ICS Flashcards
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
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
Causes of acute inflammation
Microbial infections - Hypersensitivity reactions - physical agents - Chemicals - Bacterial toxins - Tissue necrosis
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
Neutrophil action at the site of inflammation
Phagocytosis - Phagolysosome + Bacterial killing - Macrophages clear debris
Outcomes of acute inflammation
- Resolution - normal - Supporation - pus formation - Organisation - granulation tissue + fibrosis - Progression - excessive recurrent inflammation -> becomes chronic and fibrotic tissue
Chronic inflammation
Subsequent and prolonged response to Tissue injury - Lymphocytes, Macrophages and plasma cells - Longer onset, long lasting effects - Autoimmune diseases
Causes of chronic inflammation
Resistance of infective agent - Endogenous + materials - Autoimmune conditions - Primary granulomatous diseases - Transplant rejection
Macroscopic appearance of chronic inflammation
Chronic ulcer - Chronic abscess cavity - granulomatous inflammation - fibrosis
Microscopic appearance of chronic inflammation
Lymphocytes, plasma cells and Macrophages - exudate is not a common feature - Evidence of continuing destruction - Possible Tissue necrosis
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)
What are granulomas?
- An aggregate of epithelioid histocytes (macrophages) - Granuloma + eosinophil -> parasite - Secrete ACE as a blood marker
Types of granulomas
- Central necrosis - TB (identified by Ziel-Neelsen stain) - No central necrosis - sarcoidosis, leprosy, vasculitis, Crohn’s disease
What is thrombosis?
Solidification of blood constituents (mostly platelets) forming in vessels
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
Thrombosis formation (primary platelet plug)
Platelet aggregation, starts the coagulation cascade - Positive feedback loops
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)
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)
Venous thrombosis
Caused by venous stasis - low pressure, High pulse - Rubor, tumour and pain - Mainly fibrin - so treated by anticoagulants (DOACs, warfarin)
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) - Embolism (fragments of the thrombus break off into circulation)
Formation of the secondary platelet plug (coagulation cascade)
Prothrombin -> thrombin Fibrinogen -> fibrin
What is an embolism
A mass of material in the vascular system able to block in a vessel and block its lumen
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
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
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
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
What is atherosclerosis?
Fibrolipid plaques forming in the intima and media of systemic arteries - More in High pressure arteries, eg: aorta and bifurcations
What is in an atherosclerotic plaque?
- Lipids (cholesterol) - Smooth muscle - Macrophages (+foam cells) - Platelets - Fibroblasts
What are foam cells?
Macrophages that phagocytose LDLs
Atherosclerosis formation
- Macrophages form foam cells from lipids in arterial wall - fatty streak formation (platelets) > intermediate lesion - Plaque protrudes into artery lumen and disrupts laminar flow - medial thinning and platelet aggregation - Secondary platelet plug forms fibrin mesh over itself and traps red blood cells - Fibroblasts form smooth muscle ‘fibrous cap’ over this - Continuous formation of secondary platelet plug, this is a stable atheroma - plaque stabilisation/( fibrous cap formation)
Risk factors for atherosclerosis
- Smoking - High bp - Hyperlipidemia - Increasing age - Male - Poorly controlled diabetes mellitus (all risk factors for MI!!)
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
Preventative measures for atherosclerosis
smoking cessation - blood pressure control - Weight reduction - low dose aspirin - Statins - control diabetes
What is apoptosis?
Non-inflammatory, controlled cell death in single cells - cells shrink, organelles retained, CSM intact - Chromatin unaltered, fragmented for easy Phagocytosis
What is necrosis?
Induces inflammation and repair, traumatic cell death - cells burst, organelles splurge, CSM damaged - Chromatin altered, cell is f*cked
Intrinsic apoptosis mechanism
- Bax is a protein, inhibited by BCl-2 - It acts on mitochondrial membrane to promote cytochrome C reusase - This activates caspases
Extrinsic apoptosis mechanism
Fas-L or TNF-L binds to CSM receptors which activate caspases
Cytotoxic apopstosis mechanism
- CD8+ binding releases Granzyme B from CD8+ cells - Granzyme B -> Perforin -> Caspases
Types of necrosis
Coagulative, liquifactive, caseous and gangrene
Coagulative necrosis
most common type - can occur in most organs - Caused by ischaemia
Liquefactive necrosis
Occurs in the brain due to its lack of substantial supporting stroma
Caseous necrosis
Causes a cheese pattern - eg: TB
Gangrene
necrosis from rotting of the Tissue - Affected Tissue appears black due to deposition of iron sulphide from degraded haemoglobin
What is inflammation?
