitochondrial DNA, free radical generation)

Answer 11

Wrinkling of the skin (dermal elastosis) - caused by UV-B light (component of sunlight) cross linking proteins, especially collagen in the dermis - can be reduced by avoiding too much sun exposure/using sun screen. Cataracts of the eye - caused by UB-B cross-linking proteins in the lens causing opacity. - Prevented by wearing sunglasses that cut out UV light. Osteoporosis in post menopausal women - loss of bone matrix is due to a significant decline in estrogen levels which help maintain bone density (increased bone resorption, decreased bone formation). - prevented by hormone replacement therapy and vitamin D supplements. Deafness - Hair cells in the cochlear do not divide. If they are damaged by high volumes, they will die and not be replaced, thus producing deadness. - Prevented by avoiding high volume sounds throughout life.

Answer 12

A distinct form of necrosis recognised by its cheese-like crumbly appearance. It is associated with granulomatous infections like tuberculosis - tissues cellular material breakdown (stain for mycobacteria).

Answer 13

Intrinsic, extrinsic and cytotoxic

Answer 14

Occurs due to internal stimuli (DNA damage, biochemical stress, lack of growth factors) - Pathway modulated by the molecules Bcl-2 (inhibits Bax) and Bax (promotes cytochrome C release) - Cytochrome C activates caspases - the executioners of apoptosis

Answer 15

Occurs due to external stimuli - Ligands bind to receptors on the cell surface Tumour necrosis factor receptor (TNFR) binds to TNF ligand. FAS receptor binds to FAS ligand --> these interactions activate caspases for apoptosis.

Answer 16

Cytotoxic T cells release granzyme B and perforin which activate caspases for apoptosis. (perforin creates pores or channels in the target's cell membrane for granzyme B to enter the cell and activate caspases)

Answer 17

Hypertrophy --> Increase in size of an organ caused by an increase in the size of its constituent cells (without an increase in number) (occurs in organs where cells cannot divide) Examples --> skeletal muscle in athletes/body builders

Answer 18

Hyperplasia --> Increase in size of an organ caused by an increase in the number of its constituent cells(via mitotic replication) occurs in organs where cells can divide. e.g. benign prostatic hyperplasia, endometrial hyperplasia (irregular thickening of uterine lining) Take note - mixed hypertrophy/hyperplasia - is an increase in the size of an organ due to increases in the size and number of its constituent cells (e.g. smooth muscle cells of the uterus during pregnancy)

Answer 19

Metaplasia - The change in cell differentiation from one fully differentiated type to another fully differentiated type e.g. Barrett's oesophagus (squamous to glandular/columnar), bronchial epithelium from ciliated columnar to squamous epithelium due to continuous cigarette smoke (Usually due to a consistent change in the environment of an epithelial surface) Dysplasia - basically ABNORMAL GROWTH/DEVELOPMENT OF CELLS - morphological changes that may be seen in cells in the progression on to development of cancer (dysplastic cells are considered pre cancerous) Metaplasia --> dysplasia --> carcinoma in situ (pre-invasive stage of cancer development - has not breached membrane) --> invasive carcinoma (malignant, it has the potential to invade and damage surrounding tissues)

Answer 20

Chronic inflammation --> metaplasia --> dysplasia --> carcinoma in situ (hasn't breached membrane) -> invasive carcinoma

Answer 21

- A decrease in the size of an organ due to a decrease in the size or number of its constituent cells via dying(or both) Main thing is a decrease in the size of an organ/tissue Example - Alzheimer's dementia (cortex becomes smaller), quadriceps muscle following knee injuries or immobilisation

Answer 22

Congenital - present at birth Inherited - caused by an inherited genetic abnormality Acquired - caused by non-genetic environmental factors

Answer 23

Hayflick limit - The limit to which a human cell can divide. There is a limit because at each cell division, the telomere region at the end of chromosomes shortens and eventually becomes so short that it is not possible for chromosomes to divide and replicate. (telomere length appears to be paternally inherited)

Answer 24

Carcinogenesis --> The transformation of normal cells into neoplastic cells (cancer cell) through permanent mutation leading to uncontrolled/abnormal growth (possibly into a tumour subsequently) Neoplasm --> The Autonomous, abnormal, persistent new growth of cells

Answer 25

Neoplastic cells + stroma. (Cancer cell) A type of nucleated cell that has undergone genetic mutations that lead to uncontrolled or abnormal growth. These cells divide and proliferate in an unregulated manner forming a mass of of cells - Tumour. They are monoclonal. (growth pattern and synthetic activity are related to parent cell) A vascular stroma which provide mechanical support and nutrition for the neoplastic cell grows based on growth factors released by the neoplastic cell. (a connective tissue framework) (They arise from NUCLEATED cells)

Answer 26

Autocrine growth stimulation - due to overexpression of growth hormone and mutation of tumour suppression genes. - very fast growth They can evade apoptosis They have telomerase - Prevents telomere shortening with each replication Sustained angiogenesis - They have their own blood supply

Answer 27

Benign - localised and non invasive - (no basement membrane invasion) Malignant - metastases and invasive - basement membrane invading Benign - Slow growing due to low mitotic activity Malignant - Fast growing due to high mitotic activity (hyperdense nucleus) Benign - Well circumscribed (or encapsulated) (restricted) Malignant - Poor circumscription (or encapsulation) (poorly defined or irregular border of the neoplasm) Benign - Exophytic - grows upward and outward from surface epithelium Malignant - Endophytic - grows inward from surface epithelium Benign - Rare ulceration (breach in mucosal surface) and necrosis Malignant- Common ulceration and necrosis Benign - Nuclear shape often normal Malignant - Hyperchromatic and pleomorphic nuclei (can take different shapes)

Answer 28

Carcinomas- Epithelial tumours. Cancer that starts in cells that make up the skin or tissue lining organs. Sarcomas - Mesenchymal tumours. Cancer of soft tissues, connective tissue or bone (invade the LUNGS commonly) Lymphoid - Cancer of the lymph system or blood cells (lymphoma and leukemia) lymphoma - malignant neoplasm of lymphoid cells. (melanoma, mesothelioma --> malignant neoplasms)

Answer 29

They are Epithelial tumours Papilloma - non glandular benign Carcinoma - non glandular malignant Adenoma - glandular benign Adenocarcinoma - glandular malignant

Answer 30

Cancer of soft tissue, connective tissue or bone - MESENCHYMAL tumours Lipoma and liposarcoma - adipocytes Rhabdomyoma (benign) and rhabdomyosarcoma (malignant)- striated muscle Leiomyoma and leiomyosarcoma - smooth muscle Chrondroma and chondrosarcoma - cartilage Osteoma and osteosarcoma - bone Angioma - Vascular/blood vessels Neuroma - Nerves

Answer 31

Cancer of the lymph system or blood cells Leukemia and lymphoma (always malignant) --> Blood disease

Answer 32

Melanoma - melanocyte malignancy (skin cancer) Mesothelioma - Cancer of the mesothelium, typically pleura of the lungs (associated with ASBESTOS - microscopic particles that can be inhaled - long term exposure can cause cancer) Both malignant

Answer 33

They are graded based on their similarity to the parent cell 1) Well differentiated (>75% cells resemble the parent) 2) 10-75% 3) Poorly differentiated (<10% cells resemble parent)

Answer 34

- agents capable of causing cancer 1) Chemicals - e.g. paints, dues, rubber, soot. (most require metabolic conversion from pro-carcinogen to ultimate carcinogens) 2) Viruses - e.g. HPV (cervical cancer), EBV (burkitt lymphoma) - causes 10-15% of cancer 3) Ionising + non-ionising radiation - UVB (or UVA) (skin cancer) - basal cell carcinoma, squamous cell carcinoma (increased risk of xeroderma pigmentosum) 4) Hormones, parasites, mycotoxins - mycotoxins can be found in food/fungi/mold (aflatoxin - hepatocellular carcinoma) 5) Abestos (fibrous minerals that are microscopic and can be inhaled)

Answer 35

1) Haematogenous - Via the bloodstream --> common in cancers that spread to the bones, lungs and liver - breast cancer. prostate cancer (Carcinomas spread to the bone via blood) 2) Lymphatic --> spread via the lymphatic vessels - they travel in lymphatic fluid to lymph nodes --> seen in breast cancer, melanoma (carcinomas spread to the lymph nodes that drain the site of the carcinoma) 3) Transcolemic --> Cancer cells spread within body cavities (e.g pleural, peritoneal) - via exudative fluid accumulation (pleural, peritoneal, pericardial effusions) - they form tumour deposits on the surface of organs and tissues --> ovarian cancer (peritoneal cavity) A direct metastases is the spread of cancer cells from a primary tumour to nearby tissues of organs. (This is without travelling through the bloodstream or lymphatic system)

Answer 36

BLT.KP Breast, lung, thyroid, kidney, prostate

Answer 37

Sarcomas - haematogenous Carcinomas - lymphatic (exceptions- follicular thyroid, RCC, HCC)

Answer 38

Tumour grading - How differentiated the tumour cell is. - well differentiated resembles its original counterpart. (well differentiated tumours have a better prognosis as they tend to grow and spread more slowly) Tumour staging - How much the tumour has spread (TNM system) T - size and extent of invasion of the main tumour N - number of nearby lymph nodes that are involved (have cancer) - extent of lymph node metastases M - whether the cancer has metastasised - extent of spread to other parts of the body

Answer 39

Lymphomas --> uses Ann Arbour Staging system (stages 1-4 and A or B) A - asymptomatic, B - presence of B symptoms 1-4 (extent of disease and degree of metastases) TNM more for solid tumours

Answer 40

- FAP (familial adenomatous polyposis) --> mutated APC (adenomatous polyposis coli) gene, can result in thousands and millions of colorectal adenomas forming - benign polyps that have potential to become cancerous - HNPCC (lynch syndrome) --> mutated MSH2 gene (DNA mismatch repair gene) Both autosomal dominant

Answer 41

Secondary prevention - method of early detection which makes management easy - Cancers screen include: Breast (mammogram), Cervical (cervical swab), Colorectal (Fecal occult) - Heel prick test done at birth is to test for sickle cell anaemia, cystic fibrosis, hypothyroidism, etc.

