Introductory clinical sciences Flashcards
1
Q
what is inflammation?
A
The local physiological response to tissue injury
2
Q
What is acute inflammation?
A
The initial and transient series of tissue reactions to injury
3
Q
How do microbial infections cause acute inflammation?
A
o Viruses lead to death of individual cells by intracellular multiplication
o Bacteria release specific exotoxins (chemicals synthesised by them that specifically initiate inflammation) or endotoxins (associated with cell walls)
o Some organisms cause immunologically mediated inflammation through hypersensitivity reactions
o Parasitic infections and tuberculous inflammation are instances where hypersensitivity is important
4
Q
how do hypersensitivity reactions cause inflammation?
A
o Occurs when an altered state of immunological responsiveness causes an inappropriate or excessive immune reaction that damages tissue
o The types of reaction all have cellular or chemical mediators similar to those involved in inflammation
5
Q
How do physical agents cause inflammation?
A
o Tissue damage leading to inflammation may occur through physical trauma, ultraviolet or other ionising radiation, burns or excessive cooling (e.g. frostbite)
6
Q
How do irritant and corrosive chemicals cause inflammation?
A
o Corrosive chemicals provoke inflammation through gross tissue damage
o Infecting agents may release specific chemical irritants that lead directly to inflammation
7
Q
How does tissue necrosis cause inflammation?
A
o Death of tissues from lack of oxygen or nutrients resulting from infarction is a potent inflammatory stimulus
o The edge of a recent infarct often shows an acute inflammatory response, presumably in response to peptides released from dead tissue
8
Q
Suggest the macroscopic appearance of acute inflammation
A
Redness - dilation of small blood vessels
Heat - Due to increased blood flow through the region resulting in vascular dilation, and systemic fever due to chemical mediators
Swelling - Oedema (the accumulation of fluid in the extravascular space as part of the fluid exudate and mass of inflammatory cells)
Pain- stretching and distortion of tissues and chemical mediators (bradykinin) which induce pain
Loss of function- movement is consciously and reflexly inhibited by pain
9
Q
What occurs in the early stages of acute inflammation?
A
Oedema fluid, fibrin and neutrophil polymorphs accumulate in the extracellular spaces of the damaged tissue
10
Q
What is the acute inflammatory response?
A
- Changes in vessel calibre and flow
- Caused by time course mechanisms, immediate transient chemical mediators (histamine, bradykinin, NO, C5a Leukotriene B4 and platelet activating factor), immediate sustained vascular injury, prolonged endothelial injury
- Formation of exudate - the accumulation of neutrophil polymorphs within the extracellular space is the diagnostic histological feature of acute inflammation
11
Q
Name and explain the chemical mediators of acute inflammation
A
Histamine and thrombin - up-regulation of adhesion molecules on the surface of endothelial cells (neutrophil adhesion to endothelial surface)
12
Q
Name the four enzymatic cascade systems found in plasma
A
Complement
Kinins
Coagulation
Fibrinolytic
13
Q
Name the endogenous chemical mediators of inflammation and what they cause
A
- Vascular dilatation – histamine, prostaglandins, PGE2/I2, VIP, nitric oxide, PAF
- Increased vascular permeability – transient phase (histamine), prolonged phase (bradykinin, nitric oxide, C5a, leukotriene B4 and PAF, potentiated by prostaglandins)
- Adhesion of leucocytes – upregulation of adhesion molecules on endothelium, principally by IL-8, C5a, leukotriene B4, PAF, IL-1 and TNF-alpha
- Neutrophil polymorph chemotaxis – Leukotriene B4, IL-8
14
Q
What are neutrophil polymorphs?
A
- Short lived cells
- First on the scene of acute inflammation
- Cytoplasmic granules full of enzymes that kill bacteria
- Usually die at the scene of inflammation
- Release chemicals that attract other inflammatory cells such as macrophages
15
Q
What are endothelial cells?
A
- Line capillary blood vessels in areas of inflammation
- Become adhesive in areas of inflammation so inflammatory cells adhere to them
- Become porous to allow inflammatory cells to pass into tissues
- Grow into areas of damage to form new capillary vessels
16
Q
What are fibroblasts?
A
- Long lived cells
* Form collagen in areas of chronic inflammation and repair
17
Q
What are macrophages?
A
- Long lived cells
- Phagocytic properties
- Ingest bacteria and debris
- May carry debris away
- May present antigen to lymphocytes
18
Q
What are lymphocytes?
A
- Long lived cells
- Produce chemicals which attract other inflammatory cells
- Immunological memory for past infections and antigens
19
Q
Why are signs of acute inflammation modified?
A
modified according to the tissue involved and the type of agent provoking the inflammation o Serous o Suppurative inflammation o Membranous inflammation o Pseudomembranous inflammation o Necrotising inflammation
20
Q
Name the systemic effects of inflammation
A
- Pyrexia
- Constitutional symptoms
- Weight loss
- Reactive hyperplasia of the reticuloendothelial system
- Haematological changes
- Amyloidosis
21
Q
Discuss the structure of antibodies
A
• Antigen recognition
o Fab regions are variable in sequence
o Bind to different antigens specifically
• Antigen elimination
o Fc region is constant in sequence
o Binds to complement, Fc receptors on phagocytes and natural killer cells
• Variable regions bind to antigen and differ between antibodies with different specificities
• Constant regions – same for antibodies of a given H chain class or L chain type
• Variable and constant regions are encoded by separate exons
• Multiple variable region exons in the genome can recombine and mutate during B cell differentiation to give different antibody specificities
22
Q
How do antibodies protect against infection?
A
• Specific binding/ multivalency (Fab) o Neutralize (toxins) (IgG, IgA) o Immobilise motile microbes (IgM) o Prevent bind to and infection of host cells o Form complexes • Enhance innate mechanism o Activate complement (IgG, IgM) o Bind Fc receptors (enhance phagocytosis, mast cells release inflammatory mechanisms and enhance killing of infected cells by natural killer cells
23
Q
How do T cells recognise antigens?
A
- B cells recognise soluble free native antigens
- T cells recognise cell associated processed antigen
- Cytotoxic T cell recognises peptide bound to MHC1
- Virus infected cell – viral proteins broken down in cytosol
- Peptides transported to ER and bind to MHC1 on cell surface
- Activated cytotoxic T cells kill the infected cell by inducing apoptosis
- Helper T cell recognises peptide bound to MHC2
- Macrophage/dendritic cell/B cell internalises and breaks down foreign material
- Peptides bind to MHC2 in endosomes on cell surface
- Activated T helper cells help B cells make antibody and produce cytokines that activate/regulate other leukocytes
24
Q
What is an adverse drug reaction?
A
An unwanted or harmful reaction following the administration of a drug or combination of drugs under normal conditions of use
25
What is a Type A adverse drug reaction?
```
o Augmented pharmacological
o Predictable
o Dose dependent
o Common
o Morphine and constipation/ hypotension and antihypertensive
```
26
What is a Type B adverse drug reaction?
o Bizarre or idiosyncratic
o Not predictable
o Not dose dependent
o Anaphylaxis and penicillin
27
What is a Type C adverse drug reaction?
Chronic e.g. osteoporosis and steroids
28
What is a Type D adverse drug reaction?