Acute/chronic tissue injury response
What are polymorphs?
What neutrophils are referred to as sometimes - Because they have a varying number of lobulated nuclei
What is hypertrophy?
increase in cell size without cell division - eg: skeletal muscle
What is hyperplasia?
increase in cell number by mitosis - eg: bone marrow at High alititudes, prostate at older age
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
What is metaplasia?
- The change in differentiation of a cell from one fully-differentiated cell type to another - eg: GORD (squamous -> columnar epithelia)
What is dysplasia?
Morphological changes seen in cells in the progression to becoming cancer
What is carcinogenesis?
Transformation of normal cells to neoplastic (malignant) cells through permanent genetic alterations or mutations
What is a neoplasm?
An autonomous, abnormal and persistent growth
What is a tumour?
Any abnormal swelling; neoplasm, inflammation, hypertrophy, hyperplasm
What can a neoplasm arise from?
- Nucleated cells - So can’t arise from erythrocytes but can arise from their precursor
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)
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)
Complications of benign tumours
- Hormone secreting (eg: prolactinoma) - Pressure on local structures (eg: pituitary -> optic chiasm) - Obstruct flow - Transformation to malignant neoplasm - Anxiety
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
Benign epithelial neoplasms
Papilloma - Non-glandular, Non-secretory, eg: squamous cell Papilloma - Adenoma - glandular, secretory, eg: colonic Adenoma
Malignant epithelial neoplasms (carcinomas)
eg: urothelial carcinoma glandular epithelium -> adenocarcinoma
Benign connective tissue neoplasm
Lipoma - adipocytes - Chondroma - cartilage - Osteoma - bone - Angioma - vascular - Rhabdomyoma - striated muscle (Rare) - Leiomyoma - Smooth muscle (More common) - Neuroma - nerves
Malignant connective tissue neoplasms
Same as benign ones, but followed by ‘sarcoma’ instead of ‘myoma’
What is a tumour called where the cell origin is unknown?
Anaplastic
Lymphoid tumours (always malignant)
Leukemia, lymphoma - Need to be treated by systemic chemotherapy
Other tumours
- Melanoma (melanocyte malignancy) - Mesothelioma (mesothelial malignancy - typically pleural) - Teratoma - cancer of all 3 embryonic germ layers - Blastoma - embryonal tumours
Eponymously named tumours
- Burkitt’s lymphoma (B cell malignany cause by EBV) - Kaposi sarcoma (vascular endothelial malignancy, HIV associated) - Ewing’s sarcoma (bone malignancy)
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
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
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
Host factors for cancer
Race - Diet - age - Gender - Inheritance - Premalignant lesions - Transplacental exposure
Metastasis pathway
- 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
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
Method of spread for sarcomas
Mostly haematogenous
Method of spread for carcinomas
Mostly Lymphatic - Exceptions: follicular thyroid, choriocarcinoma, RCC, HCC
Tumour staging
spread determined by histopthological and clinical examination - TNM: Primary tumour, lymph node, metastases - Different for leukemias, lymphomas and CNS cancers
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
Mutation involved in colorectal cancer
FAP (familial adenamatous polyposis) - HNPCC (lynch syndrome)
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
HNPCC
Autosomal dominant - Mutated MSH gene - Involved in DNA mismatch repair
Which tumours are most likely to metastasise via bone?