Answer 42

refer to phase 2a ics document

Answer 43

Dendritic cell - Antigen presenting cells that initiate the adaptive immune response. They are mesenchymal in origin and not hematopoietic.

Answer 44

Innate immunity - Neutrophils (short lived 2-3 days) and macrophages (long lived months to years) Parasites - Eosinophil Allergy - Basophil Adaptive immunity - T cells and B cells (plasma cells)

Answer 45

Primary --> Where immune cells originate, mature or develop - Bone marrow (all cells originate here including T cells) - B cells mature here - Thymus - development and maturation of T cells (thymic tolerance) Secondary --> Where immune responses are initiated and coordinated - Lymph nodes - antigen presenting cells and T/B cell interactions --> filters lymphatic fluid allowing immune cells to encounter and respond to antigens - Spleen - RBC recycling, bacteria killing - it has lymphocytes and macrophages which can respond to infections

Answer 46

A critical process that occurs in the thymus where T cells are developed to recognise and respond to foreign antigens while remaining tolerant to the body's own tissues thus preventing autoimmune reactions. (T cell selection) Positive selection - If the T cells recognise the thymus Major histocompatibility complexes (MHCs 1 and 2), then they are selected for Negative selection - If the T cells produce an immune response (by recognising self antigens as foreign, they are selected against.)

Answer 47

This is pathological and only found in sites of chronic inflammation They are specialised collections of immune cells that form in response to chronic inflammation or infection. They sustain immune responses - allowing the continual combating of chronic inflammation There are germinal centres within, where lymphocytes undergo rapid proliferation (differentiation and antibody productioin)

Answer 48

T cells that interact with MHC 1 become CD8+ cells (Cytotoxic T cells) INTRINSIC --> They function to kill T cells that interact with MHC 2 become CD4+ cells (Helper T cells) EXTRINSIC --> They promote the immune response Elaborated more in a different flash card

Answer 49

Cytotoxic T cells --> involved in eliminating target cells 1) They secrete perforin which creates pores in the target cell's membrane, allowing Granzyme B to enter and induce apoptosis. 2) They express the Fas ligand which bind to Fas receptors on the cell's surface, activating caspases which are the main executioners of apoptosis.

Answer 50

(T cells that interact with MHC 2)Helper T cells --> Promotes immune response cytokines - signalling molecules 1) T helper 1 cells secrete the cytokine Interferon-y, which activates natural killer cells and macrophages (increases innate immune response) 2) T helper 2 cells secrete the cytokine interleukin 4 (5 and 10), which activates B cells to differentiate into plasma cells (increases adaptive immune response) - they also activate eosinophils and induce b cells to make IgE to promote release of inflammatory mediatory - important in helminth (parasitic) infections and allergies. - They also help with development of cytotoxic T cells 3) T regulatory cells also referred to as CD4+ cells - Suppress immune responses (helps with preventing autoimmunity)

Answer 51

A T cell that has not encountered an antigen or has not matured

Answer 52

1) Non specific and rapid immune response with no memory involved 2) Neutrophils and macrophages are primarily involved 3) Killing occurs via the complement system: Activation of inflammation, opsonization of pathogens, phagocytosis and killing of target cells, by lysis 4) Includes physical barriers like the skin, mucus and cillia and chemical barriers like lysozyme in tears and stomach acid, saliva.

Answer 53

IgG - The most abundant - Key in SECONDARY immune response - Found in bacterial and viral infections IgA - Secreted in breast milk and mucosa - Defends mucosal surfaces - Forms dimer (effective in defending mucosal surface) IgM - The first antibody produced in response to foreign pathogens - Forms pentamer IgE - Antibody that is produced in response to allergies (type 1 hypersenstivity) IgD - Unknown function but presumably B cell activation

Answer 54

Neutrophil - 70% of all WBCs - Key mediators of acute inflammation - Act in hours - days - They express CD 66 which allows neutrophils to adhere to blood vessel walls and migrate to sites of infection. Macrophage - Clear apoptotic debris - Act in months - years --> can be circulating or resident (e.g. kupffer cells, alveolar macrophages) Eosinophil - Contain major basic protein - Often seen in parasitic infection Basophil/mast cells (resident version of basophil) - Induces type 1 hypersensitivity reaction (allergy) - Via IgE binding --> degranulation --> histamine release (promotes inflammation) Natural killer cells - Key role in viral cell killing via secretion of perforin

Answer 55

- Stimulation of helper T cell proliferation - Stimulation of B cell production and differentiation to form antibodies

Answer 56

Innate - non specific, rapid response with no memory Adaptive- specific, slow response with memory involved Innate - Neutrophils and macrophages primarily involved Adaptive - T cells and B cells are primarily involved Innate - Killing via complement system Adaptive - Killing is antibody mediated

Answer 57

Anaphylaxis - IgE mediated IgE binds to basophils and mast cells --> upon re-exposure, degranulation of mast cells --> release of histamine which causes vasodilation, bronchoconstriction and increased permeability of vascular endothelium (urticaria, angio-oedema) Timing - Immediate (within an hour) Causes an inflammatory response Example - Atopy (genetic tendency to develop allergic disease), hayfever, asthma, eczema Occurs when an individual is sensitised to a specific allergen and upon re-exposure of the allergen, IgE antibodies are produced which trigger the release of histamine

Answer 58

Antigen-antibody complex Antibody - IgM, IgG Cytotoxic response Antibody binds to the antigen (e.g. drug that is combines with a protein) --> antibodies activate the complement system. Degranulation of neutrophils (and release of their antimicrobial contents) --> oxygen radicals are released (respiratory burst) leading to the destruction of the cell. Timing - hours to days Examples - Good pastures syndrome, pernicious anemia, rheumatic fever Basically --> categorised by the binding of IgM or IgG to antigens on the surface of target cells. It triggers an immune response that results in the destruction of the cell via the complement system

Answer 59

Immune complex formation Antibody - IgG Difference between type 2 and 3 - type 2 involves antigens that are cell bound (ABO to RBC) while type 3 involves soluble antigens The antibody and antigen bind, move somewhere downstream and activate the complement system at the site of deposition. Timing - 7-21 days E.g. SLE (Systemic lupus erythematosus), farmer's lung, malt worker's lung

Answer 60

T cell mediated When antigens enter the body, it is processed by antigen presenting cells and presented to a Th1cell --> activating the T cell which releases chemokines to recruit macrophages and cytokines e.g. interferon-y to activate them Timing- Days-weeks DELAYED response e.g. tuberculosis, type 1 diabetes mellitus, MS, guillain barre syndrome.

Answer 61

- Severe hypotension - Tachycardia + dyspnoea - Pale - Cold extremities - Puffed up face + tongue - Itching - Urticaria (Hives) - Central cyanosis (lips are blue)

Answer 62

Airway - are they breathing? Are there any signs of airway obstruction? Secure the airway with intubation PRN. Breathing - any signs of respiratory distress? Wheezing? SPO2<94%? Provide oxygen if required (salbutamol can help with wheezing) Circulation - Check pulse and BP. Are they pale or cold? Provide an IV bolus PRN - start CPR if appropriate and needed. (IV bolus improves circulation by rapidly delivering a concentrated dose of a substance into the bloodstream)-- saline solution can restore fluid balance and increase blood volume (also addresses dehydration) Disability - Assess patients level of consciousness and mental state - lie patient flat to improve cerebral perfusion (may need to inject drugs to help e.g. epinephrine) A sitting position may help to make breathing easier Exposure - Look for visible signs of an allergic reaction e.g. urticaria, flushing, angioedema → remove any triggers. As soon as symptoms are recognised, administer 500mcg of IM adrenaline. Consider antihistamine (Chlorphenamine) - not for first line but for skin symptoms,

Answer 63

A safeguard mechanism to prevent the production of autoreactive cells (where autoreactive B and T cells infiltrate and attack healthy tissues and organs - producing antibodies with high affinity for self antigens) Split into Central tolerance - which occurs in primary lymphoid organs. Thymus for T cells and bone marrow for B cells (where they mature) Peripheral tolerance - occurs in secondary lymphoid organs e.g. Spleen (in the event faulty T and B cells evade central tolerance)

Answer 64

System of immune responses of an organism against its own healthy cells, tissues, organs, etc. It can either be organ specific or non organ specific.

Answer 65

- It affects a main organ e.g. 1) Type 1 diabetes mellitus - affected endocrine pancreas where beta cells producing insulin are destroyed 2) Multiple sclerosis - Oligodendrocytes which myelinate cells of the CNS are attacked 3) Graves disease - Thyroid stimulating hormone receptors are stimulated (by TSH receptor antibodies) --> causing the secretion of thyroid - Hyperthyroidism. 4) Myasthenia gravis - antibodies attack acetylcholine receptors on muscle cells (neuromuscular junction) (interferes with transmission of nerve signals to muscles thus leading to muscle weakness and and fatigue)

Answer 66

Autoimmunity having a generalised effect. E.g. Systemic lupus erythmatosus - The immune system attacks multiple organs and tissues. - In SLE, individuals produce anti-DNA antibodies which forms an immune complex with DNA molecules. These circulate and deposit in various tissues and organs, triggering inflammation, leading to tissue damage. (joint inflammation, skin rashes, etc) Also affects lungs, brain, kidney, etc.

