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3li.naf@gmail.com By Ali N Al-Mansour organization [Insert Date] Lorem Ipsum Nunc Sit Amet Leo Total: XXX,XXX.XX Basic and clinical science for MRCP BY ALI AL-MANSOUR Cell biology and molecule Cell biology and molecule Cell organelles The table below summarizes the main functions of the major cell organelles: Organelle/macromolecule Endoplasmic reticulum Main function Rough endoplasmic reticulum     translation and folding of new proteins manufacture of lysosomal enzymes site of N-linked glycosylation examples of cells with extensive RER include pancreatic cells, goblet cells, plasma cells Smooth endoplasmic reticulum   Golgi apparatus Mitochondrion Nucleus Lysosome Nucleolus Ribosome Peroxisome Proteasome steroid, lipid synthesis examples of cells with extensive SER include those of the adrenal cortex, hepatocytes, testes, ovaries Modifies, sorts, and packages these molecules that are destined for cell secretion Site of O-linked glycosylation Aerobic respiration Contains mitochondrial genome as circular DNA DNA maintenance and RNA transcription Breakdown of large molecules such as proteins and polysaccharides Ribosome production Translation of RNA into proteins - intimately associated with the rough endoplasmic reticulum and are responsible for protein translation Catabolism of very long chain fatty acids and amino acids Results in the formation of hydrogen peroxide Along with the lysosome pathway involved in degradation of protein molecules that have been tagged with ubiquitin Lysosomes (lysis- breakage, soma- body) carry hydrolases that degrade:     Nucleotides Proteins Lipids, and Phospholipids They also remove carbohydrate, sulfate, or phosphate groups from molecules The Golgi apparatus is part of the cellular endomembrane system, which packages proteins inside the cell prior to secretion Basic and clinical science for MRCP BY ALI AL-MANSOUR Cell biology and molecule Introduction of genetics The enzyme telomerase lengthen it Thus Prokaryotes (microorganisms) preventing the limitation towards cell division It will affect the number of potential cell divisions   Circular DNA, No nuclear membrane Eukaryotes (higher organisms)   Multiple chromosomes, Nuclear membranes Both eukaryotes and prokaryotes have a ribosome, significantly larger in eukaryotes Histones allow DNA to twirl round it to form stable nucleoprotein (nucleosomes) complexes Chromosomes The human karyotype: consists of 22 pairs of autosomes and pair of sex chromosomes totaling 23 pairs altogether Centromeres provide a point of attachment for the mitotic spindle Divide the chromosome into short (p) arm and long (q) arm X-inactivation (also called lyonization) is a process by which one of the two copies of the X chromosome present in female mammals is inactivated The inactive X chromosome is silenced by its being packaged in such a way that it has a transcriptionally inactive structure called heterochromatin (inactivated genes) A Barr body is the inactive X chromosome in a female somatic cell, rendered inactive in a process called lyonization, in those species in which sex is determined by the presence of the Y (including humans) or W chromosome rather than the diploid of the X or Z • Haploid= cell with 23 chromosome as gametes • Diploid= cell with 46 chromosome • Triploid= cell with copies of each Chr • Aneupoid= contain a number of Chr not a multiple of 23 • Trisomy results in 47 chromosomes Transcription of eukaryotic genes requires noncoding sequences (introns) in the mRNA to be spliced out before translation at the ribosome Normal male and female karyotypes are 46, XY and 46, XX NUCLEIC ACID STRUCTURE Telomere are DNA sequence at distal extremities of chromosomal arms, Become progressively shorter with each cell division when it is reduced to a critical length; the cell is not capable of dividing All nucleic acids are polynucleotides A nucleotide consists of three components A base, A pentose sugar, 1-3 phosphate groups There are two kinds of nucleic acids : • (DNA) • (RNA) Basic and clinical science for MRCP BY ALI AL-MANSOUR DNA      Transfer RNA It is a double helix molecule, Each strand consists of a chain of nucleotides Each nucleotide consists of a deoxyribose sugar, a phosphate group and a nitrogenous base Four nitrogenous bases, which occur in DNA: adenine (A), thymidine (T), guanine (G), cytosine (C) (A) & (G) are purines, whilst (T) and (C) are pyrimidines There is specific base pairing: o A with T, two hydrogen bonds o G with C, three hydrogen bonds Single stranded nucleic acid molecule involved with the synthesis of proteins      Core structure is pentose sugar ribose linking the purine bases – (A) and (G) - with the pyrimidines - uracil and (C) messenger RNA Ribosomal RNA Transfer RNA During translation of mRNA, the bases are ‘read’ in a base pair or triplet code, each 3-base pair unit being referred to as a codon Made within the nucleus Functions within the cytoplasm It attaches the correct amino acid to the protein chain being synthesized according to the codon sequence on messenger RNA, which it encounters - translation Ribosomal RNA     RNA: nucleotides, which consist of phosphate, ribose and nitrogen base RNA polymerase is the enzyme that is responsible for synthesing RNA molecules mRNA has codons, which are bound by the anticodons on tRNA during translation of protein synthesis Exons are coding sequences in the mRNA and introns are areas of unknown function Types of RNA involved in gene transcription and translation:       Manufactured in the nucleolus Main constituent of ribosomes within the cytoplasm Messenger RNA RNA  Cell biology and molecule A polynucleotide subtype of RNA, which is produced by the transcription of DNA within the nucleus It passes out of the nucleus to the ribosomes within the cytoplasm Here, the precise sequence is translated into protein RNA splicing Coding sequence is interrupted by non-coding sequences Removal of the introns in RNA transcript modification is called RNA splicing Splicing occurs in the nucleus before transport to the cytoplasm Exons are expressed sequences: these sequences are those present in mature mRNA Basic and clinical science for MRCP BY ALI AL-MANSOUR Gene  Molecular biology techniques A gene is a length of DNA or RNA with a suitable number of base sequences to code for the production of a single polypeptide chain In Man, genes exist in homologous pairs within an allele It consists of exons and introns  Cell biology and molecule Gene mutations;   Mismatch: change in the nucleotide Inversion: nucleotide base removed, reverse directed & reinserted Point mutation; single base pair substitution  The following table shows a very basic summary of molecular biology techniques Technique Southern blotting Northern blotting Western blotting Description Detects DNA Detects RNA Detects proteins Uses gel electrophoresis to separate native proteins by 3-D structure Examples include the confirmatory HIV test Molecular biology techniques   SNOW (South - NOrth - West) DROP (DNA - RNA - Protein) Genome • • • • • • DNA Only about 5% of DNA codes for proteins Human genome: 30.000 genes Each cell expresses 16.000 genes Housekeeping genes: genes expressed in all cells to provide basic function for cell survival (constitutive) Southern blotting detects DNA Transcriptome • • • mRNA Microarray analysis of transcriptome  identify the expressed genes Northern blotting detects RNA Proteome • • • Protein Analysis of the proteome is better as it detects changes at the protein level, not reflected at transcriptome level due to Post translation processing (Bioinformatics) Western blotting can be used to detect and quantify proteins Enzyme-linked immunosorbent assay (ELISA)     A type of biochemical assay used to detect antigens and antibodies A colour changing enzyme is attached to the antibody if looking for an antigen and to an antigen if looking for an antibody The sample therefore changes colour if the antigen or antibody is detected An example includes the initial HIV test DNA analysis Direct testing;     Identify abnormality within a well-known specific gene PCR Restriction enzymes digestion Southern blotting Indirect testing; (linkage analysis) Used when the gene in question has not been identified before It involves tracing DNA markers in more than generation within a family Basic and clinical science for MRCP BY ALI AL-MANSOUR This is used to determine the rough location of the gene responsible for disease, relative to another DNA sequence which has its position already known (a 'genetic marker') Disease genes are mapped by measuring recombination against a panel of different markers This can identify the region of the genome in which the