Breast Lung/lymphoma Thyroid Kidney Prostate …and multiple myeloma
Haematopoesis chart
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Primary lymphoid organs
bone marrow - origin of all immune cells, B cell maturation site - Thymus - T cell maturation site, thymic tolerance
Secondary lymphoid organs
lymph nodes - site of DC, B and T cell interactions - Spleen - RBC recycling, encapsulated Bacterial cell killing
Tertiary lymphoid organs
Pathological - Germinal centres of rapidly proliferating Lymphocytes
Innate immunity
Non-specific - Rapid - Already active (little Activation needed) - NO memory - Short duration - killing Usually via complement Activation - mediated by neutrophils and Macrophages
Adaptive immunity
specific - slow - Needs Activation - have memory - killing Usually antibody mediated - Main cells are T, B and plasma cells - long lasting
Examples of physical barriers
skin - Mucus - Cilia
Examples of chemical barriers
Lysozyme in tears - Stomach acid
Compliment pathways
Classical - Lectin - Alternate
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
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)
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
Innate cells: eosinophils
Release major basic protein - Seen in parasitic infections
Innate cells: basophils
Circulate mast cells - Secrete serotonin and heparin - Important in asthma, anaphylaxis, atopic dermatitis and hay fever
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
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
Non-cellular components of innate immunity
Physical and chemical barriers
Receptors on innate cells
Toll like receptors (TLRs) and nod like receptors - respond to PAMPs and DAMPs
Which TLRs are intracellular?
3, 7, 8, 9 (rest are extracellular)
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)
What do dendritic cells do?
- Present foreign antigens to T helper cells - Stimulates further T helper proliferation - Stimulates B cell production -> antibodies
What is formed when a dendritic cell and T helper cell communicate?
Immune synapse
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
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
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
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)
Adaptive cells: B cells
maturation and production in the bone marrow - Any B cells with autoimmunity apoptose
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 and class switching mutate IGs to target different variants
What do IL4 and IL5 promote class switching to?
IL4 - IgA IL5 - IgE
IgG
- Most abundant in blood - Highly specific - Key in secondary response - 4 subtypes - Can cross the placenta
IgA
most abundant in total body - Found on mucosal linings, colostrum and breast milk (a dimer)
IgM
First Ig released in adaptive response - B cell mediated - a pentamer
IgE
- Least abundant in body - Activates mast cell + basophil degranulation in type 1 hypersensitivity (anaphylaxis)
IgD
Unknown function, irrelevant
Major histocompatability complex
- Also known as human leukocyte antigen (HLA) - On chromosome 6 - Interact with T cells - Confer susceptibility to inherited autoimmune diseases
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
Type 2 hypersensitivity
- Antibody-antigen complex formation 👴🏻 Goodpasture’s Rheumatic fever AHA Myasthenia gravis Pernicious anaemia Anti-TSH (Graves’)
Type 3 hypersensitivity
- Antibody-antigen complex deposition 💃🏻 Haemolytic uraemic syndrome and hypersensitivity pneumonitis IgA nephropathy Post-strep glomerulonephritis SLE
Type 4 hypersensitivity
- Delayed - T-cell mediated and activated by antigen presenting cells GBS MS 🐱 Contact dermatitis + coeliac Allopurinol drug reaction Tuberculin skin test and T1DM
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
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
What is autoimmunity?
Phathological response vs self - faulty immune tolerance - Molecularmimickery
Organ specific autoimmunity
T1DM - endocrine pancrease B cells - MS - oligodendrocytes of CNS - Pernicious anaemia - parietal cells of Stomach - Myesthemia gravis
Non-organ specific autoimmunity
- Affects DNA, eg: SLE - Affects cell antigens - RBCs -> autoimmune haemolytic anaemia - Platelets - > immune thrombocytopenic purpura - Rheumatoid arthritis
Immunodeficiency can be…
- Inherited (defects in T cells), eg: IgA deficiency (north Europe), SCID (death within 2 years) - Acquired, eg: HIV
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 ->
What are the Pfizer and Biotech Moderna COVID-19 vaccines made from?
mRNA
What are vaccinations?
A form of active immunity
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
Active immunity natural vs artificial
Natural - Body encounters pathogen + produces memory cell after infection Artificial - Vaccine mimics encountering pathogen + stimulates Ig production
Passive immunity natural vs artificial
Natural - Maternal Igs passed onto feeding baby in breast milk/colostrum Artificial - Antivenom, injection of Ig from another organism
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
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
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
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
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
Types of drug administration
Systemic - Enteral (GI tract: PO and PR) - Par-enteral (non-GI tract) Local
Examples of parenteral drug administration (not via GI tract)
Intravenous - Intramuscular - Subcutaneous - Inhalers - Sublingual
Examples of local drug administration
Topical - Intranasal - Eye drops - Inhalation - Transdermal
What is pharmacodynamics?