Answer 67

Inherited (genetic) - Defects in T cells e.g. SCID- severe combined immunodeficiency (caused by adenosine deaminase deficiency, where infants lack the enzyme required for T-cell survival) Acquired- HIV (Unprotected sex, sharing injection drug equipment)

Answer 68

- In HIV, there is a decrease in helper T cells, increasing your susceptibility to diseases. (present with TB, pneumocystic pneuomonia - alveoli attacked) - B cells can be deficient - Neutrophil and macrophage deficiency (required for phagocytosis and acute inflammation) - Complement deficiency - Low C3 and C4 proteins which are required for activation of the complement cascade (innate immune killing of bacteria) --> Associated with systemic lupus erythmatosus - Hyposplenism - Lack of function of the spleen - less RBC cycling, less killing of encapsulated bacteria

Answer 69

Active - our own immune system produces immunoglobulins to protect us against a pathogen - Immunological memory - memory cells produced for long term protection - Secondary response (upon re-exposure to pathogen) Passive - The administration of PRE-FORMED immunity from one person or animal to another person - Immunoglobulin passed to host (only antibody mediated, not cell mediated) - No memory - Primary response - immediate and temporary effect - Short lived

Answer 70

Active natural - Body encounters pathogen and produces memory cells against it (after the infection) Passive natural - Maternal antibodies/immunoglobulins are passed onto feeding baby in breast milk Active artificial - Vaccine mimics encountering pathogen and stimulates immunoglobulin production Passive artificial - Antivenom (injection of immunoglobulin from another organism)

Answer 71

Enteral (via the GI tract) 1) Oral - mouth 2) Suppositories - via the rectum Paranteral (bypasses the GI tract) 3) Injection - Intramuscular - injected directly into muscle - Subcutaneous - drug injected directly under the skin - Intravenous - injected directly into bloodstream 4) Inhalation - vapour 5) Skin patches/topical - transdermal 6) Eye/ear drops

Answer 72

1) Receptors (Majority) 2) Enzymes 3) Transporters 4) Ion channels

Answer 73

Agonists - full affinity (binds well to receptor) and full efficacy (fully activates the receptor) Antagonists - full affinity and zero efficacy (inactivates the receptor) (Can competitively or non competitively inhibit receptors) (irreversible antagonist -- won't come off the receptor and will never become available for an agonist) Most common receptors are G-protein coupled receptors.

Answer 74

Efficacy- The maximum effect a drug can produce, regardless of dose (the ability of a drug receptor complex to produce a maximum functional response) Potency - How much of a drug is needed to elicit a response in the body

Answer 75

Competitive --> Potency is decreased, efficacy is not. Ligand concentration is rate limiting. Thus, an increase in agonist concentration can overcome this. Non competitive --> Both potency and efficacy is decreased. Ligand concentration is not rate limiting.

Answer 76

Non-selective beta blocker --> binds to all beta receptors (B1 and B2) - Propanolol Selective beta blocker --> binds to a specific beta receptor (B1) - Atenolol, bisoprolol Non-selective beta agonist --> B1, B2 - Epinerphrine, isoprenaline (so efficacy and potency for B2 and B1 will be similar) Selective beta agonist (B2) - Salbutamol (Efficacy is similar but potency for B2 receptors is higher then B1)

Answer 77

COX-1 - Important function in producing prostaglandins which protect the stomach lining. (it is also important in blood clotting pathways - production of thromboxane A2) NSAIDS - inhibit COX-1 and COX-2, decreasing prostaglandins production. Inhibiting COX-1--> decreased prostaglandins-->decreasing gastric mucosal protection, decreasing stomach pH resulting in gastric ulcers (and risk gastrointestinal bleeds). Inhibiting COX-2 --> Decreased prostaglandins --> has an anti-inflammatory effect (basically both COX-1 and 2 are responsible for producing prostaglandins but for different things) ACE inhibitors -- inhibit the conversion of angiotensin 1 to angiotensin 2 --> results in an antihypertensive response, reduced aldosterone, hyperkalemia (as principal cells no longer secrete as much potassium)

Answer 78

Proton pump inhibitors e.g omeprazole --> irreversibly inhibits H+ K+ ATPase pumps (decreasing gastric pH) Diuretics (reduces fluid buildup by promoting the excretion of NaCl and water) - Loop diuretics act on the symporter in the ascending loop of henle to inhibit the reabsorption of sodium, chloride and potassium (NKCC2) e.g. furosemide - Thiazide diuretics inhibit the sodium chloride cotransporter in the DCT (increasing excretion of sodium and potassium) Spironolactone diuretics - Aldosterone receptor antagonist. A potassium sparing diuretic which acts on ENaC channels of the collecting duct, causing the excretion of sodium and water.

Answer 79

Calcium channel blockers (muscle + glial cells)- cause vasodilation and decreased contractility. It slows the heart rate - amlodipine. Local anaesthesia - e.g. Lidocaine blocks Na+ voltage gated channels in nerve cells, preventing the propagation of nerve impulses. Potassium channel blockers - e.g. Repaglinide, nateglinide lower blood glucose levels by blocking potassium channels to stimulate insulin secretion. --> Type 2 diabetes treatment

Answer 80

The fate of a chemical substance administered to a living organism ((It examines how drugs are absorbed, distributed, metabolised and excreted in the body. ))(what the body does to the drug) (Pharmacodynamics - what the drug does to the body)

Answer 81

1) Manufacture (synthesis) 2) Storage (in vesicles) 3) Release 4) Receptor activation and breakdown of neurotransmitter 5) Reuptake

Answer 82

Botox - Acetylcholine release is inhibited which can lead to paralysis Acetylcholinesterase inhibitors - Inhibits the enzyme acetylcholinesterase from breaking down acetylcholine, increasing the level and duration of cholinergic stimulation. (can result in cholinergic crisis)

Answer 83

It happens when there is an increased level and duration of cholinergic stimulation (due to inhibition of acetylcholinesterase enzyme) - basically has an agonist effect. (antagonist effect with TCA drugs will have opposite effect of sludge) SLUDGE Salivation Lacrimation Urination Defecation GI distress Emesis (vomiting) ------ These are all due to excessive parasympathetic nervous stimulation. Can also lead to severe muscle weakness, paralysis and respiratory distress. TREAT WITH ATROPINE (as it crosses BBB can cause delirium, confusion and hallucination)

Answer 84

Regenerate - Hepatocytes, pneumocytes, skin epithelium (blood cells, osteocytes) Cannot regenerate - Myocardial cells, neurones.

Answer 85

Kupffer cells, alveolar macrophages, osteoclasts, microglia.

Answer 86

(Sepsis occurs when inflammation spreads through your entire body) During inflammation, precapillary sphincters relax which allows for increased blood flow to the site of injury/infection. During sepsis, BP decreases as blood volume is the same while area for blood flow increases (when all the pre capillary sphincters open)

Answer 87

Sepsis is caused by the body's extreme response to infection. It leads to widespread inflammation, causing widespread vasodilation. Endothelial cells also become more porous, allowing fluid and proteins to leak from the bloodstream to surrounding tissues --> thus decrease in blood volume.

Answer 88

Brain, liver, lungs

Answer 89

Helicobacter.Pylori

Answer 90

Parasympathetic - Rest and digest - Pupil constricts - Bronchoconstriction - Increased GI motility and secretion - Bladder contraction (detrusor muscle) - Penis erect - Decreased heart rate Sympathetic - Fight or flight - Pupil dilates - Bronchodilation - Decreased GI motility and secretion - Detrusor relaxes - Penis shoots (ejaculation) - Increased heart rate

Answer 91

Tyrosine --> DOPA --> Dopamine --> Noradrenaline --> Adrenaline

Answer 92

Alpha 1 - Blood vessels and sphincter --> vasoconstriction, bladder contraction and pupil dilation (alpha 2 - negative feedback - suppresses noradrenaline (catecholamine) release)- slows heart rate Beta 1 - Heart. --> Agonism increases inotropy (force of contraction of the heart) and increases BP and renin release. Beta 2 - Lungs. --> Agonism causes bronchodilation (e.g. SABAs and LABAs)

Answer 93

Dopamine agonist (e.g. bromocriptine) --> used in prolactinoma, acromegaly and early parkinson's Dopamine antagonist (e.g. metoclopraminde, antiemetics) --> used for nausea and vomiting. Haloperidol --> used for psychiatric disorders Dopamine receptors are mostly found in the nucleus accumbens in the brain.

Answer 94

- It is the main inhibitory neurotransmitter. (reduces neuronal excitability) e.g. Benzodiazepines - lorazepam, diazepam --> used for anxiety, sleep disorders, alcohol withdrawal, epileptics

Answer 95

Acute - less than 3 months (nociceptive pain - caused by damage to body tissues) Chronic - more than 3 months Cancer Neuropathic (nerve pain - damage to nerves)

Answer 96

(They are the first order neurons that synapse with second order neurons in the dorsal grey horn) Both carry pain, temperature, touch and pressure information A - thinly myelinated C - Unmyelinated A - larger (1.5mm) C - Smaller (0.2-1.5mm) A- Associated with sharp well localised pain that first occurs C- Associated with lingering, poorly localised sensation that follows the first quick sensation of pain A - Faster conduction speed (5-40m/s) C - Slower conduction speed (0.5-2m/s)

Answer 97

1) Gate control theory - By rubbing the painful site, the non-noxious A beta fibres (activated by light touch, pressure) are activated which inhibit the A delta or C fibres causing pain. 2) Periaqueductal grey - descending pain pathway - When the PAG receives pain signals from the brain, it sends it to the locus coeruleus which releases noradrenaline throughout the CNS --> reducing the perception of pain. - Noradrenaline can bind to alpha 2 adrenergic receptors on presynaptic nerve cells to inhibit the release of neurotransmitters like substance P or can hyperpolarise the postsynaptic membrane, thus reducing the transmission of pain signals. 3) Medication - NSAIDS - Opioids/analgesics - Local anaesthesia

Answer 98

First step - Mild pain --> Non-opioid analgesic with or without adjuvant therapy Second step - mild to moderate pain --> Weak opioids (hydrocodone, codeine, tramadol) with/without non opioids, with/without adjuvant therapy Third step - Moderate to severe pain --> Strong opioid (morphine, oxycodone), with/without non-opioid analgesics, with/without adjuvant therapy Mild - Paracetamol, ibuprofen Moderate - Naproxen, tramadol Severe - Morphine

Answer 99

- All adverse drug reactions should be reported by MHRA yellow card scheme. (ALL ADRs should be reported for black triangle medicines) Type ABCDEFG Type A- Augmented - Most common type of ADR (80%), predictable (COMMON IN CLINICAL TRIALS) - Dose dependent (too much of the drug) and reversible upon withdrawing drug (e.g. Bradycardia with beta blockers) Bizarre - - Are there any odd responses? Unpredictable? - Not dose dependent (Anaphylaxis with penicillins, bleeding with anticoagulants) Chronic - - ADRs that continue after the drug has been stopped - Related to cumulative dose. (Heart failure with pioglitazone) Delayed - ADRs that becomes apparent some time after use of the drug. (Has the patient used the drug in the past that could be an issue now?) (Leucopenia with chemotherapy) End of use - (withdrawal) --> - ADR develops after the drug has been stopped - Is the patient withdrawing from the drug? (Insomnia after stopping benzodiazepine） Failure of treatment - Unexpected treatment failure (due to drug-drug interaction or drug-food interactions) - Poor compliance with administration instructions (Failure of DOAC due to enzyme inducers like carbamazepine) Genetic - Drug causes irreversible damage to genome (Phocomelia in children of women taking thalidomide)