disease gene lies, then allowing more detailed investigation of this region Southern blotting is a laboratory procedure in which DNA fragments that have been electrophoresed through a gel are transferred to a solid membrane such as nitrocellulose The DNA can then be hybridized with a labelled probe and exposed to X ray film Mitosis Occurs in somatic cells Results in diploid daughter cells Daughter cells are genetically identical to parent cell FISH is a form of in situ hybridisation in which the probe is labelled with fluorescent bases, which can then be visualised under a fluorescent microscope Somatic cell hybridisation is a physical gene mapping technique in which somatic cells from two different species are fused and allowed to undergo cell division Chromosomes from one species are selectively lost, resulting in clones with only one or a few chromosomes from one of the species SSCP is a technique for detecting variation in DNA sequence by running single-stranded DNA fragments through a non-denaturing gel Fragments with differing secondary structure (conformation) caused by sequence variation will migrate at different rates   Mitosis Mitosis occurs during the M phase of the cell cycle It describes the process in which somatic cells divide and replicate producing genetically identical diploid daughter cells This allows tissue to grow and renew itself During the S phase of the cell cycle the cell prepares itself for division by duplicating the chromosomes The table below shows the phases of mitosis itself: Prophase Prometaphase Metaphase Cell division The table below demonstrates the key differences: Results in haploid daughter cells Daughter cells contain one homologue of each chromosome pair and are therefore genetically different Somatic cells have 22 pairs of autosomes and pair of sex chromosomes, i.e 46XY or 46XX Cells with a normal chromosome complement are known as diploid cells Gametes (ova or spermatozoa) have a single copy of each chromosome and are known as haploid cells Anaphase There are two types of cell division; mitosis and meiosis Meiosis Occurs in gametes Remember:  'In situ hybridization' It uses a labelled complementary DNA or RNA probe to localise a specific sequence within a tissue Firstly, the tissues are treated to fix the target, and then the probe is added This then hybridises to the target, following which excess probe is washed away In the classical form, the probe is labelled with radiolabelled bases, which can then be identified using plain film Cell biology and molecule Telophase Cytokinesis Chromatin in the nucleus condenses Nuclear membrane breaks down allowing the microtubules to attach to the chromosomes Chromosomes aligned at middle of cell The paired chromosomes separate at the kinetochores and move to opposite sides of the cell Chromatids arrive at opposite poles of cell Actin-myosin complex in the centre of the cell contacts resulting in it being 'pinched' into two daughter cells Basic and clinical science for MRCP BY ALI AL-MANSOUR • Cell division results in daughter cells, each of which can – Enter its own G1 phase – Become an inactive resting (G0) or – Die (cell loss fraction) Cell cycle Phase G0   Notes 'resting' phase quiescent cells such as hepatocytes and more permanently resting cells such as neurons Gap 1, cells increase in size determines length of cell cycle under influence of p53 S   Synthesis of DNA, RNA and histone centrosome duplication G2  Gap 2, cells continue to increase in size M   Exons: segment of the gene transcripted into mRNA then translated into proteins Introns: segment of the gene transcripted then removed by splicing (not translated) Promotor elements: binding sites for initiation of transcription complex at 5’    G1  Mitosis - cell division Cyclins: are proteins key regulators of cell cycles which can bind to enzymes known as cyclin dependent kinases These regulate the progression of the cell cycle Different cyclins are expressed at different stages of the cell cycle TATA box    A promotor element At 25-30 base pairs from the start of transcription Anchor to RNA polymerase II Enhancers    Present at 5’ or 3’ Not obligatory for initiation But ↑ gene expression Transcription factor is a protein that binds to specific DNA sequences, thereby controlling the rate of transcription of genetic information from DNA to messenger RNA   Basal = constitutive - Housekeeping genes Inducible = temporal, spatial expression of genes for tissue phenotype Application of Transcription factor;    Cell biology and molecule Many congenital malformations are due to inherited mutation of TF Can be oncogenic e.g cMyC, P53 Steroids affect TF Basic and clinical science for MRCP BY ALI AL-MANSOUR Protein synthesis consists of two phases Transcription is where one strand of (DNA) double helix is used as a template by (RNA) polymerase to synthesise mRNA from RNA nucleotides The mRNA then migrates into the cytoplasm maturing, for example, by the splicing of non-coding sequences  Transposons are genetic sequences that have been transposed from one part of DNA to another Translation occurs when the ribosome binds to mRNA at the start codon and tRNA brings amino acids into position along the mRNA template Ribosomal RNA interacts with tRNA during translation by providing peptidyl transferase activity  The ribosome moves from codon to codon along the mRNA producing a polypeptide sequence Translation always begins with a methionine residue The mRNA is translated in the 5’ to 3’ direction and is read in groups of bases, which are known as codons New amino acids are added to the carboxyl terminus of the growing peptide chain Plasmids Are circular molecules of bacterial (DNA) separate from the bacterial chromosome They usually:     are small consist of a few thousand base pairs carry one or a few genes, and Have a single origin of replication Genes on plasmids with multiple copies are usually expressed at higher levels In nature these genes often encode for proteins such as those needed for bacterial resistance Plasmids can be used to clone genes by splicing a particular gene into a plasmid and then allowing the bacteria to multiply - this is then called recombinant plasmid DNA Cell biology and molecule Bacteria develop resistance to antibiotics by gaining genes that encode for particular proteins that offer protection to the organism Sometimes this is by mutation and at other times the gene may be acquired from another bacterial species The genes are usually found in plasmids - circular segments of DNA separate from the bacterial chromosome Plasmids can easily spread from one bacteria to another - a sort of resistance package that bacteria can share Restriction enzymes cut DNA at sequences specific for each restriction enzyme HindIII and EcoRI are examples of restriction enzymes DNA ligase and polymerase are involved in joining and linking DNA together EX: Two strains of Staph aureus are isolated and both are resistant to ampicillin Strain retains its resistance to amplicillin when grown from multiple generations in the absence of ampicillin However strain loses its resistance when grown in the absence of ampicillin Which of the following best explains the loss of antibiotic resistance in strain 2? Answer: e) Loss of a plasmid containing the resistance gene Bacteria develop resistance to antibiotics by gaining genes which encode particular proteins which offer protection organism Sometimes this occurs by mutation but at other times gene may be acquired from another bacterial species The genes are contained in plasmids (circular segments of DNA) separate from bacterial chromosome Plasmids can easily spread from one bacteria or equally lost Transfer, loss and gain of plasmids are relatively common compared to single mutations Basic and clinical science for MRCP BY ALI AL-MANSOUR Cell biology and molecule PCR The following cycle then takes place PCR is a molecular genetic investigation technique The main advantage of PCR is its sensitivity Mixture is heated to almost boiling point causing denaturing (uncoiling) of DNA Only one strand of sample DNA is needed to detect a particular DNA sequence Mixture is the allowed to cool: complimentary strands of DNA pair up, as there is an excess of the primer sequences they pair with DNA preferentially It now has many uses including prenatal diagnosis, detection of mutated oncogenes and diagnosis of infections The above cycle is then repeated, with the amount of DNA doubling each time PCR is also extensively used in forensics Prior to the procedure it is necessary to have two DNA oligonucleotide primers These are complimentary to specific DNA sequences at either end of the target DNA Reverse transcriptase PCR    Initial prep:   Sample of DNA is