Action of the drug on the body
What is pharmacokinetics?
Action of the body on the drug
What is an agonist?
- Full affinity - Full efficacy - Mimics endogenous substance eg: Salbutamol is a beta 2 agonist
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
Types of receptor ligands
Agonists (including partial) - Antagonists - Allosteric modulators
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
What does a competitive antagonist do?
Binds to the active site - Decreases efficacy reversibly - affinity is unchanged - Ligand concentration is rate limiting eg: naloxone
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
Ways drugs cross membranes
Passive diffusion - Facilitated diffusion - active transport - Endocytosis
Factors of pharmacokinetics
Absorption - Distribution - Metabolism - Elimination
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
What does drug distribution depend on?
- Blood flow to area - Permeability of capillaries - Protein binding (albumin=slower) - Lipochilicity/lipophobicity - Volume of distribution
What drugs can the kidney excrete?
Water soluble drugs - not lipid soluble drugs
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
What are inducer drugs
increase cytochrome P450 activity and speed up Metabolism of other drugs - May result in sub-therapeutic dose
What are inhibitor drugs?
Decrease cytochrome P450 activity, reduce Metabolism of other drugs - May result in toxicity - eg: erythromycin, grape juice
Examples of inducers
PCARBS Phenytoin Carbamazepine Alcohol (chronic use) Rifampicin Barbiturates (St John’s Wort) Sulfonylureas and smoking
Examples of inhibitors
ODEVICES Omeprazole Disulfiram Erythromycin Valproate Isoniazid Ciprofloxacin Ethanol (acute use) Sulphonamides and SSRIs
First order elimination of drugs
Catalysed by enzymes - rate of Metabolism directly proportional to drug concentration
Zero order elimination of drugs
enzymes saturated by High drug doses - rate of Metabolism is constant - eg: ethanol, phenytoin
First order vs zero order drug elimination
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Allosteric modulators
increase/Decrease normal Ligand binding - eg: benzodiazepine
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 categorising them in this way (eg: atenolol is a less selective B1 blocker)
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
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
How does local anaesthesia work
Blocks Na+ voltage gated channels
Specific vs selective drugs
specific - Act on certain targets - selective - Act on subtype of target
Neurotransmitter in between synapses in cholinergic pharmacology
Always acetylcholine acting on nicotine
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
Drugs at the neuromuscular junction
- Botolinum toxin (botox) - Curare (nAch-R antagonist) - Ach-ase inhibitors
How does botox work?
Binds to presynaptic vesicles - Ach Release inhibited - Paralysis
How do Ach-ase inhibitors work?
Inhibit the breakdown of Ach - Increased concentration at the neuromuscular juntion
Overstimulation of Ach at the neurmuscular junction
Cholinergic crisis Salivation Lacrimation Urination Defacation GI distress Emesis Anything that understimulates Ach does the opposite
Parasympathetic (Ach) responses
Rest + digest - Pupil constricts - Lower heart rate - Bronchoconstritction - Increased GI motility and secretion - Detrusor muscle contracts - Penis points (erect)
Sympathetic (NAd) response
Fight or flight - Pupil dilates - Increased heart rate - Bronchodilation - Decreased GI motility and secretion - Detrusor muscle relaxes - Penis shoots (ejaculation)
Adrenaline formation
Tyrosine -> DOPA -> Dopamine -> Noradrenaline -> Adrenaline
NAd alpha 1 and 2 receptors
- Vessels + sphincters - Agonism causes: - Vasoconstriction - Bladder contraction - Pupil dilation - (eg: tamsulosin alpha blocker for benign prostatic hyperplasia)
NAd beta 1 receptors
heart - Agonism Causes Increased force of heart contraction - Higher blood pressure - Renin Release
NAd beta 2 receptors
lungs - Agonism Causes Bronchodilation
Agonism and antagonism in beta 2 receptors
Agonists: Short and long acting beta 2 agonists for asthma Antagonists: Non-selective beta blockers
Drug for community acquired pneumonia
Antibiotics such as amoxicillin/clarythromycin
Drug for HAP
Co-amoxiclav (3x daily, 500 or 125mg for 5 days)
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
What should you take with isoniazid
Pyramidine to prevent: - B6 deficiency - Siderobastic anaemia - Peripheral neuropathy
Drug for cellulitis
High dose oral antibiotic If MRSA, give vancomycin
Side effect of trimthoprim
Can cause birth defects in the first trimester of pregnancy
Drug for H.Pylori🧢
Clarythromycin Amoxicillin PPI For 7 days
Drug for gastroenteritis
- Campylobacter -> clarythromycin - Amoebiasis -> metronidazole and diloxanide - Giardiasis -> tinidazole
Drug for C.Difficile
- Vancomycin - 125mg - 4x a day - for 10 days
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
Drug for infective endocarditis
Antibiotics
Types of pain
- Acute (nociceptive) - Cancer - Neuropathic (nerve pain) - Chronic non-cancer (3+ months)
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?