Answer 100

Absorption The transfer of a drug from the site of administration to the systemic circulation Route of administration (IV is 100% bioavailability) Absorption is affected by acidity (which can affect drug ionisation), motility e.g. GI motility and the solubility of drugs Distribution How the drug is distributed in the plasma according to its chemical properties (hydrophilicity) and size. Are they able to cross the blood brain barrier? Affected by protein binding - higher protein binding means longer duration of action but reduced distribution. Metabolism The chemical transformation of the drug e.g. by CYP 450 in the liver. \ Increased metabolism of the drug means that more will be excreted and less will enter systemic circulation Excretion Increased hydrophilicity allows excretion via urine and faeces Acids are cleared faster if urine is weakly basic and vice versa

Answer 101

Opioids act on receptors in the CNS (GI tract and respiratory centres also) - to inhibit the transmission of pain signals Naturally occurring - Morphine, codeine Modified - diamorphine (heroin) Take note diamorphine is 2x more potent than morphine Side effects: Addiction, GI (constipation, nausea, vomiting), Respiratory distress (can reduce the brain's sensitivity to CO2 levels causing respiratory distress), immune suppression 50% of oral morphine is metabolised by first pass metabolism in the liver. 10mg orally is equivalent to 5mg parenterally so make sure to halve dose if giving parenterally

Answer 102

Tolerance - There is a reduction in agonist effect over time (slow process) -- develops with continuous, repeated exposure to high concentrations of a substance. (body becomes less responsive to the drug --> you need a higher dose to achieve the same effect) Desensitisation - a rapid short term process where the receptor becomes less responsive to a stimulus. Due to uncoupled receptors, internalised receptors (which are engulfed into endosomes), degradation of receptors Dependence - Psychological state of craving euphoria

Answer 103

Antiplatelets (Inhibit platelet activation and aggregation) - Aspirin - COX1 inhibition --> reduced thromboxane A2 production --> decreased platelet activation and aggregation --> reduced risk of clots forming. - Clopidogrel - irreversibly binds to P2Y12 receptors, preventing ADP from binding to platelets --> reduced platelet activation and aggregation Anticoagulants (interferes with coagulation cascade) - Heparin - enhances activity of antithrombin 3 --> inhibits clotting factors 2 (thrombin) and 10 --> reduced clotting ability Warfarin --> Antivitamin K (inhibits vitamin K epoxide reductase which activates vitamin K) --> reduces the production of vitamin K dependent clotting factors --> reduced clotting ability (so you give vitamin K to people on warfarin who bleed excessively) Direct oral anticoagulants (DOAC) - rivaroxaban, apixaban - inhibits factor 10a --> reducing clotting ability - especially used in DVT and PE Thrombolytics - e.g. Alteplase - tissue plasminogen activator with activates and converts plasminogen to plasmin that breaks down fibrin, dissolving the clot and restoring blood flow. (used in acute MI and ischemic strokes)

Answer 104

NSAIDS - gastric ulcers, gastric bleeding ACE inhibitors - dry cough (due to accumulation of bradykinin), low BP, (they dilate blood vessels which can decrease blood flow to the kidney, resulting in acute kidney injury). PPI - can increase risk of fractures (interferes with bone remodelling) Loop diuretics and thiazides - Hypokalemia and dehydration Spironolactone - hyperkalemia

Answer 105

CUSHINGOIND MAP Cataract, Ulcer, striae (abdominal), hypertension, increased infection risk, necrosis of bone, growth restriction, osteoporosis, myopathy, pancreatitis.

Answer 106

A basal cell carcinoma of the skin only invades locally (it does not spread to other parts of the body) - You treat it with complete local excision

Answer 107

- Shortness of breath - Fatigue - Muscle weakness - Night sweats - Fever - Weight loss - Spleen enlargement

Answer 108

First need to confirm the diagnoses of breast cancer. Has it spread to the axilla? If yes - Axillary lymph node clearance is needed If no - has it spread to the rest of the body? If yes - systemic chemo therapy needed If no - surgery with or without axillary lymph node clearance. Take note that even if a tumour is completely excised, micro metastases may be present. Adjuvant therapy can be used (extra treatment after surgical excision- chemotherapy (good for fast dividing tumours - lymphoma, leukemia, but not slow dividing), radiotherapy, hormone therapy - adjuvant anti-oestrogen therapy - Tamoxifen... Herceptin given for HER2 protein treatment) You do a mastectomy (removal of entire breast) if the tumour is large, you do a lumpectomy (surgical removal of cancerous tumour and a margin of surrounding tissue but preserving as much breast as possible) if the tumour is small. (also even if excised, it may have spread to other parts of the body already)

Answer 109

The transformation of normal cells to neoplastic cells through permanent genetic alterations or mutations. Take note: Oncogenesis is tumour causing.

Answer 110

Most chemical carcinogens require metabolic conversion from pro-carcinogen to ultimate carcinogens. (depending on where these enzymes are, the carcinogens can be spread?) Polycyclic aromatic hydrocarbons - Lung cancer (smoking) and skin cancer (mineral oils) Aromatic amines - bladder cancer (rubber/dye workers) Nitrosamines - Gut cancer (processed meat) Alkylating agents - leukemia (chemotherapy)

Answer 111

DNA Viruses Hepatitis B virus (HBV) - Hepatocellular carcinoma Human papillomavirus (HPV) - Squamous cell carcinomas of the (CAPN'H) - Cervix, anus, penis, neck and head Epstein Barr virus (EBV) - Burkitt lymphoma (uncontrolled growth of B cells)- nasopharyngeal carcinoma Human herpes virus 8 - kaposi sarcoma (most well known) - Vascular endothelial malignancy (GI tract) Merkle cell polyomavirus - merkle cell carcinoma RNA Virus Hepatitis C virus (HCV) - Hepatocellular carcinoma Human T-lymphotrophic virus = Adult T-cell leukemia

Answer 112

Hormones - Increased estrogen - endometrial/mammary (breast) cancer + nasopharyngeal carcinoma - Anabolic steroids - hepatocellular carcinoma Mycotoxins (toxins produced by moulds/fungi) - Aflatoxin B1 --> hepatocellular carcinoma Parasites - Schistosoma - bladder cancer (from infested water) - Clonorchis sinensis - cholangiocarcinoma - bile duct cancer(from raw fish)

Answer 113

Cervical lymph nodes in the neck --> drain lymph from the head and neck Axillary lymph nodes in the armpits --> drain lymph from the upper limb, breast and trunk above umbilicus Inguinal lymph nodes in the groin area --> drain lymph from the lower extremity, genitals, (dorsal perineum)

Answer 114

- Ethnicity (increased oral cancer in india) - Diet (excess alcohol, obesity can increase risk of breast and colon cancer) - exercise can reduce risk of colon and breast cancer - Constitutional factors : age, gender (incidence increases with age) --> you can inherit familial polyposis coli (chromosome 5) or familial adenomatous polyposis - Premalignant lesions (e.g. colonic polyps, ulcerative colitis, undescended testis) - Transplacental exposure (e.g. diethylstilboestrol can increase vaginal cancer) (unprotected sex can increase risk of HPV related cancer (cervis, penis, oropharyngeal)

Answer 115

(most commonly caused by epstein-barr virus) - Also known as Glandular fever. Symptoms - Swollen lymph nodes in neck and armpits, fatigue, fever, sore throat, swollen liver or spleen.

Answer 116

Alcohol - Mouth, oesophagus, liver, colon and breast Obesity - breast, oesophagus and colon Unprotected sex - Cervix, penis, oropharyngeal

Answer 117

A LESION resulting from the autonomous abnormal growth of cells that persist after the initiating stimulus has been removed. Neoplasia - the autonomous, abnormal, persistent new growth of cells. (A new growth) (25% of the population develops neoplasms)

Answer 118

The formation of a cancer where normal cells are transformed to cancer cells. Normal colon --> DNA methylation and APC gene mutations --> Adenoma --> further mutation --> carcinoma Normal lung --> (Chronic lung injury) cells get injured --> cells become atypical - atypical adenomatous hyperplasia --> carcinoma in situ --> invasive carcinoma (progressive accumulating of DNA damage)

Answer 119

Proto-oncogenes - genes which promote cell growth and survival, promoting carcinogenesis e.g. myc. Tumour suppressor gene - genes which inhibit cell growth and proliferation, playing a role in inhibiting carcinogenesis. e.g. BRCA, P53

Answer 120

Chance - sporadic genetic mutations Hereditary - inherited genetic mutations (lynch syndrome, xeroderma pigmentosa) Environment - environmental exposures and toxins (smoking, radiation, asbestos) Micro-organism - oncogenic virus, bacteria, epstein barr virus, human papilloma virus, H pylori.

Answer 121

aPTT- (Partial thrombin time) - Measures how long it takes your blood to form a clot. - in intrinsic pathway PT- (prothrombin time) Measures how long it takes your blood to clot in the extrinsic pathway. TT- (thrombin time) Measures the time it takes for a fibrin clot to form in the plasma. INR- international normalised ratio - used to measure the dose of oral anticogulant medication given, most commonly warfarin. --> the ratio of a patients PT compared with a control.

Answer 122

Proteins C and S produced by the liver. (Protein S is a cofactor of protein C) - They inactivate factors 5 and 8 (protein C is activated when thrombin is bound to endothelial proteins like thrombomodulin) Antithrombin 3 - anticoagulant - inhibits action of thrombin and some other clotting factors. Antiplasmin - protein inhibiting the activity of plasmin (antiplasmin maintains the stability of clots once they are formed) Nitric oxide and prevents platelets from adhering Prostacyclin decreases thromboxane A2 which in turn prevent platelets from adhering.