Delayed e.g. malignancies after immunosuppression
29
What is Type E adverse drug reaction?
o End of treatment
| o Occur after abrupt withdrawal of drug
30
What are the causes of an adverse drug reaction?
* Pharmaceutical variation
* Receptor abnormality
* Abnormal biological system unmasked by the drug
* Abnormalities in drug metabolism
* Immunological causes (allergy)
* Drug-drug interactions
* Multifactorial
31
What is idiosyncrasy?
* Inherent abnormal response to a drug
* Genetic abnormality
* Enzyme deficiency
* May be due to abnormal receptor activity
* Rare but serious
32
What are the strengths of the yellow card system of ADR reporting?
* Acts as an early warning system for identification of previously unrecognised reactions
* Provides information about factors which predispose patients to ADRs
* Allows comparisons of ADR profiles between products within same therapeutic class
* Continual safety monitoring of a product throughout its life span as a therapeutic agent
* Can work rapidly
* Easily accessible
* Applied widely across all drugs
* Fairly cheap to operate
33
What are the weaknesses of the yellow card system of ADR reporting?
* Cannot provide estimates of risk as the true number of cases is underestimated and total number of patients is unknown
* Relies on ADR being recognised
* Not all ADRs are reported
* Reporting is high for newly marketed drugs but decreases over time
* Uncertainty as to whether reaction is cause by drug
* Uncontrolled and biased
34
What is a serious reaction?
```
• A reaction that
o Is fatal
o Is life threatening
o Is disabling or incapacitating
o Results in hospitalisation
o Prolongs hospitalisation
```
35
What is type 1 hypersensitivity?
• Prior exposure to the antigen/drug
• IgE antibodies formed after exposure to molecule
• IgE becomes attached to mast cells or leukocytes, expressed as cell surface receptors
• Re-exposure causes mast cell degranulation and release of pharmacologically active substances
• Anaphylaxis
o Occurs within minutes and lasts 1-2 hours
o Vasodilation
o Increased vascular permeability
o Bronchoconstriction
o Urticaria
o Angio-oedema
36
What is a type 2 hypersensitivity reaction?
* Drug or metabolite combines with a protein
* Body treats it as a foreign protein and forms antibodies (IgG, IgM)
* Antibodies combine with the antigen and complement activation damages the cells
* Antibody dependent cytotoxicity
37
What is a type 3 hypersensitivity reaction?
* Antigen and antibody form large complexes and activate complement
* Small blood vessels are damaged or blocked
* Leukocytes attracted to the site of reaction release pharmacologically active substances leading to an inflammatory process
* Includes glomerulonephritis and vasculitis
* Immune complex mediated
38
What is a type 4 hypersensitivity reaction?
* Antigen specific receptors develop on T lymphocytes
* Subsequent administration lads to local or tissue allergic reaction
* Example: Contact dermatitis
* Lymphocyte mediated
39
What is non-immune anaphylaxis?
* Due to direct mast cell degranulation
* Previously called anaphylactoid reactions
* Some drugs recognised to cause this
* No prior exposure
* Clinically identical
40
Name the main features of anaphylaxis
* Exposure to drug causes immediate rapid onset
* Swelling of lips, face, oedema, central cyanosis
* Wheeze/ shortness of breath
* Hypotension
* Cardiac arrest
41
What is the management of anaphylaxis?
* Commence basic life support
* Stop the drug if infusion
* Intramuscular adrenaline 500 micrograms (300mcg if using epipen)
* High flow oxygen
* IV fluids
* IV antihistamine (chlorphenamine 10mg)
* IV hydrocortisone
* If anaphylactic shock, may need adrenaline IV with close monitoring
42
What is the role of adrenaline in the management of anaphylaxis?
* Vasoconstriction – increase in peripheral vascular resistance, increased blood pressure and coronary perfusion via alpha 1-adrenoreceptors
* Stimulation of beta1-adrenorecptors positive ionotropic and chronotropic effects on the heart
* Reduces oedema and bronchodilation via beta2-adrenoreceptors
* Attenuates further release of mediators from mast cells and basophils by increasing intracellular c-AMP and so reducing the release of inflammatory mediators
43
What are the clinical criteria for drug allergy?
* Does not correlate with pharmacological properties of the drug
* No linear relation with dose
* Reaction similar to those produces by other allergens
* Induction period of primary exposure
* Disappearance on cessation/ reappearance on re-exposure
* Occurs in a minority of patients on the drug
44
What is an allergy?
An abnormal response to harmless foreign material
45
What is atopy?
The tendency to develop allergies
46
What is the pathogenesis of allergy?
```
• Usually involves IgE
• Genetic factors
• Cells involved include:
o Mast cells
o Eosinophils
o Lymphocytes
o Dendritic cells
o Smooth muscle
o Fibroblasts
o Epithelia
• Mediators: cytokines, chemokines, lipids and small molecules
```
47
Where are low affinity IgE receptors found and what are their functions?
• Expressed on B cells, T cells, monocytes, eosinophils, platelets and neutrophils
• Functions:
o Regulation of IgE synthesis
o Triggering of cytokine release by monocytes
o Antigen presentation by cells
48
What are high affinity IgE receptor-expressing cells?
Basophils
49
Name the preformed compounds in mast cells
o Histamine – arteriolar dilation, capillary leakage – induces cholinergic reflex bronchoconstriction
o Chemotactic factors- Some cytokines (IL-4, SCF)
o Proteases - Tryptase and chymase
o Proteoglycans - Chondroitin sulfate and Heparin
50
Name the lipid derived mediators in mast cells
o Leukotrienes – capillary endothelial contraction with vascular leakage (increased pemeability
o Prostaglandin D2 – potent inducer of smooth muscle contraction
o Platelet activating factor – increases platelet aggregation, degranulation, increases vascular permeability and activates neutrophil secretion
51
Name indirect activators of mast cells
o Allergens
o Latex, wasp/bee venoms, foods, drugs, pollens, house dust mite faeces, animal dander
o Prior sensitization is required (generally through mucosal surface)
o Bacterial/viral antigens
o Protein L of Pneumococcus magnus; protein A of S. aureus – superantigens
o gp120 of HIV-1
52
Name the direct mast cell activators
o Cold/mechanical deformation (asthma?)
| o Aspirin, tartrazine, preservatives, NO2, latex, proteases
53
What do beta lactams do?
Destroy cell walls
54
Why are cephalosporins used?
- Good for people with penicillin allergy
- Better for more resistant bugs
- Are able to access different parts of the body (meningitis)
55
Explain the use of glycopeptides
* Cell wall destruction
* Vancomycin and teicoplanin
* Gram positive activity only
* Use in MRSA and penicillin allergy
56
Name the 5 antibiotic functional groups
```
o Inhibitors of cell wall synthesis
o Inhibitors of protein synthesis
o Inhibitors of nucleic acid synthesis
o Anti-metabolites
o Inhibitors of membrane function
```
57
Explain the use of macrolides
* Inhibit protein synthesis
* Clarithromycin and erythromycin
* Activity: gram positives and atypical pneumonia pathogens
58
Explain the use of lincoasmides
* Inhibit protein synthesis
* Clindamycin
* Activity – gram positives
* Use- cellulitis if penicillin allergy and necrotising fasciitis
59
Explain the use of tetracyclines
* Inhibit protein synthesis
* Doxycycline (oral)
* Activity – broad spectrum but mainly gram positive
* Use – cellulitis if penicillin allergy and chest infections
60
Explain the use of Ciprofloxacin
* IV and oral
* Activity – gram negative
* Use – urinary tract infections, gallbladder infections and abdominal infections
61
Explain the use of trimethoprim
o Activity – broad spectrum but mainly used for gram negatives
o Use- urinary tract infections
62
Explain the use of nitrofurantoin
o Activity – gram negatives
| o Use – urinary tract infections
63
What is a tumour?