added to test tube along with two DNA primers a thermostable DNA polymerase (Taq) is added used to amplify RNA RNA is converted to DNA by reverse transcriptase gene expression in the form of mRNA (rather than the actually DNA sequence) can therefore be analyzed Using the enzyme reverse transcriptase, the cDNA is then amplified by conventional polymerase chain reaction (PCR) Basic and clinical science for MRCP BY ALI AL-MANSOUR Antibiotics: mechanisms of action The lists summaries the site of action of the commonly used antibiotics Inhibit cell wall formation    Penicillins Cephalosporins Glycopeptide antibiotic Penicillin is mainly useful for group A Strep Group B Strep Meningococcal and pneumococcal infections, though anthrax are also sensitive Gentamicin is synergistic to the action of benzylpenicillin Benzylpenicillin is bactericidal, inhibiting cell wall synthesis, enabling gentamicin to enter the bacterial cell It acts at the level of the ribosome, inhibiting protein synthesis Classified as: -  Inhibit protein synthesis        Aminoglycosides (misreading of mRNA) Chloramphenicol Macrolides (e.g erythromycin) Tetracyclines Fusidic acid Linezolid (Quinu & dalfo) pristin Inhibit DNA synthesis     Quinolones (e.g ciprofloxacin) Metronidazole Sulphonamides Trimethoprim Inhibit RNA synthesis     Penicillinase-sensitive penicillins: benzylpenicillin, phenoxymethylpenicillin Penicillinase-resistance penicillins: Flucoxacillin Broad-spectrum penicillins: amoxycillin, co-amoxiclav and ampicillin antipseudomonal penicillins : carbenicillin , piperacillin Cephalosporins     First generation -, cephalexin Second generation - Cefuroxime, Third generation - Cefotaxime, ceftazidime, ceftrioxon and cefixime 4th: cefepem Glycopeptide antibiotic   Vancomycin Ticoplanin Mechanism of action Rifampicin  Inhibit cell wall formation Penicillins Acts by inhibiting cell wall synthesis Mutations in PBPs (enzymes required for cell wall synthesis) result in penicillin resistance, Penicillin binds to specific penicillin-binding proteins (PBPs) in the cell wall, mainly of Gram-positive organisms or beta-lactamases which cleave the beta lactam ring Inhibits cell wall formation by binding to DAla-D-Ala, preventing polymerization of peptidoglycans Mechanism of resistance  Penicillin is a bactericidal antibiotic Antibiotics Alteration to the terminal amino acid residues of the NAM/NAG-peptide subunits (normally D-alanyl-D-alanine) to which the antibiotic binds Adverse effects     Nephrotoxicity Ototoxicity Thrombophlebitis Red man syndrome; occurs on rapid infusion of Vancomycin Basic and clinical science for MRCP BY ALI AL-MANSOUR Antibiotics Antibiotics: protein synthesis inhibitors Drug Mechanism of action Aminoglycosides Binds to 30S subunit causing misreading of mRNA Tetracyclines Binds to 30S subunit blocking binding of tRNA  For TTT: Acne vulgaris, Lyme disease, Chlamydia, Mycoplasma pneumoniae Binds to 50S subunit, inhibiting peptidyl transferase Binds to 50S subunit, inhibiting translocation (movement of tRNA from acceptor site to peptidyl site) Binds to 50S subunit, inhibiting translocation (movement of tRNA from acceptor site to peptidyl site) Chloramphenicol Clindamycin Macrolides: Erythromycin was the first macrolide used clinically Newer examples include clarithromycin and azithromycin Linezolid Quinupristin & dalfopristin antibiotics FUCIDIC ACID Mechanism of resist Increased efflux of the bacteria by plasmid-encoded transport pumps, ribosomal protection Adverse effects Nephrotoxicity, Ototoxicity, vestibular toxin Discoloration of teeth, photosensitivity Notes Gentamicin streptomycin neomycin Doxycycline & minocycline & Tetracyclines Aplastic anaemia Post-transcriptional methylation of the 23S bacterial ribosomal RNA Common cause of C difficile diarrhoea Nausea (especially erythromycin), P450 inhibitor, prolonged QT interval Commonly used for patients who are allergic to penicillin Stopping formation of the 70s initiation complex Thrombocytopenia (reversible on stopping), monoamine oxidase inhibitor: avoid tyramine containing foods Spectrum, highly active against Gram positive organisms including: MRSA, VRE, GISA (Glycopeptid e Intermediate Staphylococc us aureus) Blocking tRNA complexes binding to the ribosome Thrombophlebitis (give via a central line), arthralgia, P450 inhibitor Most Gram positive bacteria, exception: Enterococcu s faecalis* Basic and clinical science for MRCP BY ALI AL-MANSOUR Antibiotics Antibiotics: Inhibit DNA synthesis Drug Quinolones Metronidazole Sulphonamides Trimethoprim Mechanism of action Inhibit topoisomeras II (DNA gyrase) and topoisomerase IV -Ve dihydropetrol synthesase Inhibiting dihydrofolate reductase Mechanism of resist Mutations to DNA gyrase, efflux pumps which reduce intracellular quinolone concentration Sulphonamides and trimethoprim have been used in combination because of their synergistic activity - as co-trimoxazole Adverse effects Notes Lower seizure threshold, tendon damage (including rupture), ciprofloxacin Myelosuppression, transient rise in creatinine: trimethoprim competitively inhibits the tubular secretion of creatinine resulting in a temporary increase which reverses upon stopping the drug TTT of UTI Adverse effects Notes Shortness of breath Acute renal failure Thrombocytopenic purpura GI symptoms influenzal syndrome Hepatic reactions with alterations of liver function, jaundice, urticaria and rashes Urine, saliva and other secretions coloured orange-red Rifampicin is a drug that is indicated in: TB, meningococ Meningitis prophylaxis, leprosy levofloxacin Antibiotics: Inhibit RNA synthesis Drug Rifampicin Mechanism of action - Ve protein synthesase by rpo mutation tha Mechanism of resist Mutations to DNA gyrase, efflux pumps which reduce intracellular quinolone concentration        Basic and clinical science for MRCP BY ALI AL-MANSOUR Antibiotics Antibiotics: anaerobic activity Antibiotics: bactericidal vs bacteriostatic The following antibiotics have anti-anaerobic activity Bactericidal antibiotics      penicillins cephalosporins (except ceftazidime) erythromycin metronidazole tetracycline The following antibiotics not have anti-anaerobic activity    gentamicin ciprofloxacin ceftazidime         penicillins cephalosporins aminoglycosides nitrofurantoin metronidazole quinolones rifampicin isoniazid Bacteriostatic antibiotics      chloramphenicol macrolides tetracyclines sulphonamides trimethoprim Basic and clinical science for MRCP BY ALI AL-MANSOUR Vancomycin Dosing Glycopeptide antibiotic used in the treatment of Grampositive infections, particularly (MRSA)  Mechanism of action   Inhibits cell wall formation by binding to DAla-D-Ala moieties, preventing polymerization of peptidoglycans   Mechanism of resistance  Alteration to the terminal amino acid residues of the NAM/NAG-peptide subunits (normally D-alanyl-D-alanine) to which the antibiotic binds Adverse effects     Nephrotoxicity Ototoxicity Thrombophlebitis Red man syndrome; occurs on rapid infusion of vancomycin Tetracyclines are a class of antibiotics, which are commonly used, in clinical practice Examples     Ototoxicity: irreversible, due to auditory or vestibular nerve damage Nephrotoxicity: accumulates in renal failure, lower doses and more frequent monitoring is required Contraindications  Myasthenia gravis Protein synthesis inhibitors Binds to 30S subunit blocking binding of aminoacyl-tRNA Mechanism of resistance  Increased efflux of the bacteria by plasmidencoded transport pumps, ribosomal protection Indications     Acne vulgaris Lyme disease Chlamydia Mycoplasma pneumoniae Adverse effects   Doxycycline Tetracycline Mechanism of action Gentamicin Adverse effects Due to the significant ototoxic and nephrotoxic potential of gentamicin it is important to monitor plasma concentrations Both peak (1 hour after administration) and trough levels (just before the next dose) are measured If the trough (pre-dose) level is high the interval between the doses should be increased If the peak (post-dose) level is high the dose should be decreased Tetracyclines   Type of aminoglycoside antibiotic It is poorly lipid soluble and must therefore be given parentally Antibiotics discolouration of teeth photosensitivity Basic and clinical science for MRCP BY ALI AL-MANSOUR Macrolides Erythromycin was the first macrolide used clinically Newer examples include clarithromycin and azithromycin Macrolides act by inhibiting bacterial protein synthesis by blocking translocation If pushed to give an answer they are bacteriostatic in nature, but in reality this depends on the dose and type of organism being treated Mechanism of resistance  Post-transcriptional methylation of the 23S bacterial ribosomal RNA Mechanism of action       