Answer 123

The paradoxical combination of haemorrhage and thrombosis. Caused by - infection - neoplasm - major trauma e.g. burns - liver disease Uncontrolled activation of clotting factors and the coagulation cascade --> widespread clotting --> body uses up platelets/fibrin/clotting factors --> haemorrhage From excessive clotting (ischemia, impaired organ perfuion, end-organ damage). --> to excess bleeding (shock, hypotension, increased vascular permeability). 2

Answer 124

Carcinoma in situ - (first mutations produce cancer celles) The tumour/abnormal cells have not breached the basement membrane -- if you excise it at this stage, there is no where for the carcinoma to spread. Micro-invasive carcinoma - A tumour that can metastasise to other parts of the body but low chance. e.g.Cervical Invasive carcinoma - Spreads further than micro-invasive carcinomas, they breach the basement membrane into the extracellular matrix. e.g. invasive ductal breast carcinoma.

Answer 125

5 step process 1) The tumour breaches the basement membrane (requires enzymes e.g. proteases and cell mobility) 2) Intravasation - Migration into vessels (usually lymphatic vessels and venules - small thin walled vessels) --> requires collagenase 3) Survival in the circulating system - due to lymphocytes an immune response will be triggered --> tumour cells A) Aggregate with platelets B)Shed surface antigens which lymphocytes pickup or C) Adhere to other tumour cells to resist the immune response 4) Extravasation - (exit of circulating tumour cells) --> Can be done via collagenase or adhesion receptors (allow for rolling and margination of tumour cells and eventual emmigration and diapedesis) into normal tissue adhering allows them to resist blood flow and exit the blood stream 5) Growth at metastatic site - via growth factors (the tumour cells produce) Where tumour cells grow bigger than 1-2mm, they need their own blood supply. Tumour cells produce angiogenesis promoters e.g. vascular endothelial growth factor.

Answer 126

Tumour has invaded venule --> Vena cava --> to the heart --> via pulmonary artery to the lungs --> could result in an embolism in a capillary in the lungs (common site for metastases) --> can also invade the pulmonary venules after growing too big and invade the left side of the heart. Tumours of the gut such as from the colon, stomach, pancreas and intestine can spread to the liver via the portal venous system. (which can spread to the lungs via inferior vena cava)

Answer 127

1) Monoclonal antibodies - Blocks receptor for growth factor. They block signalling pathways that promote cancer cell growth. -- competitive inhibition (But if there is a mutation so that the receptor is always switched on regardless of binding of growth factor, then monoclonal antibodies won't help - use small molecular inhibitors) e.g. Cetuximab, herceptin (inhibit tyrosine kinase activity?) 2) Small molecular inhibitors - There is no activation of the receptor as the intracytoplasmic domain is blocked. (They bind to the inside of growth factor receptors.) e.g Gleevec

Answer 128

A benign mass of organised tissue native to a particular anatomical location e.g. typically found in the lungs, breast, colon. Growth is related to overall body growth.

Answer 129

Anaplastic thyroid cancer Anaplastic - Where cell type of origin cannot be determined (degree of differentiation can't be determined)

Answer 130

Males - Lung (commonest), prostate, bowel Females - Lung, breast, bowel

Answer 131

A malignant epithelial neoplasm

Answer 132

- Pressure on adjacent structures can cause pressure necrosis - If they grow into the lumen of a structure, it can obstruct flow - They can produce hormones - e.g. benign tumour in thyroid gland can cause hyperthyroidism - They can transform into a malignant neoplasm - They can cause anxiety

Answer 133

- Destruction of adjacent tissues - Metastases - Blood loss from ulcers - Obstruct flow - Produce hormones - Paraneoplastic effects /syndromes - disorders that occur when the immune system has a reaction to a neoplasm e.g lung cancer can cause finger clubbing, small cell lung cancer can cause SIADH (inappropriate ADH secretion) - Anxiety and pain

Answer 134

- Growth self sufficiency - Evade apoptosis - Ignore anti-proliferative signals - Limitless replication potential - Sustained angiogenesis - Invades tissues - Escape immune surveillance

Answer 135

Spontaneous regression: melanoma, lymphoma Regression of metastases after removal of primary tumour Infiltration of tumours by lymphocytes and macrophages Higher incidence of cancer after immunosuppression, immunodeficiency. (AIDS)

Answer 136

Dual function - Immunosurveilance and immunoediting. Immunosurveillance - The immune system's continuous monitoring and recognition of abnormal or transformed cells (pre-cancerous and cancerous) which could develop into tumours. Immunoediting- Immune responses can change tumours to be hidden from recognition by the immune system (tumour escape) and tumours can promote immune supression (immune evasion). (So while the immune system protects the body from cancer, it can also drive the development of tumours- helping them to adapt) Three stages of immunoediting: - Elimination - cancer cell immunosurveillance - T kymphocytes identify and eliminate tumour cells - Equilibrium - a phase of tumour dormancy where tumour cells and immunity enter into an equilibrium, keeping tumour expansion in check. - Escape - the final outgrowth of tumours that have overcome immunological restraints of the equilibrium phase. They are capable of spreading.

Answer 137

- Hypoxia is a prominent feature of malignant tumours - When the blood supply is unable to keep up with the growing tumour cells, hypoxic tumour cells can adapt to low oxygen. Tumour hypoxia is a poor patient prognosis - It stimulates new vessel growth - Suppresses immune system - Resistant to radio and chemotherapy - Increased tumour hypoxia after therapy

Answer 138

Whole-killed - uses the killed version of the germ that causes the disease (killed via chemicals or heat). The organism must be grown in vitro (which could be expensive) - Usually need 2 shots (booster shots) e.g. Influenza, polio, hepatitis A

Answer 139

Whole-killed (inactivated), toxoid and live attenuated.

Answer 140

- Uses a weakened form of the pathogen that causes the disease (weakened via multiple mutations) - Better immune response so lower doses are required - Route of administration may be more favourable (oral) - Fewer doses are required to provide protection However - Impossible to balance attenuation and immunogenicity - Possibility of the pathogen reverting to its virulent form (can cause the disease) - Transmissibility - Can be passed to non-vaccinated individuals. - May not be safe for immunocompromised individuals. (people with weakened immune system) E.g. Measles, mumps, rubella, smallpox, chickenpox (Organisms replicate within the host and induce and immune response which is protecting against the wild-type organism but does not cause the disease) So attenuation means - an organism is cultured in such a way it does not cause disease when inoculated in humans.

Answer 141

Toxoid vaccines use an inactivated toxin made by the germ that causes a disease. (immune response is targeted to the toxin instead of the whole germ) e.g. DIPHTHERIA and TETANUS

Answer 142

These vaccines are genetically engineered (using specific parts) of bacteria, yeast, insect or mammalian cells) - Avoids the problem of needing to grow the pathogen in vitro. - However it is difficult to find a protein that is protective and can generate a strong enough immune response. - e.g. Hepatitis B, HPV, SARS-Co-V2

Answer 143

Recombinant DNA technology to insert the genetic code of the spike protein into the host cell is used to produce large quantities of the spike protein which is combined with an adjuvant (to enhance immune response) --> the injected spike proteins are engulfed by APCs and broken down into peptides which are presented on the cell surface by major histocompatibility complex to elicit an immune response (activation of T and B cells) e.g. Novavax, hepatitis B, HPV

Answer 144

An adenovirus (common virus with mild respiratory infections) is genetically altered to be non-replicating and to carry the synthesised spike protein gene (Complementary DNA). When injected, the adenovirus vector enters host cells and release the modified genetic material. The viral DNA is transcribed and translated by the cell's machinery to produce spike proteins. Some spike proteins are broken down and presented as peptides on the cell surface by MHCs which activate T cells. T helper cells activate B cells for antibody production and cytotoxic T cells for the destruction of infected cells, while memory B and T cells contribute to a swift and potent immune response upon re-exposure to SARS-CoV-2, preventing viral binding and facilitating destruction. e.g. Oxford AstraZeneca Pro - Effective in delivering therapeutic genes into target cells Con - Pre-existing immunity in individuals due to previous exposure to the virus being used as a vector can limit the effectiveness of the therapy.

Answer 145

mRNA of the target foreign protein is synthesised in vitro (from a DNA template). It is complexed with lipid nanoparticles that stabilise and protect the mRNA from degradation and allows the mRNA to cross the plasma membrane. The mRNA is translated in the cytoplasm and the protein is presented on the surface of the cell with MHC, stimulating the immune response. - Avoids the need to grow the pathogen or viral vector - No live organism involved - mRNA is relatively cheap to produce Con - Requires extremely cold storage conditions e.g. Pfizer, moderna

Answer 146

Diphtheria, tetanus, pertussis, polio, haemophilus influenzae type b (Hib) and hepatitis B) - One injection, Meningococcal B - One injection Rotavirus - One oral application

Answer 147

A vaccine which links polysaccharide antigens from a bacteria (bacteria capsule) to a carrier protein which elicits an immune response when injected. (not sure if this is true but the polysaccharide antigens would be weaker antigen compared to the carrier protein- stronger antigen so the immune system has a stronger response to the weaker antigen) e.g. Haemophilus influenzae type b

Answer 148

55% plasma (water, electrolytes, proteins, lipids, sugars) <1% Leukocytes (WBC) 45% erythrocytes, platelets Serum is plasma without fibrinogen and clotting factors.