Any abnormal swelling
64
What is a neoplasm?
A lesion resulting from the autonomous or relatively autonomous abnormal growth of cells which persists after initiating stimulus has been removed (a new growth made up of neoplastic cells and stroma)
65
What are neoplastic cells?
o Derive from nucleated cells
o Usually monoclonal
o Growth pattern related to parent cell
o Synthetic activity related to parent cell (collagen, mucin, keratin and hormones)
66
What is the stroma of a neoplasm?
o Connective tissue framework
o Mechanical support
o Nutrition
67
Characterise a benign neoplasm
* Localised
* Non-invasive
* Slow growth rate
* Low mitotic activity
* Close resemblance to normal tissue
* Circumscribed or encapsulated
* Nuclear morphometry often normal
* Necrosis and ulceration rare
* Growth on mucosal surfaces often exophytic
68
Why worry about benign neoplasms?
```
o Pressure on adjacent structures
o Obstruct flow
o Production of hormones
o Transformation to malignant neoplasm
o Anxiety
```
69
Characterise malignant neoplasms
* Invasive
* Metastases
* Rapid growth rate
* Variable resemblance to normal tissue
* Poorly defined or irregular border
* Hyperchromatic, pleomorphic nuclei
* Increased mitotic activity
* Necrosis and ulceration common
* Growth on mucosal surfaces and skin often endophytic
* Encroach upon and destroy surrounding tissue
* Are poorly circumscribed
* Have a crab like cut surface
70
Why worry about malignant neoplasms?
```
o Destruction of adjacent tissue
o Metastases
o Blood loss from ulcers
o Obstruction of flow
o Hormone production
o Paraneoplastic effects
o Anxiety and pain
```
71
Where might neoplasms arise from?
o Epithelial cells
o Connective tissues
o Lymphoid/haemopoietic organs
72
Name two types of benign epithelial neoplasm
* Papilloma – Benign tumour of non-glandular, non-secretory epithelium
* Adenoma – benign tumour of glandular or secretory epithelium
73
Name two types of malignant epithelial neoplasms
* Carcinoma – malignant tumour of epithelial cells
| * Carcinomas of glandular epithelium – adenocarcinoma
74
Define carcinogenesis
The transformation of normal cells to neoplastic cells through permanent genetic alterations or mutations and applies to malignant neoplasms
75
Define carcinogen
Agent known or suspected to cause cancer
Carcinogenic - cancer causing
Oncogenic - tumour causing
76
Discuss chemical carcinogens
o No common structural features
o Some act directly
o Most require metabolic conversions from pro-carcinogens to ultimate carcinogens
o Enzyme required may be ubiquitous or confined to certain organs
o Examples include aromatic amines, nitrosamines, polycyclic aromatic hydrocarbons and alkylating agents
77
Discuss radiant energy as a carcinogen
o UV light and increased exposure to UVA or UVB
| o Ionising radiation with long term effect
78
Discuss biological agents as carcinogens
o Hormones – oestrogen and anabolic steroids
o Mycotoxins
o Parasites
79
Discuss host factors as carcinogens
```
o Race
o Inherited predisposition
o Age
o Gender
o Premalignant conditions
```
80
What are the mediators of the autonomic nervous system?
* Parasympathetic and sympathetic fibres coming out of the CNS both release acetylcholine, which acts on specific receptors called nicotinic receptors
* The post-ganglionic parasympathetic fibres release more acetylcholine, this time acting on muscarinic receptors
* The post ganglionic sympathetic fibres release noradrenaline, acting on alpha and beta adrenoreceptors (except when they innervate sweat glands where they release acetylcholine to stimulate muscarinic receptors)
* The non-adrenergic, non-cholinergic autonomic nervous system also releases and uses other neurotransmitters such as nitric oxide and vasoactive intestinal peptide (parasympathetic) or ATP and neuropeptide Y (sympathetic system)
* Multiple transmitters can be released at any one time exerting mixed effects with slightly different time courses
81
What is the role of nicotine in cholinergic pharmacology?
Nicotine stimulates all autonomic ganglia via specific ganglionic nicotinic receptors, activating both sympathetic and parasympathetic nervous
82
What is the role of muscarine in cholinergic pharmacology?
Muscarine activates the muscarinic receptors of the parasympathetic nervous system
83
Where are muscarinic receptors found?
* M1: Mainly in the brain
* M2: Mainly in the heart – their activation slows the heart
* M3: Glandular and smooth muscle – cause bronchoconstriction, sweating, salivary gland secretion
* M4/5: Mainly in the CNS
84
Give an example of a muscarinic agonist
Pilocarpine
stimulates salivation, activating the parasympathetic nervous system
• Contracts iris smooth muscle so may be used to treat glaucoma by facilitating drainage of aqueous humour (parasympathetic nervous system)
85
Name the catecholamines and their sites of release
* Noradrenaline – released from sympathetic nerves fibre ends
* Adrenaline – released from the adrenal glands (fight or flight, management of anaphylaxis
* Dopamine – precursor or adrenaline and noradrenaline
86
What are alpha agonists?
* Alpha 1 activation causes vasoconstriction, particularly in the skin and splanchnic beds
* Used in treatment of septic shock
* Adrenaline will raise blood pressure and cardiac work
* Alpha 2 agonists lower blood pressure
87
What are alpha blockers?
* Opposing effects to agonists
| * Block alpha 1 to lower blood pressure
88
What are beta agonists?
* Beta 1 activation will increase heart rate and chronotropic effects and may increase risk of arrhythmias
* Beta 2 causes muscle relaxation
* Beta agonists will cause tachycardia and affect glucose metabolism in the liver (beta 1/3 affect carbohydrate and lipid metabolism
* Beta 3 agonists can reduce over active bladder symptoms
89
What are beta blockers?
• Lower blood pressure (By reduction in cardiac output and gradual reductions in central sympathetic outflow activity), reduce cardiac work and treat arrhythmias
90
What is chronic inflammation?
The subsequent and prolonged tissue response following the initial response
91
Name 4 causes of chronic inflammation
* Primary chronic inflammation
* Transplant rejection
* Progression from acute inflammation
* Recurrent episodes of acute inflammation
92
Suggest the macroscopic features of chronic inflammation
* Chronic ulcer
* Chronic abscess cavity
* Thickening of the wall of a hollow viscus
* Granulomatous inflammation
* Fibrosis
93
Suggest the microscopic features of chronic inflammation
* The cellular infiltrate consists characteristically of lymphocytes plasma cells and macrophages
* A few eosinophil polymorphs may be present, but neutrophil polymorphs are scarce
* Some of the macrophages may form multinucleate giant cells
* Exudation of fluid is not a prominent feature but there may be production of new fibrous tissue from granulation tissue
* There may be evidence of continuing destruction of tissue at the same time as tissue regeneration and repair
* Tissue necrosis may be a prominent feature, especially in granulomatous conditions such as tuberculosis
94
How do growth factors regulated angiogenesis?