Things that affect drug absorption
Acidity (eg: PPI), ionised drugs can’t cross phospholipid bilayer - motility (eg: erythromycin) - Solubility
Types of opioids
Naturally ocurring from the poppy - morphine + codeine - Modification - diamorphine (heroin), oxycodone, dihydrocodeine - Synthetic opioids - eg: pethidine
What do opioids act on?
CNS + GI tract receptors - Resp centres of the brain (pontine)
Side effects of opioids
Addiction - Constipation - Nausea and vomiting - Respiratory distress/depression
Tolerance vs dependance
tolerance - Physiological, body has gotten used to a certain amount of drug, desensitisation - Dependance - Physcological, craving euphora
Treatment for opioid induced respiratory depression
naloxone (competitive opioid inhibitor) - IV is fastest route
Types of anticoagulants
warfarin - Direct oral anticoagulation - Thrombolytics - LMWH (low molecular Weight heparin)- Antiplatelets (aspirin, clopidogrel)
What to give a patient bleeding on Warfarin?
Vitamin K
How to NSAIDs decrease inflammation?
By inhibiting Cox2
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
Side effects of PPIs
Prolonged use can increase fracture risk
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)
Where are DA receptors mostly found?
Nucleus accumbens in brain
GABA
- Main inhibitory CNS neurotransmitter - Agonists - benzodiazepines (eg: lorazepan and diazepan) - Anxiety, sleep disorders, alcohol withdrawal, status epilepticus,
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
Glutamate
Main excitatory CNS neurotransmittor
Drug factors that influence drug interactions
- Solubility - Narrow therapeutic index:
Factors that affect drug excretion
Acids cleared faster if urine is weakly basic - Bases clear faster if urine is weakly acidic
Side effects of beta blockers
low blood pressure - slow HR - Symptoms of shock
What can ankle swelling be caused by?
Calcium channel blockers (eg: amlodipine) OR heart failure
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
Thiazides
- eg: bendroflumethiazide and indapemide - Inhibits Na-Cl channel cotransporter in distal convoluted tubule - Increased Cl-, Na+ and water excreted
Spironolactone
Inhibits ENaC channel in collecting duct (aldosterone antagonist) - Increased Na+ and Water excreted - Increased K+ retention
Mechanism of warfarin
Antivitamin K because in inhibits Vitamin K epoxide reductase
Thrombolytics
“Clot buster” - eg: alteplase, Activated Tissue plasminogen, activates plasmin to degrade fibrin
Lifespan of neutrophil polymorphs
2-3 days
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
Examples of acute inflammation
acute appendicitis - Frostbite - Streptococcal sore throat - Lobar pneumonia
Treating inflammation
Ice/cold - Antihistamines - aspirin/ibuprofen - Inhibit prostaglandins - Corticosteroids - upregulate inhibitors of inflammation and downregulate Chemical mediators of inflammation
What is the acute mediator of inflammation?
Histamine
Ischaemia vs infarction
Ischaemia - reduction in blood flow Infarction - reduction in blood flow with subsequent cell death
Endothelial damage theory for atherosclerosis
Endothelial cells are delicate - Easily damaged by cigarette smoke, shesring forces as arterial divisions, Hyperlipidemia, glycosylation products
p53 DNA damage pathway
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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
Apoptosis in HIV
can induce apoptosis in CD4 helper cells - Reduces their numbers enormously to produce An immunodeficient state
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
Why do we get deafer as we get older?
Hair cells in cochlea can’t divide
Basal cell carcinoma
the skin only invades locally - can be cured by complete local excision
What is adjuvant therapy?