Answer 149

Polymorphonuclear - Neutrophil, eosinophil, basophil Mononuclear - Monocyte, T cell and B cell

Answer 150

Complement - A group of 20 serum proteins secreted by the liver that needs to be activated to be functional. (they circulate in inactive forms) Antibodies - which bind specifically to antigens (immunoglobulins - 5 distinct classes) Cytokines - proteins secreted by immune and non-immune cells (e.g. interferon, interleukin

Answer 151

A group of 20 serum proteins secreted by the liver. They need to be activated to be functional. 1) Direct lysis 2) Attract more leukocytes to site of infection (chemoattract) 3) Coat invading organisms (opsonisation)

Answer 152

Interferon alpha and beta - produced by virus infected cells and interferon gamma -produced by activated T helper 1 cells --> Induce an antiviral state in cells =activate natural killer cells, stimulate dendritic cells Interleukin - Can be pro-inflammatory (IL1) or anti-inflammatory (IL10) - IL4 secreted by T helper 2 cells can activate B cells to differentiate into plasma cells (has anti inflammatory properties) Colony stimulating factors - Involved in directing the division and differentiation of stem cells in the bone marrow (into leukocytes) Tumour necrosis factors - alpha and beta - Mediates inflammation - Mediates cytotoxic reactions (can induce apoptosis - alpha) Chemokines - - Leukocyte chemoattractants (determine the movement and positioning of immune cells to ensure effective and targeted immune response)

Answer 153

- Coagulation - stop bleeding - Acute inflammation - Leukocyte recruitment - Kill pathogens, neutralise toxins, limit pathogen spread - Clear pathogens/dead cells via phagocytosis) - Proliferation of cells to repair damage - Remove blood clot (remodel extracellular matrix) - Re-establish normal structure and function of tissue

Answer 154

A series of reactions that brings cells and molecules of the immune system to sites of infection or damage.

Answer 155

Lyse microbes directly - MAC (Membrane attack complex - final step of complement cascade) Chemotaxis - C3a and C5a (IMPORTANT) Opsonisation - C3b (inserts itself into the membrane of bacteria) - IMPORTANT

Answer 156

Fab regions (the two outgoing portions in a Y) -- ANTIGEN RECOGNITION - Variable in sequence - Bind different antigens specifically (antigen binding sites) Fc region (the single bottom port of the letter Y) - ANTIGEN ELIMINATION - Constant in sequence - Binds to complement Fc receptors on phagocytes, NK cells

Answer 157

(FC region) Heavy chain - constant region - Bind to immune cells (Phagocytes, NKC) (Fab region has both types) Light chain and heavy chain- variable region - Has antigen binding sites

Answer 158

25 kD - light chain (kappa and lambda) 50 kD - heavy chain

Answer 159

Fab (antigen recognition) - specific binding - Neutralise e.g. toxins (IgG and IgA) - Immobilise motile microbes (IgM) - Prevent binding to and infection of host cell Fc (antigen elimination) - enhance innate mechanisms - Activate complement system (IgM, IgG) - Phagocytes can bind to Fc receptors (IgG and IgA) - increase opsonisation and enhance phagocytosis - Mast cells can bind to Fc receptors (IgE) - release of inflammatory mediators - NK cells can bind to Fc receptors (IgG) - enhanced killing of infected cells

Answer 160

B cells - Soluble, free, native antigens T cells - cell associated, processed antigens

Answer 161

- They are encoded by the major histocompatibility gene complex on chromosome 6 (cluster of genes) - They are important in graft rejection (as they play a role in the recognition of foreign tissues- mismatched MHC molecules between donor and recipient can trigger an immune response) - They are highly polymorphic (diversity of alleles allowing the recognition of a wide range of pathogens) - Also known as HLA (human leukocyte anitgen) - They play a crucial role in presenting antigens to T cells and initiating T cell responses.

Answer 162

1) In a virus infected cell --> viral proteins are broken down in the cytosol --> in the endoplasmic reticulum, peptides bind to MHC1 molecules --> it is transported to cell surface --> Cytotoxic T cells recognise the peptide bound to MHC1 and are activated to kill the infected cell by inducing apoptosis 2) Macrophages/dendritic cells/B cells internalise foreign material and transported to endosomes--> within endosomes, the antigens are broken down to peptides and the peptide fragments bind to MHC2 molecules which are transported to the cell surface --> helper t cells recognises the peptide bound to MHC2 and are activated --> helps B cells make antibody, produce cytokines that activate/regulate other leucocytes.

Answer 163

IL1 - Macrophages, endothelial and epithelial cells --> induces inflammation, fever, activates leukocytes IL2 - T cells - Stimulates T, B and NK cell growth IL4 - T helper 2 cell, mast cell - - Differentiates naive T cells into T helper 2 cell - Stimulates B cell proliferation and differentiation to plasma cells - antibody production - Induces IgE production IL8 - induces neutrophil chemotaxis (slight macrophages chemotaxis also) IL10 - monocytes, TH2 cells --> - down regulates TH1 cytokines - Anti inflammatory Interferon gamma - TH1 cells, NK cells --> activated macrophages and NK cells, increases MHC2 expression Tumour necrosis factor alpha - t cells, macrophages, NK cells --> activates neutrophils, can induce apoptosis, can induce cachexia (wasting - loss of muscle and body fat)

Answer 164

TH1 - Interferon gamma, IL2, TNF-beta TH2 - Interleukin 4,5,6,10 and 13 TREG - Interleukin 10, transforming growth factor beta.

Answer 165

Type 1 hypersensitivity - an immediate reaction to environmental antigens mediated by IgE Atopy - an inherited trait for type 1 hypersensitivity Allergens - antigens that trigger allergic reactions

Answer 166

Chemokines - group of proteins that direct movement of leukocytes (and other cells) from the bloodstream into tissues or lymph organs (by binding to specific receptors on cells) CXCL - mainly neutrophils CCL - Monocytes, lymphocytes, eosinophils, basophils CX3CL - Mainly T lymphocytes and NKC XCL - mainly T lymphocytes

Answer 167

They are proteins of the innate immune system which play a role in recognising molecular patterns associated with pathogens. These include pathogen associated molecular patterns (PAMPS) and damage associated molecular patterns (DAMPS)- released during tissue damage or stress. PRRs are expressed in cells such as dendritic cells, macrophages, monocytes and neutrophils. Upon binding to a specific ligand they initiate signalling cascades that lead to immune responses (inflammatory pathways, production of antibodies, recruitment of immune cells)

Answer 168

Pathogen associated molecular patterns --> - Bacterial carbohydrates (Mannose) - Nucleic acid (bacterial DNA) - Bacterial peptides (flagellin, microtubules, peptidoglycan) Above no need to know in depth. Membrane bound PRRs - Toll like receptors - C type lectin receptors (recognise particularly mannose) Cytoplasmic sensor PRRs - Nod like receptors (- detects microbial infections or cellular stress - upon activation, they lead to the release of pro-inflammatory cytokines (interleukin-1) - RIG-I-like receptors (primarily involved in detecting viral RNA. When activated, they trigger signalling pathways that lead to the production of interferons and other antiviral molecules)

Answer 169

2- Peptidoglycans in gram positive bacteria (components of the cell wall of gram positive bacteria) 4- Lipopolysaccharides (components of outer membrane of gram negative bacteria) 5- Flagellin (for bacterial motility) 7 - Single stranded RNA from bacteria 9 - Non-methylated DNA Intracellular - 3,7,8,9 Extracellular- 4 and 5

Answer 170

Classical - Antibodies bind to antigens via FAB portion (antigen-antibody complex) --> (complement protein binds to fc portion of the antibodies --> triggers complement cascade (MAC-lysis, chemotaxis via inflammation, opsonisation which enhances phagocytosis) Alternative - Complement protein C3b can bind directly to the antigen (of microbe) --> complement cascade Lectin pathway - mannose-binding lectin to mannose (on the surface of bacteria --> complement cascade All 3 pathways converge at the level of C3 activation, leading to the formation of the membrane attack complex (lyse microbes directly)- final stage of complement cascade

Answer 171

Oxygen dependent - Superoxides are converted to H2O2 then free radicals which can kill the microbes. - Nitric oxide can also kill microbes directly or can result in vasodilation which increases extravasation of neutrophils Oxygen independent - (Enzymes) e.g. lysozyme. Proteins e.g. defensins and TNF. pH

Answer 172

MHC 1 --> Human leukocyte antigen (HLA) - A, B and C - Found on the surface of all nucleated cells (relevant to graft rejection) MHC2 --> coded by HLA DP, DQ and DR - Primarily found on the surface of antigen presenting cells (dendritic cells, macrophages, B cells)

Answer 173

Recognition - T cells bind to specific antigens presented by MHC on the surface of APC. (MHC1 - cytotoxic , MHC2 - helper) Division - Activated T cells undergo CLONAL EXPANSION - proliferation of T cells. Differentiation - Helper T cells can differentiate into TH1 or TH2 cells - Cytotoxic T cells --> effector cytotoxic T lymphocytes DIFFERENTIATION IS INFLUENCED BY CYTOKINES Effector functions - Differentiated T cells perform their functions. - Cytotoxic T cells release perforin and granzymes - Helper T cells release cytokines (e.g. interferon and interleukin) to influence activity of other immune cells Memory - Some T cells survive and become memory T cells which are long lived and can quickly respond upon re-exposure to the same antigen.

Answer 174

When there is a high concentration of IL-12 in the surrounding environment, naive CD4+ T cells will differentiate into TH1 cells. Low concentration of IL-12 --> TH2 cells.

Answer 175

Dendritic cells, macrophages and B cells

Answer 176

Systemic inflammatory syndromes which involve an elevated level of circulating cytokines and chemokines and immune cell hyperactivation. - Can lead to widespread inflammation throughout the body - Can cause tissue damage - Organ failure - Associated with severe illnesses and viral infections like SARS (triggered by pathogens, cancers, autoimmune conditions, etc)

Answer 177

IgG - 70-75% IgM - 10% IgA - 15% IgD - 1% IgE - 0.05%

Answer 178

Non functioning mutations in the NOD2 gene can lead to Crohn's disease Gain of function mutations in TLR7 is associated with SLE

Answer 179

B cell activation - They become activated upon binding to a specific antigen. Clonal expansion and differentiation - B cells go to lymph nodes where they undergo CLONAL EXPANSION (proliferate) and differentiate into plasma cells. Antibody production - Plasma cells generally produce antibodies mainly of IgM (primary response)class. - Over time B cells undergo class switching to produce antibodies of IgG class (secondary response) Memory - Some B cells persist after the immune response and become memory cells for long lasting immunity.

Answer 180

1) Passive distribution through hydrophobic membranes (Lipid soluble molecules) 2) Passive distribution through aqueous pores (very small water soluble drugs) - most are too big 3) Carrier mediated transport - Proteins which transport sugars, amino acids, neurotransmitters, etc.