Bind to specific receptors on cell membranes and trigger a series of events culminating in cell proliferation
95
How do macrophages move?
Amoeboid motion through tissues
96
What is a granuloma?
An aggregate of epithelioid histiocytes
97
What are epithelioid histiocytes?
o Large vesicular nuclei
o Eosinophilic cytoplasm
o Elongated
o Tend to be arranged in clusters
o Little phagocytic activity but adapted to a secretory function
o One product is angiotensin converting enzyme
o Measurement of ACE can act as a marker for systemic granulomatous disease
98
where do histiocytic giant cells tend to form?
- where particulate matter that is indigestible by macrophages accumulates
- When foreign particles are too large to be digested by just one macrophage
99
How do histiocytic giant cells form?
They develop when two or more macrophages attempt to simultaneously engulf the same particle
100
Define the process of drug development
```
• Drug development is the process of bringing a new pharmaceutical drug to the market.
o lead compound identification
o pre-clinical research
o filing for regulatory status
o clinical trials. on humans
o marketing the drug.
```
101
What is a stereoisomer?
• Stereoisomers - stereoisomers have the same molecular formula and sequence of bonded atoms,but differ in the three-dimensional orientations of their atoms in space.
102
Name and explain 2 types of drug interaction
* Synergy – when the interaction causes an increase in the effects of one or both the drugs
* Antagonist – Interaction causes a decrease in effect of one or both drugs
103
Suggest patient risk factors for drug interaction
* Polypharmacy
* Old age
* Genetics
* Hepatic disease
* Renal disease
104
What is a narrow therapeutic index?
o Where the difference between the effective dose and toxic dose is small
105
What is a steep dose-response curve?
o Small changes in the dosage of a drug produce large changes in the drug’s concentration in the patient’s blood plasma
106
What is saturable hepatic metabolism?
o In addition to dose effects the capacity to metabolise the drug is greatly decreased
107
Explain the antigonic physiological systems
o a drug A that acts on a certain organ.
o This effect will increase with increasing concentrations of physiological substance S in the organism.
o Now drug B acts on another organ, which increases the amount of substance S.
o If both drugs are taken simultaneously it is possible that drug A could cause an adverse reaction in the organism as its effect will be indirectly increased by the action of drug B
108
How do changes in motility effect drug absorption?
o Some drugs, such as the prokinetic agents increase the speed with which a substance passes through the intestines. If a drug is present in the digestive tract's absorption zone for less time its blood concentration will decrease. The opposite will occur with drugs that decrease intestinal motility
109
How does pH affect drug absorption?
o Drugs can be present in either ionised or non-ionised form, depending on their pKa (pH at which the drug reaches equilibrium between its ionised and non-ionised form).
o The non-ionized forms of drugs are usually easier to absorb, because they will not be repelled by the lipid bilayer of the cell, most of them can be absorbed by passive diffusion, unless they are too big or too polarized, in which case they may have non-specific transporters distributed on the entire intestine internal surface, that carries drugs inside the body.
110
How can you avoid drug interactions?
* Prescribe rationally
* BNF
* Medicines information system
* Ward pharmacist
* Patient information leaflet
* Internet
111
What is a drug?
a medicine or other substance which has a physiological effect when ingested or otherwise introduced into the body
112
Define ligandability
The ability of a protein target to bind to small molecules with high affinity
113
What is a drug 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
114
Name different types of drug receptor
o Ligand gated ion channel – nicotinic ACh receptor
o G protein coupled receptor – beta adrenoreceptors
o Kinase linked receptors – receptors for growth factors
o Cytosolic/nuclear receptors – steroid receptors
• G protein coupled receptors
o Largest and most diverse group of membrane receptors in eukaryotes
o Ligands include light energy, peptides, lipids, sugars and proteins
115
What is an agonist?
A compound that binds to a receptor and activates it
116
What is an antagonist?
A compound that reduces the effect of an agonist
117
What is an enzyme inhibitor?
* An enzyme inhibitor is a molecule that binds to an enzyme and decreases its activity
* An enzyme inhibitor prevents the substrate from entering the enzymes active site and prevents it from catalysing its reaction
118
What are statins?
* Block the rate limiting step in the cholesterol pathway
* A class of lipid-lowering medication that reduces the levels of LDL
* Reduce cardiovascular disease and mortality in high risk patients
119
Explain the difference between uniporters, supporters and anti porters.
* Uniporters – use energy from ATP to pull molecules in
* Symporters – use the movement of one molecule in to pull in another molecule against a concentration gradient (Na-K-Cl transporter e.g. furosemide inhibits NKCC in ascending loop of Henle)
* Antiporters – one substance moves against its gradient, using energy from the second substance moving down its gradient
120
What are fungi?
* Eukaryotic
* Chitinous cell wall
* Heterotrophic
* Move by means of growth or through the generation of spores which are carried through air or water
121
What is the difference between yeast and mould?
* Yeasts are small single celled organisms that divide by budding
* Moulds form multicellular hyphae and spores
* Some fungi exist as both yeasts and moulds switching between the two when conditions suit – dimorphic fungi
122
Explain the effect of fungi on humans
```
• Few cause human infection
o Inability to grow at 37oC
o Innate and adaptive immune response
• The vast majority of human mycoses are caused by very few genera
• Life threatening fungal disease occurs in:
o Immunocompromised hosts
o Post surgical patients
o Travel-associated fungal infections
Dimorphic fungi
```
123
Explain the process of treating fungal disease
* Aim of antimicrobial drug therapy is to achieve inhibitory levels of agent at the site of infection without host cell toxicity
* Relies upon identifying molecules with selective toxicity for organism targets
* Target does not exist in humans
* Target is significantly different to human analogue
* Drug is concentrated in organism cell with respect to humans
* Increased permeability to compound
* Modification of compound in organism or human cellular environment
* Human cells are “rescued” from toxicity by alternative metabolic pathways
* Generally much more difficult for fungi than bacteria because they are eukaryotic
124
What is the virulence factor?
any product that contributes to pathogenicity/virulence
125
What is a gram negative bacteria?
A bacteria consisting of fewer layers of peptidoglycan in the cell wall and a second cell surface membrane consisting of lipoproteins and lipopolysaccharides
126
Explain the process of serogrouping
• Lancefield grouping is a method of grouping coagulase negative bacteria based on bacterial carbohydrate cell surface antigens
o Lancefield A-H and K-V
o Antiserum to each group added to a suspension of bacteria and clumping indicates recognition
• Not all groups are equally important
o Group A – S.pyogenes: important pathogen
o Group B – S.agalactiae: neonatal infections
127
What is a gram positive bacteria?
A bacteria with multiple layers of peptidoglycan in the cell wall
128
Outline the processes involved in viral replication
* Attachment – viral and cell receptors
* Cell entry – only central viral core carrying the nucleic acid and some associated proteins enter host cell
* Interaction with host cells – Use cell materials (enzymes, amino acids and nucleotides) for their replication and undermine host cell defence mechanism
* Replication – may localise in nucleus, cytoplasm or at cell membranes
* Release – By cell lysis or exocytosis from the cell over a period of time (HIV)
129
How does HIV replicate?