Extra treatment given after surgical excision Eg: radiotherapy in breast cancer
Example of chronic inflammatory process from the start
Infectous mononucleosis
Metaplasia in smoking
Cilliated bronchial epithelium with mucocillary escalator -> squamous epithelium
What is oncogenesis?
The transformation of normal cells to benign or malignant tumours through permanent genetic alterations or mutations
Carcinogen definitions
Carcinogenic = cancer causing Oncogenesis = tumour causing Mutagenic = act on DNA
Types of carcinoma
In situ and invasive
Angiogenesis promoters
vascular Endothelial growth factor - basic fibroblast growth factor
Angiogenesis inhibitors
Angiostatin - Endostatin - Vasculoatatin
Tumours that are most likely to metastasise to the lung
Sarcomas, any common cancers
Tumours that are most likely to metastasise to the liver
GI tract tumours - Carcinoid tumours lf intestine - Pancreatic - breast - Bronchial
Cons of conventional chemotherapy
not selective for tumour cells - targets other cells, causing hair Loss, diarrhoea and myelosuppresion
What tumours is chemotherapy good for?
Fast dividing ones: - Germ cell tumours of testis - Acute leukemia - Lymphomas - Embryonal paediatric tumours - Choriocarcinoma
What is targeted chemotherapy?
Exploits some difference between cancer cells and normal cells to target drugs to the cancer cells - More effective - less side effects
Arterial ulcers
Punched out holes - little exudate - tips of toes + lateral maleolus - Pale cool skin - low distal pulse - Peripheral vascular disease
Venous ulcers
less demarcated - Lots of exudate - medial malleolus + inner calf - Warm erythematous skin - Deep vein thrombosis
Additive/summative drug interaction
Total effect is the sum of the two drugs put together
Synergy drug interaction
Taking the two drugs together increases the effect
Antagonist drug interaction
Reduces the effect of the agonist
Potentiation drug reaction
Effect of one drug is increased but the other one isn’t
Where are most drugs metabolised and excreted?
Metabolised: liver Excreted: kidneys
Example of drug interaction that affects absorption
morphine Decreases motility in the GI system, decreasing Absorption
What happens if you add a drugs that is higher protein binding than the original drug?
The original drug won’t work (competitive inhibition)
Morphine metabolism
Metabolised into morphine-6-glucoronide by CYP450 - cleared out by the kidney - Adding phenytoin makes the transfer More effective, causing a morphine overdose (enzyme induction)
What does metronidazole do?
Decreases effect of CYP450 - effect duration of morphine is Longer as it’s being Metabolised slower - this is enzyme inhibition
What is INR in pharmacology?
International normalised ratio - High INR = too much water or drug induced = enzyme inhibition
Types of receptors
Ligand-gated ion channels - nicotinic Ach receptors - G protein coupled receptors (most common) - beta-adrenoreceptors - Kinase-linked receptors - for growth factors - Cystolic/nuclear receptors - steroid Hormones
What is a receptor?
A component of a cell that interacts with a specific ligand and initiates a change of biochemical events leading to the ligands observed effects
Exogenous vs endogenous ligands
Exogenous - drugs Endogenous -hormones, neurotransmitters etc
What are the only polysaccharide vaccines?
Pneumococcal disease - Meningococcal disease - Samonella typhi
Which vaccines are administered as live attentuated in the UK?
BCG - MMR
Classical PAMPs
Flagellin - Lipopolysaccharide - Peptidoglycan - Liparabinomannan of mycobacteria
What immunoglobulins are involved in inactivated vaccines?