Answer 181

1) Drug ionisation Ionised drugs have poor lipid solubility and are poorly absorbed. 2) Lipid solubility

Answer 182

Weak acids are better absorbed in the stomach. Because the stomach is an acidic environment, weak acids are more likely to remain in their non-ionised form (good lipid solubility) - thus well absorbed Weak bases are better absorbed in the intestine because the small intestine has a more alkaline environment allowing weak bases to remain in their non-ionised form (good lipid solubility --> well absorbed)

Answer 183

- Gastric enzymes (drug molecules may be digested) - e.g. peptides and proteins like insulin - Low pH - molecules may be degraded - Food (full stomach can slow absorption) - Gastric motility - Previous surgery Intestine Drug structure - Large hydrophilic molecules are poorly absorbed + lipid soluble/unionised molecules diffuse down concentration gradient. Medicine formulation - capsule or tablet coatings can control the timing of drug release. (modified release can control the rate of absorption) P glycoprotein causes substrates/drugs to be removed from the intestinal endothelial cells back into the lumen.

Answer 184

Metabolism of drugs preventing them from reaching systemic circulation. - Degradation by enzymes in intestinal wall - Absorption into hepatic portal vein and metabolism in the liver. (Avoided via rectal route of administration or IV administration)

Answer 185

The proportion of administered drug that reaches the systemic circulation.

Answer 186

- The extent of drug absorption and extent of first pass metabolism - Route of administration - Variation between individuals - genetic, disease states

Answer 187

Rectal - Avoids first pass metabolism - Absorption can be variable - Patient preference (may not want) Inhaled - Well perfused (large surface area) - Inhaler technique can limit effectiveness Subcutaneous - Faster onset then oral administration - Not as rapid as IV Transdermal (skin patch) - Provides continuous drug release - Avoids first pass metabolism - Only suitable for lipid soluble drugs - Slow onset of action

Answer 188

- Size (small - larger distribution) - Lipid solubility (Lipophilic - larger distribution) - Protein binding (Increased protein binding - less distribution) Volume of distribution - theoretical volume a drug will be distributed in the body (drugs that distribute well have high Vd)

Answer 189

- High lipid solubility --> can pass through BBB - Intrathecal administration - chemotherapy - Inflammation (sepsis can cause BBB to become leaky)

Answer 190

Renal impairment - Reduced kidney function can lead to accumulation and toxicity of renally cleared drugs (as kidneys excrete drugs and drug metabolites) Sepsis - Can lead to increased permeability of blood vessels (leaky blood vessels) --> allows drugs to move between blood stream and tissues WITH GREATER PENETRATION OF BBB Liver impairment: Hypoalbuminemia - In conditions of liver impairment like cirrhosis or acute liver failure, the synthesis of albumin may be reduced --> many drugs bind to albumin so when albumin levels are low, the amount of unbound drugs increase --> leading them to distribute more extensively into tissues Obesity: caution dosing drugs with a small Vd (meaning it is not well distributed to fat) Older age: change in body composition (decrease in lean body mass, increase in body fat), leads to smaller Vd of water-soluble drugs (tends to stay in systemic circulation), therefore higher plasma conc which can be toxic

Answer 191

Systemic - Nutritional dysregulation (reduced nutrient sensing can lead to metabolic dysfunction) Cellular level - Cellular senescence (cells lose the ability to divide and undergo functional changes--> senescent cells can accumulate in tissues over time and contribute to inflammation and tissue dysfunction) - due to telomere shortening and dna damage - Stem cell exhaustion (stem cells undergo a decline in their ability to proliferate and differentiate, impairing tissue renewal) Molecular level - Telomere shortening - leads to cellular senescence (telomeres gradually shorten with aging) - Compromised autophagy (a process responsible for the degradation and recycling of damaged cellular components --> reduced autophagy contributes to the accumulation of damaged proteins and organelles within cells. - Loss of proteostasis --> process regulating proteins within the cell --> leads to accumulation of misfolded or aggregated proteins - Epigenetic alteration -- DNA methylation can affect gene expression and contribute to age related phenotypes - Mitochondrial dysfunction - dysfunction (due to accumulation of ROS) can lead to increased oxidative stress

Answer 192

Immunosenescence - dysregulated immune function which contributes to increased susceptibility of the elderly to infection. Innate response - Decreased MHC 2 expression --> impairs the activation of T helper cells - Decreased phagocytosis - diminished ability to clear pathogens leads to increased susceptibility to infections. - Decreased interferon gamma (released by TH1 cells) --> lack of activation of macrophages and NKC Adaptive response - Decline in naive T cells - Decreased antibody production Inflammaging - chronic, low grade inflammation in aging - Increased inflammatory cytokines due to mitochondrial dysfunction, cellular senescence and impaired autophagy

Answer 193

The process whereby dying or dead cells are cleared away by macrophages.This is essential for preventing inflammation and resolving the immune response. Macrophages engulf the cells and form a phagosome --> which fuses with lysosomes to form a phagolysosome --> cellular debris is degraded by lysosomal enzymes --> macrophage releases anti-inflammatory signals and pro-resolution cytokines. However when efferocytosis is impaired/inefficient, apoptotic cells may undergo secondary necrosis which leads to the release of histotoxic neutrophil contents --> tissue damage. Also when macrophages sense the presence of uncleared apoptotic cells, they release pro-inflammatory cytokines--> can lead to chronic inflammation

Answer 194

Neutrophils and monocytes - Decreased chemotaxis and phagocytosis. Decreased superoxide generation and NET generation NK cells - increased numbers, decreased cytotoxicity Dendritic cells - Decreased recruitment to lymphoid organs, phagocytosis, decreased antigen presentation.

Answer 195

Transient SASP - Development, repair, regeneration, tumour suppression Persistent SASP - Age-related diseases, chronic inflammation, tumour progression Transient - Antifibrotic, anti inflammatory, Senescent cell clearance, tissue repair Persistent - Profibrotic, pro-inflammatory, senescent cell accumulation, tissue dysfunction Transient -- Beneficial as it is a temporary response to acute stress which contributes to tissue repair, clearance of senescent cells and supports the healing process Persistent - Detrimental as it can lead to sustained inflammation, tissue dysfunction and fibrosis --> chronic state may contribute to the development and progression of age related diseases. (heart failure, atherosclerosis, COPD, Parkinson's, alzheimer's, benign prostatic hyperplasia, osteoarthritis, type 2 diabetes)

Answer 196

Thymus involution - decreased thymic output of mature T cells Bone marrow - decreased B cell maturation - Impaired haematopoiesis due to increased adiposity of bone marrow Spleen + lymph nodes - Reduced number and size of follicles. Reduced B cell migration into follicles (i'm assuming follicles is lymph nodes) Lungs - increased infiltration of pro-inflammatory cells leading to lung tissue damage

Answer 197

CD8+ Elderly - decrease in proliferation ability and cytotoxicity of CD8+ T cells. Centenarians - Highly differentiated CD8+ T cells B cell Elderly - decrease in naive b cells Centenarians - increase in naive B cells (but decrease in number of B cells) NK cells Elderly - impaired cytotoxicity Centenarians - maintained cytotoxicity Neutrophil Elderly - Decreases in phagocytic ability, adhesion and chemotaxis Centenarians - increase in neutrophil chemotaxis and microbial capacity Inflammatory mediators Elderly - increased inflammatory molecules Centenarians - increased anti inflammatory molecules.

Answer 198

Modification of lifestyle - Physical activity - Caloric restriction - Maintain optimal nutrition Pharmacological interventions - Statins - IL7 therapy - -which promotes the survival, proliferation and maturation of T cells. - Caloric restriction mimics (possible anti inflammatory drugs, cell replacement therapy, gene therapy against aging related diseases) This reduces the risk of infections, chronic diseases and autoimmunity leading to improved health and reduced mortality

Answer 199

First order - Rate of elimination is proportional to the plasma drug concentration (a constant % of the drug) Zero order - A constant amount of the plasma drug is eliminated over a unit of time (as elimination is irrespective of plasma concentration and small increases in dose may cause large increases in plasma concentration , caution is needed when adjusting doses - dose changes should be small)

Answer 200

Cmax - Maximum plasma concentration Tmax.- time taken to get to Cmax (slower absorption - increased Tmax) Clearance - rate of drug elimination by all eliminating organs (rate of drug elimination/drug plasma concentration) - efficiency of irreversible elimination of the drug from the body - Drug is considered cleared after 5 half lives T 1/2 AKA half life is the time taken for plasma drug concentration to fall 50%

Answer 201

Single oral dose - Drug is absorbed in the GI tract but must undergo first-pass metabolism in the liver before entering the systemic circulation. - The time taken for the drug to reach its peak concentration in the plasma (Cmax) varies based on drug's solubility, presence of food in the stomach, etc. Bioavailability would be less than 100% also. (Graph is --> an increase till C max, and then a decrease (drug elimination) Single IV dose - Drug directly injected into bloodstream bypassing the absorption phase and first-pass metabolism - Administration is a rapid and complete delivery thus graph - plasma concentration is highest at the beginning and slowly declines over time. - 100% bioavailability

Answer 202

Liquids - small, polar molecules --> Urine, bile, sweat, tears, breast milk Solids - Large molecules: Faeces Gas -(volatiles)- expired air

Answer 203

1) Clearance - If clearance by organs (hepatic, renal, faeces, breath) is high, the drug is quickly eliminated (shorter half life) (in organ dysfunction, drug half life will be increased) 2) Volume of distribution - A drug with a larger volume of distribution will have a longer half life Age - half life of drugs are longer in elderly Disease states can influence half life also Protein binding - drugs with high affinity for albumin will have longer half lives.