Glycoproteins on the HIV molecule (gP160 made of gP120 and gP 41) allow it to attach and fuse onto the CD4 and CCR5 receptors
The viral capsid the enters the cell and enzymes and nucleic acid are uncoated and released
Using reverse transcriptase single stranded RNA is converted into double stranded DNA
Viral DNA then is integrated into the cells own DNA by integrase enzyme
When the infected cell divides the viral DNA is read and transcibed and long chains of viral proteins are made
viral RNA is repackaged (spliced) and protein chains are cleaved and reassembled by the protease enzyme into individual proteins that combine to form a working virus
Budding here immature virus pushes out of the cell taking with it some cell membrane
Immature virus breaks free to undergo more maturation
130
Outline the genomic structures involved in HIV
* POL- Encodes the enzymes reverse transcriptase, integrase and protease
* ENV- Encodes the envelope proteins
* NEF- Increases infectivity
* Tat – Contributes to viral replication and enhances production of host transcription factors (NF-kB)
* GAG – Encodes structural proteins – made as a polyprotein and cleaved by HIV protease
* REV – Binds to viral RNA and allows export from nucleus and also regulates splicing
131
outline the initial infection process of HIV
* Virus enters via mucosa – vagina, rectum, intestinal (at delivery or via breastfeeding in infants)
* Likely on a single ‘founder virus’ enters.
* Local infection within a mucosal macrophage or dendritic cell is established and then spreads to other cells
* As these are antigen presenting cells, some will migrate to local lymph node to present antigen to T cells
* Now the virus from the macrophage infects the T cell and subsequent T cells, these leave the lymph node and infection spills into the blood stream resulting in viraemia.
* Exponential rise in T cell infection occurs
132
How does the humoral immune response respond to HIV?
– Neutralising antibodies against primary isolates are of low magnitude.
– The envelope glycoprotein is poorly immuogenic and shows genetic diversity.
133
How does the cell mediated immune system respond to HIV?
– CD8 (cytotoxic T lymphocytes) play a role in early decline in virus but are incomplete.
– MHC class I-restricted CTL are observed within peripheral blood within a few months of infection and persist during chronic phase,
– Virus escapes from CTL responses through mutations
– CTL responses are quantitatively and qualitatively poor
– Unlike most viral infections HIV infection results in a paucity of virus specific CD4+ T-lymphocyte responses.
– Failure of CD4+ T-lymphocyte proliferation.
134
Outline the consequences on CD4+ lymphocytes on HIV
* Excessive and inappropriate activation
* Decreased proliferation with antigens or mitogens.
* Impaired production of IL-2 and IL-2R.
* Preferential involvement of memory T- cells.
* Skewing of CD4+T-cell receptor Vb repertoire.
* Progressive decline in number and function of CD4 T-lymphocytes characterises HIV infection and leads to susceptibility to infection.
135
Outline the mechanism by which CD4+ become depleted in HIV
* Direct cytotoxicity of directly infected cells
* Potential mechanisms:
* impaired cell homeostasis, syncytia formation, apoptosis and immune-mediated.
* Bystander cell killing
* Apoptosis; gp120 binding to CD4 sensitising cells to apoptosis. Fas Ligand upregulation by tat.
* Decreased production.
* Infection of CD34+ progenitors in bone marrow.
* Infection of Thymocyte progenitors and disruption of thymic microenvironment.
* Redistribution.
* Significant trafficking of CD4+ T-cells from periphery to lymphoid tissue.
136
Outline other examples of immune dysfunction in HIV
* CD8+ T-cells show enhanced activation and decreased cytolytic and non-cytolytic function.
* B-cells show enhanced activation and decreased proliferation resulting in increased non-specific but decreased specific Ab production.
* Decreased NK, neutrophil and Macrophage function.
* Perturbed cytokine networks: ↓Th1 responses, ↑Th2/Th0.
137
Where are common reservoir sites of HIV?
```
o Genital tract
o Central nervous system
o gastrointestinal system
o bone marrow
• Particular cells act as reservoir too
o Macrophages and microglia
o Resting T-cells such as CD4+ CD45RO+ memory cells only support replication when activated.
```
138
What are the benefit of being aware of HIV status?
* Access to appropriate treatment and care
* Reduction in morbidity and mortality
* Reduction in mother-to-child-transmission (MTCT)
* Reduction of sexual transmission
* Public health
* Cost-effective - Savings on social care, lost working days, benefits claimed, costs associated with further onward transmission
139
Identify at risk groups for HIV
* Men who have sex with men
* Heterosexual women
* Injecting drug users
* Commercial Sex Workers
* Heterosexual men
* Truck Drivers
* Migrant workers
* Most affected age group is 15-24 year olds
140
What is innate immunity?
non-specific, instinctive and not dependant on lymphocytes
141
What is adaptive immunity?
specific acquired immunity, requires lymphocytes and antibodies
142
Discuss neutrophils
* 10-14uM
* 3-11,000 per mm3 of blood
* Lifespan of 6 hours to 12 days
* Play important role in innate immunity
* Primary lysosomes contain myeloperoxidase, muramidase, acid hydrolases and proteins (defensins)
* Secondary granules contain lactoferrin and lysozyme
* Primary lysosomes combine with phagosomes containing microbes to digest them
* Have Fc and complement receptors (IgG)
* Can kill microbe by secreting toxic substances (superoxides)
143
Discuss monocytes
* Mononuclear leukocyte
* 14-24uM
* 100-700 per mm3 of blood
* Lifespan ranges months
* Play an important role in innate and adaptive immunity, phagocytosis and antigen presentation
* Differentiate into macrophages in the tissues
* Have lysosomes containing peroxidase that can kill microbes
* Have Fc and complement receptors
* Have pattern recognition receptors, toll like receptors and mannose receptors
144
Discuss macrophages
* Reside in tissues
* Lifespan ranges from months/years
* Play important role in innate and adaptive immunity, phagocytosis and antigen presentation
* Most often first line of non-self recognition
* Main role is to remove foreign (microbes) and self (dead/tumour cells)
* Have lysosomes containing peroxidase (free radicals)
* Have Fc and complement receptors
* Have scavenger, toll like and mannose receptors
* Present antigens to T-cells
145
Discuss eosinophils
* 10-14uM
* 100-400 per mm3 blood
* Lifespan of 8-12 days
* Granules stain for acidic dyes
* Mainly associated with parasitic infections and allergic reactions
* Granules contain major basic protein – a potent toxin for helminth worms
* Major basic protein activates neutrophils, induces histamine release from mast cells and provokes bronchospasm
* Polymorphonuclear leukocyte
146
Discuss basophils
* 10-12uM
* 20-50 per mm3 of blood
* Lifespan of 2 days
* Polymorphonuclear leukocyte
* Granules stain for basic dyes
* Very similar to mast cells
* Express high affinity IgE receptors
* Binding of IgE to receptor causes degranulation releasing histamine, the main cause of allergic reactions
* Mainly involved in immunity to parasitic infections and allergic reactions
147
Discuss mast cells
* 10-14uM
* Only in tissues
* Very similar to basophils
* Express high affinity IgE receptors
* Binding of IgE to receptor causes degranulation releasing histamine which is the main cause of allergic reactions
* Mainly involved in immunity to parasitic infections and allergic reactions
148
Discuss T-lymphocytes
* Mononuclear leukocyte that matures in thymus
* 5-12uM
* 300-1,500 per mm3 blood, found in blood, lymph nodes and spleen
* Lifespan of hours to years
* Recognise peptide antigen displayed by antigen presenting cells
* T helper 1 (CD4) – Help immune response to intracellular pathogens
* T helper 2 (CD4) – Help produce antibodies to extracellular pathogens
* Cytotoxic T cell (CD8) – Can kill cells directly
* T reg – regulate immune responses
149
Discuss b-lymphocytes
* Mononuclear leukocyte
* 5-12uM
* 300-1,500 per mm3 of blood
* Lifespan from hours to years
* Recognise antigen displayed by antigen presenting cells
* Express membrane bound antibody on cell surface
* Differentiate into plasma cells that make antibodies
* Found in blood, lymph nodes and spleen
150
What is the role of natural killer cells in the immune response?