IgM followed by IgG
Codeine
Needs to be converted to morphine to work - 10% of people don’t have cytochrome CYP2D6 that converts it - 10% of people have too much of the enzyme - Don’t give it to kids or breastfeeding mothers
Oral bioavailibility of opioids
- 50% - 5mg diamorphine = 10mg morphine = 100mg pethidine - Give double amount of oral morphine compared to IM
Opioid withdrawal
- Starts within 24 hours - Lasts about 72 hours
Patient risk factors for adverse drug reactions
- Gender (F>M) - Elderly - Neonates - Polypharmacy - Genetic predisposition - Hypersensitivity - Hepatic/renal impairments - Adherance problems
Drug risk factors for adverse drug reactions
Steep dose-response curve - low therapeutic index - Commonly Causes ADRs
Augmented ARD
Extension of Primary effect (eg: bradycardia and propanolol, hypoglycaemia and insulin) - Secondary effect (eg: bronchospasm with propanolol) - High morbidity, low mortality - Excludes drug abuse and overdose
Bizzare ARD
- Not predictable or related to pharmacology - Not dose dependant - Can’t be readily reversed - Can be allergy or hypersensitivity - Low morbidity, high mortality
Continuous ARD
Uncommon - related to cumulative dose - Time related - eg: steroids and osteoporosis, analgeis nephropathy, colonic dysfunction due to laxatives
Delayed ARD
Uncommon - Usually dose related - Shows itself some Time after use of drug
Ending of drug use ARD
Uncommon - occurs soon after drug withdrawn - eg: opiate withdrawal, adrenocortical insufficiency due to glucocorticoud withdrawal, withdrawal seizures when anticonvulsants are stopped
Failure ARDs
common - dose related - Often Caused by drug interactions - eg: oral contraceptive pill, warfarin
What to report on an MHRA yellow card
all suspected reactions to herbal medicines and black triangle drugs - all serious suspected reactions for established drugs, vaccines, contrast media and drug interactions
Affinity vs efficacy vs potency
affinity - How Well a Ligand Binds to its Receptor - efficacy - How Well a Ligand successfully activates its Receptor - Potency - relative strength of the drug, How Well it Causes a response in the body
What is the EC50?
The dose required to pertain 50% of a response
What is a therapeutic range?
Upper and Lower bounds of safe doses of a drug. - Narrower range = Need More care in dispensing
Treatment for cardiogenic shock
Dobutamine - Increases force and rate of Cardiac contraction
When to give opioids?
in Chronic severe pain relief - Mostly cancer pain
Stages of atherogenesis
- Endothelial demage 2. Fatty streaks 3. Intermediate lesions 4. Fibrous plaques/advanced lesions 5. Plaque erosion 6. Plaque rupture
TLRs and their targets
TLR2: Gram positive bacteria and mycobacteria (inc fungi)TLR4: Gram negative bacteria and lipopolysaccharides TLR5: Bacteria and flagellin TLR7: Single-strand RNA TLR9: Non-methylated DNA
Risk factors for morphine metabolism
Elderly - not eating or drinking - reduced kidney function - do renal profile to assess metabolic function before prescribing
What is the mechanism of action for erythromycin?
Inhibits protein syntesis by binding to ribosomal 50s subunit
Cell wall and nucleic acid synthesis (MEMORISE)
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Risk factors for developing tuberculosis
- HIV - Born in high prevalance area - Close contact with TB positive person - Children under 5 - History of TB - Immunosippression - Homelessness - Prison - Excessive alcohol - IVDU - Smokers - Co-morbidities - Diabetes - End stage CKD receiving RRT - Malignancy
Which cell type is the primary receptor for HIV?
CD4+ Retroviral therapy targets within this cell type: - Fusion/entry inhibitors - Reverse transcriptase inhibitors - Integrase inhibitors - Protease inhibitors
Mechanism of ACh release
Action potential arrives at presynaptic terminal - Ach is Release into synapse and Binds to postsynaptic Receptor - Broken down by AChesterase into acetate and choline - choline reuptaken by presynaptic terminal - Binds with Acetyl CoA to form new Ach
What are the three classes of enzyme inhibitors?
reversible - irreversible - Partially reversible
Side effects of acetylcholinesterase inhibitors
Nausea - diarrhoea - Dizziness - bradycardia - Insomnia - Headaches - muscle cramps (link to parasympathetic Activation)
What blood markers are secreted in sarcoidosis?
ACE and calcium
Cells that regenerate
Hepatocytes - Pneumocytes - all blood cells - gut epithelium - skin epithelium - Osteocytes
Mechanism of aspirin
- Irreversibly inhibits Cox-2 - Prevents the breakdown of arachidonic acid into prostaglandin H2 (non-selective for Cox-1 and Cox-2)
Furosemide
- Loop diuretic - Inhibits Na-K-Cl channels in ascending loop of Henlé - Increases ion and water excretion and inhibits their absorption in PCT