Answer 204

It is when the rate of drug input is equal to the rate of drug elimination (Continuous IV infusion) - can google for a picture of the graph but essentially plasma concentration of the drug increases till it plateaus which is termed Css - drug plasma concentration at steady state. (The time to Css will be 5 half lives) Continuous IV infusion used for - Critical care patients - Administering of antibiotics - Unfractionated heparin (anticoagulant) - General anaesthetics (infusion rate can be titrated up and down to achieve desired therapeutic effect) If you reduce the dose of the drug by 50%, the time taken to reach Css doesn't change but there is a 50% reduction in Css. (if clearance of a drug is reduced (longer half life), time to Css (half life x 5) increases so you give a lower dose so that Css is reached faster)

Answer 205

- It is a higher initial dose of a drug given at the beginning of treatment to rapidly achieve the desired steady state (therapeutic concentration) --> which is within the therapeutic window (between maximum safe concentration (MSC) and maximum effective concentration (MEC)

Answer 206

The use of genetic and genomic information to tailor pharmaceutical treatment to an individual. (patient's genome is used to identify most appropriate treatment and dose)

Answer 207

- Variations in drug receptors can affect the interaction between drugs and their targets - Variations in efficacy of the drug depending on the individual - It can increase the incidence of adverse drug reactions - Genetic variations in drug metabolising enzymes can affect the efficiency of drug clearance

Answer 208

LIgand gated ion channels (nicotinic ACh receptor) - Ion channels are membrane proteins that allow ions to pass through channel pores which cause the cell to undergo a shift in electric charge distribution (charge determined by influx of cation or efflux of anion) G protein coupled receptors (beta adrenoreceptors) Kinase linked receptors (receptors for growth factors) Nuclear (cytosolic) receptors - (steroid receptors)

Answer 209

- Beta adrenoreceptors Largest most diverse group of membrane proteins - targets by >30% of drugs - Activity is regulated by factors that control their ability to bind to an hydrolyse GTP to GDP = On Ligand binding (peptides, lipids, sugars) to the extracellular domain, the receptor interacts with G protein to dissociate GDP and causes GTP to bind to adenyl cyclase (or PLC/phospholipase C) --> ATP is then converted to cAMP which activate protein kinases.

Answer 210

(receptors for growth factors) Kinases are enzymes which catalyse the phosphorylation of proteins. - When a signal dimer (pairing of two molecules) binds to the receptor, it results in the activation of kinases --> tyrosine molecules are phosphorylated --> intracellular signalling molecules bind to the phosphorylated tyrosine molecules initiating a cascade of intracellular signalling events (cell growth, differentiation).

Answer 211

- Steroid hormone receptors - They function as transcription factors, modifying gene transcription - When a ligand binds, the nuclear receptor is activated and it binds to specific DNA sequences via zinc fingers --> this results in the modulation of expression of target genes (transcription of the gene) which can lead to cellular responses like differentiation.

Answer 212

Describes how drugs activate receptors by inducing or supporting a conformational change in the receptor from "off" to "on"

Answer 213

Full agonist - full efficacy (100% response) Partial agonist - less efficacious than a full agonist (maximum efficacy will be less than 100%- no matter the dose) Inverse agonist - A drug that binds to the same receptor as an agonist induces a pharmacological response opposite of the agonist. (An antagonist is something that blocks or reduces the action of an agonist but inverse agonists not only block the activity, they induce an opposite effect)

Answer 214

Receptor related - Affinity and efficacy Tissue related - Number of receptors and signal amplification (same receptor and agonist but tissue can have different amplification responses)

Answer 215

Starts within 24 hours and lasts 72 hours.

Answer 216

Treatment for opioid induced respiratory distress --> Naloxone IV (opioid antagonist) Opioids can inhibit the activity of the brainstem, the area where the respiratory centres are (which are responsible for breathing) - decreases the sensitivity of brainstem to CO2 levels and so respiratory rate decreases

Answer 217

Codeine is a prodrug and needs to be metabolised by CYP2D6 to morphine in order to work. In populations where CYP2D6 activity is decreased, codeine will have a reduced effect In populations where CYP2D6 is overactive, they may be at increased risk of respiratory depression (Tramadol also)

Answer 218

Titrate the dose of the medication to suit the patient

Answer 219

Beta blcoker - ACE inhibitor - Anti platelets - Statin - Blocks the effect of the sympathetic nervous system on the heart - Decreases rate and contractility - Decreased workload for the cardiac muscle - Reduced incidence of heart failure. Alpha blocker - Doxazosin, tamsulosin Used for hypertension Take note: that too much beta blocker will not only block beta 1 receptors but can also start to block beta 2 receptors resulting in bronchoconstriction (dangerous in people with asthma)`

Answer 220

A - false, its an alpha 1 agonist so treats hypotension by causing vasoconstriction B - True, its action as an alpha 1 blocker relaxes the smooth muscle of the bladder wall C - False, salbutamol is a beta 2 receptor agonist (2 lungs!) D - False, beta blockers, especially non-selective ones, can exacerbate asthma E - False, Isoprenaline is a non-selective alpha and beta agonist. Beta 3 receptor is involved in lipolysis but B2AR agonist drugs for obesity are still in research stage

Answer 221

M1 receptor (CNS and periphery) - Increases gut motility and secretions in the gut, also CNS effects (cognition, learning, memory) (M1,M4,M5 - brain + spinal cord (CNS)) M2 receptor (mostly in heart) - Reduced contractility and bradycardia M3 receptor (mainly smooth muscles and glands) - vasodilation, bronchoconstriction, pupil constriction, salivary glands, bladder. Nicotinic receptors - Primary role in synaptic transmission in the CNS and at neuromuscular junction (some vasodilatory effects)

Answer 222

Nicotinic antagonist - Trimethaphan (rarely used. for hypertensive crisis) Nicotinic agonist - Nicotine Muscarinic antagonists - Atropine (crosses BBB), Glycopyrrolate (doesn't cross BBB), Hyoscine, Ipratropium (topical effect in lungs) Muscarinic agonists - Pilocarpine, muscarine (found in poisonous mushrooms) AGONISTS OF BOTH RECEPTORS - Acetylcholine, Neostigmine (reversible acetylcholinesterase inhibitor), organophosphates (irreversible acetylcholinesterase inhibitor)

Answer 223

Non selective alpha antagonists - Phenoxybenzamine, phentolamine Selective alpha 1 antagonists - Prazosin, doxazosin Selective alpha 1 agonists - phenylephrine, metaraminol Selective alpha 2 agonists - Clonidine, dexmedetomidine Non Selective alpha agonists - noradrenaline Non selective beta antagonists - Propanolol, carvedilol Selective B1 antagonists - Metoprolol, atenolol Selective B1 agonist - Dobutamine Selective B2 agonist - Salbutamol non selective beta agonist - isoprenaline ADRENALINE IS AN AGONIST OF ALL

Answer 224

- Lead compound identification - Pre-clinical research - Filing for regulatory status - Clinical trials on humans - Marketing the drug

Answer 225

Pharmacodynamic interactions - Occurs when one drug affects the pharmacological response of another drug by acting on the same drug receptors or physiological system. This can either have a SYNERGISTIC effect or ANTAGONISTIC effect. (Could result in adverse reactions) - Highly selective drugs are less likely to be problematic Pharmacokinetic interactions - Occurs when one drug affects the absorption, distribution, metabolism or excretion of another drug. Simply, pharmacokinetic interactions involve changes in how the body absorbs, distributes, metabolises or eliminates a drug. Pharmacodynamic interactions influence how a drug functions at its target site, altering its effect within the body.

Answer 226

CYP 450 - majority of phase 1 metabolic reactions CYP 3A4 CYP 2D6 CYP2C9 CYP1A2

Answer 227

Absorption - A drug could increase stomach pH reducing the absorption of another drug (famotidine increases stomach pH, decreasing absorption of ketoconazole) - 2 drugs that form an insoluble drug complex (when taken together) will not be absorbed (doxycycline and oral iron) - P glycoproteins throughout the body functions to remove toxic substances including drugs from the body. Some drugs may upregulate P glycoproteins therefore reducing absorption of drugs. (Carbemazepine a PGP inducer can reduce rivaroxaban levels) Distribution - Amiodarone could displace warfarin from albumin creating unbound warfarin molecules --> increasing risk of bleeding (as it is an anticoagulant) Metabolism - Drugs that are either enzyme inducers or inhibitors could have effects on another drug. Enzyme inducers --> increase expression of enzymes (e.g. CYP) --> leading to increased inactive metabolites which are excreted -->reduced levels of drug (subtherapeutic, treatment failure) (Rifampicin and CYP3A4) Enzyme inhibitors --> decrease expression of enzymes (e.g. CYP) --> decreased inactive metabolites which are excreted --> increased levels of drug in the blood (toxicity, adverse drug reactions) (Clarithromycin and CYP3A4) Excretion - 2 drugs could compete for elimination from the body via organic anion transporters (or OCT) resulting in reduced elimination of 1 drug --> toxicity (e.g. methotrexate and NSAIDS)

Answer 228

A response to a medicinal product or combination of medicinal products which is noxious and unintended.

Answer 229

Grapfruit juice is a CYP3A4 inhibitor (avoided by patients taking warfarin, statins) Milk can affect absorption of some drugs due to insoluble complex formed with calcium (doxycycline, levothyroxine, etc) Eating foods high in vitamin K (kale, spinach, broccoli) will oppose the action of warfarin Cranberry juice is a CYP2C9 inhibitor (avoided by patients taking warfarin)

Answer 230

D- Dose related - Hyper susceptibility - (ADRs at subtherapeutic dose - anaphylaxis with penicillin - Collateral effects (side effects) - ADRs at therapeutic dose - Toxic effects - ADRs at subpratherapeutic doses (liver damage with paracetamol) T- Timing - ADRs which develop during any time during the treatment. (Rapid (drug given too quickly), first dose, early (occurs early on in treatment but resolve as treatment progresses), intermediate (occurs after some delay), late (risk increases with prolonged/repeated exposure, delayed - some time after exposure or after drug withdrawal) S- Susceptibility - Certain patient groups may have a specific susceptibility to ADRs - Age - Gender - Disease states (e.g. CVD) - Physiological states (pregnancy)

Answer 231

- Females are at higher risk than males - EBV, HIV - Previous drug reactions - Uncontrolled asthma - Certain HLA groups

Answer 232

- Disappearance on cessation - Re-appears on re-exposure - Occurs in a minority of patients on the drug

Answer 233

Plasma, interstitial fluid, intracellular fluid and fat.

Answer 234

- Obtain a complete drug history - Look out for high risk drugs with a narrow therapeutic index/window - Look out for new drugs Patients may be at high risk of drug interactions due to: - Polypharmacy - Kidney or liver impairment - Extremes of age