• Recognise and kill virus infected cells and tumour cells by apoptosis
151
Describe the complement system
* Group of around 20 serum proteins that need to be activated to be functional
* Classical – antibody bound to microbe
* Alternative – complement binds to microbe
* Lectin – activated by mannose binding lectin bound to microbe
* Can lyse microbes directly, increase chemotaxis and opsonisation
152
What is an epitope?
The part of the antigen that binds to the antibody receptor binding site
153
What is affinity?
Measure of the binding strength between an epitope and an antibody binding site
154
Describe IgG
* Predominant in human serum
| * 70-75% of total Ig in serum
155
Describe IgM
* Accounts for 10% of Ig in serum
* Pentamer, formation requires J chain
* Mainly found in blood (cannot cross endothelium due to large size)
* Mainly primary response, initial contact with antigen
* The monomeric from is present as an antigen specific receptor on B cells
156
Describe IgA
* Accounts for 15% of Ig in serum
* In humans, 80% of serum IgA is as a monomer
* The predominant Ig in mucous secretions such as saliva, colostrum, milk, bronchiolar and genitourinary secretions
157
Describe IgD
* Accounts for 1% of Ig in serum
| * A transmembrane monomeric form is present on mature B cells
158
Describe IgE
* Accounts for roughly 0.05% of serum Ig
* Basophils and mast cells express an IgE specific receptor that has high affinity for IgE
* Basophils and mast cells are continually saturated with IgE
* Binding antigens trigger release of histamine by these cells
* Associated with allergic response and defence against parasitic infections
159
What are cytokines?
proteins secreted by immune and non-immune cells
160
What are interferons?
o Induce a state of antiviral resistance in uninfected cells and limit spread of infection
o IFN alpha and beta – produced by virus infected cells
o IFN gamma – released by activated Th1 cells
161
What are interleukins?
o Produced by many cells
o Can be proinflammatory or anti-inflammatory
o Can cause cells to divide, differentiate and secrete factors
162
What are colony stimulating factors?
o Involved in directing the division and differentiation on bone marrow stem cells
o Precursors of leukocytes
163
What is tumour necrosis factor?
o Mediate inflammation and cytotoxic reactions
164
What are chemokines?
• Chemotactic cytokines
• Group of approximately 40 proteins that direct movement of leukocytes and other cells from the blood stream into the tissues or lymph organs by binding to specific receptors on cells
The attract leukocytes to sites of infection and inflammation
165
How do antibodies exert their effect?
* Neutralise toxin by binding to it
* Increase opsonisation – phagocytosis
* Activate complement
166
What are some differences between innate and adaptive immunity?
Adaptive Immunity
• Response is specific to antigen
• Memory is specific to antigen
• Quicker response
Innate Immunity
* First line of defence
* Provides barrier to antigen
* Is present from birth
* Primitive
* Instinctive response
* Does not depend on immune recognition by lymphocytes
* Does not have long lasting memory
167
Suggest physical barriers to infection
```
o Skin
o Sebum (pH 3-5)
o Intact skin prevents penetration and growth
o Lysozyme in tears
o Mucus and cilia
o Gut acids
o Flushing of urinary tract
o Temperature
• Mucous membranes
o Saliva
o Tears
o Mucous secretions and entrapment
o Cilia beat to remove microbes
o Commensal colonies for attachment and nutrients
```
168
Outline 2 mechanisms of bacteria destruction
• O2 dependent
o Reactive oxygen intermediates
o Superoxides converted to hydrogen peroxide then hydroxyl radical
o Nitric oxide causes vasodilation increasing extravasation
• O2 independent
o Enzymes such as defensins, lysozymes, pH, TNF
169
Name 3 accessory molecules to inflammation
* C reactive protein – Serum protein produced by the liver, binds to some bacterial cell walls and promotes opsonisation, binds to C1q and activates complement
* Mannose binding lectin – binds to lectin on microbes, promotes opsonisation via MBLR and activates complement
* Surfactant protein-A – binds haemagglutinin in influenza and reduces ability of virus to infect cells
170
What is the role of major histocompatibility complex?
* Display peptides from self or non-self proteins (eg. degraded microbial proteins) on the cell surface – invasion alert
* In humans coded by Human Leukocyte antigen (HLA) genes
* MHC I – coded by HLA (A, B & C genes) - glycoproteins on ALL nucleated cells (graft rejection).
* MHC II - coded by HLA (DP, DQ& DR) - glycoproteins ONLY on antigen presenting cells
* MHC III – code for secreted proteins (complement)
171
Name three routes of infection transmission and how they can be managed
* Environment – design, cleaning, isolation
* Staff – barrier precautions, isolation, handwashing
* Patients – isolation, antimicrobial stewardship
172
When should hand washing take place?
– Before and after handling patients/clients
– After handling any item that is soiled
– After using the toilet
– Before and after handling food
– Before and after an aseptic procedure
– After removing protective clothing including gloves
173
When should alcohol gel be used?
– Following hand washing, prior to a ward based invasive procedure
– Following hand washing, when caring for a patient with barrier precautions
– Between tasks, when hands are visibly clean
174
What is endogenous infection and how can it be prevented?
• Infection of a patient by their own flora
• Important in hospitalised patients, especially those with invasive devices or surgical patients
• Prevention
o Good nutrition and hydration
o Antisepsis/skin prep where indicated
o Control underlying disease - Drain pus
o Remove lines and catheters as soon as clinically possible
o Reduce antibiotic pressure as much as clinically possible e.g. short courses, narrow spectrum
175
What are pathogens?
Micro-organisms capable of causing disease
176
Suggest 3 key attributes of a pathogen
o Infectivity, the ability to become established in host, can involve adherence and immune escape
o Virulence, the ability to to cause disease once established
o Invasiveness, the capacity to penetrate mucosal surfaces to reach normally sterile sites
177
What is the microbiome?
The totality of micro-organisms, their genetic elements and their environmental interactions in an environment.
178
How are toxins classified?
o tissue target
o molecular action
o biological effect
o contribution to disease process
179
How do bacteria compete with host cells and colonising flora?
```
o sequestering nutrients
o using novel metabolic pathways
o out-competing other micro-organisms
• This involves sensing changes in competing bacteria, in cell density, in nutrient availability and other environmental factors using ‘two component sensor-kinase’ systems to alter gene transcription regulating
o Virulence factors
o Competence to exchange genetic material
o Biofilm formation
o Production of bacteriocins
```
180
What are adhesions?
• Help bacteria bind to mucosal surfaces
• Types:
o Fimbriae and pili filamentous proteins e.g. Neisseria gonorrhoeae
o Non fimbrial proteins e.g. Fibronectin binding protein of Treponema pallidum
o Lipid e.g. lipid teichoic acid of Streptococcus pyogenes
o Glycosaminoglycans of Chalmydia sp.
o Lectins of viruses and parasites
o Miscellaneous viral capsids, gripping disc of Giardia lamblia
181
How do opioids work?
* Use existing pain modulation system
* G protein coupled receptors – act via secondary messengers
* Inhibit the release of pain transmitters at spinal cord and midbrain and modulate pain perception in higher centres to change the emotional perception of pain
182
What is potency?
whether a drug is strong or weak relates to how well the drug binds to the receptor
183
What is tolerance?
Down regulation of the receptors with prolonged use (higher doses needed to achieve the same effect
184
What are the side effects of opioids?
* Respiratory depression
* Sedation
* Nausea and Vomiting
* Constipation
* Itching
* Immune suppression
* Endocrine effects
185
How is morphine metabolised?
* Morphine is metabolised to morphine 6 glucuronide which is more potent than morphine and is renally excreted
* With normal renal function this is cleared quickly
* In renal failure it will build up and may cause respiratory depression
* Caution in patients with renal failure <30% renal function
* Use oxycodone if morphine use will be dangerous
186
What are cell associated pattern recognition receptors?
* Receptors that are present on the cell membrane or in the cytosol of the cells
* Recognise a broad range of molecular patterns
* Toll like receptors are the main family
187
What are membrane bound pattern recognition receptors?
• Family of receptors that may participate in pathogen recognition and particularly in pathogen phagocytosis
o Mannose receptor on macrophages (fungi)
o Dectin-1 (widespread on phagocytes, helps recognise beta glucans in fungal walls)
o Scavenger receptors on macrophages
188
What are nod-like receptors?
• Detect intracellular microbial pathogens by detecting peptidoglycan, muramyl dipeptide
• NOD2
o Widespread expression
o Recognises muramyl dipeptide, a breakdown product of peptidoglycan
o Activates inflammatory signalling pathways
o Non-functioning mutations – Crohn’s disease
o Hyperfunctioning mutations – Blau syndrome
189
What are rig-like receptors?
* Detect intracellular double stranded viral RNA and DNA
| * They couple effectively to activation of interferon production, enabling antiviral response
190
How does damage recognition stimulate the immune response?
• Toll like receptor are adapted to recognise a range of endogenous damage molecules which may share characteristics of hydrophobicity
• Appearance of host molecules in unfamiliar contexts can activate toll like receptors
• Toll like receptor signalling by cellular damage products activates immunity to initiate tissue repair and perhaps enhance local antimicrobial
• Damage molecules
o Extracellular – fibrinogen, hyaluronic acid, tenascin C
o Intracellular – HMGB1, mRNA, heat shock proteins, uric acid, stathmin
191
What is the role of pattern recognition receptors in adaptive immunity?
* Activation of TLR’s and other PRR’s drives cytokine production by antigen presenting cells that can increase the likelihood of successful T cell activation
* TLR4 agonists already used as vaccine adjuvants
192
What is the role of pattern recognition receptors in disease?
* Recognition of host molecules in autoimmune disease
* Failure to recognise pathogens or increased inflammatory responses
* Atherosclerosis, arthritis, COPD, inflammatory bowel disease
193
Name the routes of drug administration
```
o Oral
o Intravenous
o Intraarterial
o Intramuscular
o Subcutaneous
o Inhalational
o Topical
o Sublingual
o Rectal
o Intrathecal
```
194
What is pharmacokinetics?
• The action of drugs in the body including absorption, distribution, metabolism and excretion
195
Define drug absorption
• Absorption is the process of transfer from the site of administration into the general or systemic circulation
196
What is pinocytosis?
* A form of carrier mediated entry into the cytoplasm
* Usually involved in the uptake of endogenous macromolecules and can be involved in the uptake of recombinant therapeutic proteins
197
Discuss drug ionisation
* Ionisation is a basic property of most drugs that are either weak acids or weak bases
* Ionisable groups are essential for the mechanism of action of most drugs as ionic forces are part of the ligand receptor interaction
* Drugs with ionisable groups exist in equilibrium between charged and uncharged forms
* The extent of ionisation depends on the strength of the ionisable group and the pH of the solution
* Ionised form regarded as most water soluble and un-ionised as lipid soluble
198
Why is oral drug delivery the most convenient?
• Large surface area and high blood flow of small intestine can give rapid and complete absorption of oral drugs
199
Evaluate transcutaneous drug delivery
* Human epidermis is an effective barrier to water soluble compounds
* Limited rate and extent of absorption of lipid soluble drugs
* Need potent, non-irritant drugs
* Slow and continued absorption useful with transdermal patches
200
Evaluate intradermal and subcutaneous drug delivery
* Avoids barrier of stratum corneum
* Mainly limited by blood flow
* Small volume can be given
* Use for local effect or to deliberately limit rate of absorption
201
Evaluate intramuscular drug delivery
* Depends on blood flow and water solubility
* Increase in either enhances removal of drug from injection site
* Can make a depot injection by incorporating drug into lipophilic formulation which releases drug over days or weeks
202
Evaluate intranasal drug delivery
* Low levels of proteases and drug metabolising enzymes
* Good surface area
* Can be used for local or systemic effects
203
Evaluate inhalation drug delivery
* Large surface area and blood flow but limited by risks of toxicity to alveoli and delivery of non-volatile drugs
* Largely restricted to volatiles such as general anaesthetics and locally acting drugs such as bronchodilators in asthma
* Asthma drugs are non-volatile so given as aerosol or dry powder
204
Define drug distribution
• The process by which the drug is transferred reversibly from the general circulation to the tissues as the blood concentration increases and then returns from the tissues to the blood when the blood concentration falls
205
Why must prescribing guidelines be checked when prescribing to a pregnant woman?
* Lipid soluble drugs readily cross the placenta
* Placental blood flow is relatively low so slow equilibriation with foetus
* Large molecules do not cross placenta
* Foetal liver has low levels of drug metabolising enzymes so relies on maternal elimination
206
Define elimination
* The removal of a drugs activity from the body
* May involve metabolism – the transformation of the drug molecule into a different molecule
* Excretion – the molecule is expelled in liquid, solid or gaseous waste
207
Explain Phase 1 metabolism of drugs
o These reactions involve the transformation of the drug to a more polar metabolite
o This is done by unmasking or adding a functional group
o Oxidations are the most common reactions catalysed by CYP450
o Not all oxidations involve CytP450
o Some drugs are metabolised in plasma (e.g. Suxamethonium & plasma cholinesterase), lung or gut
o Ethanol is metabolised by alcohol dehydrogenase
o Monoamine oxidase inactivates noradrenaline
o Xanthine oxidase inactivates 6-mercaptopurine
o Reductions and hydrolysis also occur
208
Explain phase 2 metabolism of drugs
o Phase 2 conjugation involves the formation of a covalent bond between the drug/phase 1 substrate and an endogenous substrate
o The resulting products are usually less active and readily excreted by the kidneys
209
How are drugs and metabolites excreted?
o Fluids – important for low molecular weight polar compounds
o Solids – faecal elimination important for high molecular weight compounds excreted in bile
o Gases – expired air important for volatiles
210
Define antibiotic
• Agents produced by micro-organisms that kill or inhibit the growth of other micro-organisms in high dilution
211
How do antibiotics work?
o Binding to cell wall and inhibition of cell wall synthesis – penicillin binding proteins
o Interference with nucleic acid synthesis or function
o Inhibition of DNA gyrase
o Inhibition of ribosomal activity and protein synthesis
o Inhibition of folate synthesis and carbon unit metabolism
212
What is bacteriostatic?
• Prevents growth of bacteria
• Antibiotics that inhibit protein synthesis, DNA replication or metabolism
• They also reduce
o Exotoxin production
o Endotoxin surge less likely from gram negative bacteria
o Reduced bacterial component release
• A minimum inhibitory concentration will be required
213
What is bactericidal?
• Kills bacteria
• Antibiotics that generally inhibit cell wall synthesis
• Useful if
o Poor tissue penetration
o Difficult to treat infections
o Need to eradicate infection quickly
• A minimum bactericidal concentration will be required
214
Describe the mechanisms of antibiotic resistance
• Change antibiotic target
o Bacteria changes the molecular confirmation of antibiotic binding site or masks it
• Destroy antibiotic
o The antibiotic is destroyed or inactivated
• Prevent antibiotic access
o Modify the bacterial membrane porin channel size, numbers and selectivity
• Remove antibiotic from bacteria
o Proteins in bacterial membranes act as an export or efflux pump so level of antibiotic is reduced
215
What are protozoa?
* Single celled eukaryotic organisms
* Definitive nucleus
* Consumers of bacteria, algae and microfungi
216
What are flagellate protozoa?
* Flagellum as main locomotor organelle
| * Usually reproduce by binary fission
217
What are amoebae protozoa?
• Move by means of flowing cytoplasm and production of pseudopodia
218
What are sporozoa protozoa?
* No locomotor extensions
* All species are parasitic
* Most are intracellular
* Reproduce by multiple fission
219
What are ciliate protozoa?
* Very large group
* Cilia that beat rhythmically at some stage in lifecycle
* 2 types of nuclei (macronucleus and micronucleus)
220
What are microsporidia protozoa?
* Very small
* Production of resistant spores
* Unique polar filament coiled inside spore
* Little known about human disease; causes diarrhoea in the immunocompromised
221
What are the clinical features of malaria?
```
• Very varied
• FEVER almost invariable
• Other common:
o Chills & sweats
o Headache
o Myalgia
o Fatigue
o Nausea & vomiting
o Diarrhoea
```
222
What is the half-life of a drug?
The time taken for a concentration to reduce by one half
223
What is bioavailability?
The fraction of the administered drug that reaches the systemic circulation unaltered
224
Discuss the distribution of drugs
* Rate and extent of movement of a drug into and out of tissues from blood
* Water soluble drugs rate of distribution depends on rate of passage across membranes
* Lipid soluble drugs rate of distribution depends on blood flow to tissues that accumulate drugs
* The extent of distribution of drugs is more clinically important as this determines the total amount of drug that has to be administered to produce a particular plasma concentration
225
Why is drug administration repeated?
• Repeated drug does are used to maintain a constant drug concentration in the blood and at the site of action for therapeutic effect
226
Explain the use of a loading dose
* If a drug has a long half-life it will take a long time to reach steady state
* If giving a high initial dose this loads the system and shortens the time to steady state
* Loading dose = Css x Vd
* After the loading dose the steady state can be maintained by the maintenance dose given by the equation Css = DxF/t x CL
227
Why are deaths referred to a coroner?
o Presumed natural- caused of death unknown and not seen by a doctor in the last 14 days
o Presumed iatrogenic – Peri/postoperative deaths, anaesthetic deaths, abortion, complications of therapy
o Presumed unnatural – Accident, industrial death, suicide, unlawful killing, neglect, custody death, war/industrial pension
228
Who can refer patients for an autopsy?
o Doctors
o Registrar of births, marriages and deaths
o Relatives, police, anatomical pathology technicians, and other properly interested parties
229
Explain passive immunity
• Transfer of preformed antibodies
• Natural
o The transfer of maternal antibodies across the placenta to the developing foetus
o Provides protection against diphtheria, tetanus, rubella, mumps, poliovirus
• Artificial
o Treatment with pooled normal human IgG or immunoserum against pathogens or toxins
• Does not activate immunological memory so no long term protection
• Antisera is frequently used to neutralise toxins after the immune system eliminated the primary infection (Clostridium tetani and Clostridium botulinum)
230
Explain active immunisation
* Manipulating the immune system to generate a persistent protective response against pathogens by safely mimicking natural infection
* Mobilise the appropriate arms of the immune system and generate immunological memory
* The importance of the memory B cell response depends on the nature of the pathogen
* First stage is to engage the innate immune system
* Elicit danger signals that activate immune system (PAMP’s)
* Engage toll like receptors
* Activate specialist antigen presenting cells
* Engage the adaptive immune system
231
What are capsular polysaccharides?
highly polar, hydrophilic cell surface polymers consisting of oligosaccharide repeating units
• These molecules are the main antigens involved in the protective immunity to encapsulated bacteria
• Capsular polysaccharides interfere with bacterial interactions with phagocytes by blocking opsonisation
232
What is opsonisation?
• Opsonisation is the coating of the organisms by specific antibodies and complement which enables host phagocytes to ingest and destroy invading bacteria
233
What are the advantages of using recombinant vector vaccines?
o Create ideal stimulus to immune system
o Produce immunological memory
o Flexible - different components can be engineered in
o Safe - relative to live attenuated pathogen
234
What are the disadvantages of using recombinant vector vaccines?
o Require refrigeration for transport
o Can cause illness in compromised individuals
o Immune response to virus in subjects can negate effectiveness
235
What is an adjuvant?
```
any substance added to a vaccine to stimulate the immune system
• Can include:
o Whole killed organisms
o Aluminium salts
o Oil in water emulsions
o Saponins
o Monophosphoryl lipid A
o TLR agonist
```
236
What are nematode worms?
(roundwords)
Intestinal
Larva migrans
Tissue (Filaria)
237
What are trematode worms?
```
(flatworms, flukes)
Blood
Liver
Lung
Intestinal
```
238
What are cestode worms?
Tapeworms
Non-invasive
Invasive
239
What are the features of helminth-related diseases?
• Rare in the UK
• Adult worms cannot usually reproduce without a period of development outside the body
o This may involve specific environmental conditions, animal hosts and vectors
• Although they usually produce innumerable larvae or eggs (which may themselves cause disease), the total worm burden cannot increase without constant re-exposure to infection
• The pre-patent period is the interval between infection and the appearance of eggs in the stool
• Some animal species causing human disease never develop into adults within the human body (they cannot adapt fully to the human host)