Common interactions  Statins should be stopped whilst taking a course of macrolides Macrolides inhibit the cytochrome P450 isoenzyme CYP3A4 that metabolises statins Taking macrolides concurrently with statins significantly increases the risk of myopathy and rhabdomyolysis Quinolones Trimethoprim is an antibiotic, mainly used in the management of urinary tract infections Mechanism of action  interferes with DNA synthesis by inhibiting dihydrofolate reductase Adverse effects   Ciprofloxacin Levofloxacin MRSA Lower seizure threshold in patients with epilepsy Tendon damage (including rupture) - the risk is increased in patients also taking steroids Cartilage damage has been demonstrated in animal models and for this reason quinolones are generally avoided (but not necessarily contraindicated) in children Trimethoprim Quinolones are a group of antibiotics, which work by inhibiting DNA synthesis and are bactericidal in nature Examples include:   Mutations to DNA gyrase, efflux pumps which reduce intracellular quinolone concentration Adverse effects Adverse effects Gastrointestinal side effects are common Nausea is less common with clarithromycin than erythromycin Cholestatic jaundice: risk may be reduced if erythromycin stearate is used P450 inhibitor (see below) Inhibit topoisomeras II (DNA gyrase) and topoisomerase IV Mechanism of resistance   Antibiotics Myelosuppression Transient rise in creatinine: trimethoprim competitively inhibits the tubular secretion of creatinine resulting in a temporary increase which reverses upon stopping the drug Basic and clinical science for MRCP BY ALI AL-MANSOUR (MRSA) was one of the first organisms which highlighted the dangers of hospital-acquired infections Antibiotics have activity against MRSA but should be reserved for resistant cases Linezolid Who should be screened for MRSA?   All patients awaiting elective admissions (exceptions include day patients having terminations of pregnancy and ophthalmic surgery Patients admitted to mental health trusts are also excluded) From 2011 all emergency admissions will be screened Linezolid is a type of oxazolidonone antibiotic which has been introduced in recent years It inhibits bacterial protein synthesis by stopping formation of the 70s initiation complex and is bacteriostatic nature Spectrum, highly active against Gram positive organisms including:  How should a patient be screened for MRSA?    Nasal swab and skin lesions or wounds The swab should be wiped around the inside rim of a patient's nose for seconds The microbiology form must be labelled 'MRSA screen'   Adverse effects   Suppression of MRSA from a carrier once identified   Nose: mupirocin 2% in white soft paraffin, tds for days Skin: chlorhexidine gluconate, od for days Apply all over but particularly to the axilla, groin and perineum thrombocytopenia (reversible on stopping) monoamine oxidase inhibitor: avoid tyramine containing foods Quinupristin & dalfopristin antibiotics    The following antibiotics are commonly used in the treatment of MRSA infections:    MRSA (Methicillin-resistant Staphylococcus aureus) VRE (Vancomycin-resistant enterococcus) GISA (Glycopeptide Intermediate Staphylococcus aureus) Injectable streptogrammin antibiotic Combination of group A and group B streptogrammin Inhibits bacterial protein synthesis by blocking tRNA complexes binding to the ribosome Spectrum vancomycin teicoplanin linezolid   Most Gram positive bacteria Exception: Enterococcus faecalis* Adverse effects Some strains may be sensitive to the antibiotics listed below but they should not generally be used alone because resistance may develop:      Rifampicin macrolides tetracyclines aminoglycosides clindamycin    Thrombophlebitis (give via a central line) Arthralgia P450 inhibitor *not to be confused with Enterococcus faecium, which is sensitive to Quinupristin & dalfopristin Infective endocarditis: management Relatively new antibiotics such as linezolid, quinupristin/dalfopristin combinations and tigecycline Basic and clinical science for MRCP BY ALI AL-MANSOUR Scenario Initial blind therapy  Suggested antibiotic therapy Native valve   Amoxicillin, consider adding lowdose gentamicin   If penicillin allergic, MRSA or severe sepsis Meningitis: Management If prosthetic valve  BNF recommendations on antibiotics vancomycin + low-dose gentamicin vancomycin + rifampicin + lowdose gentamicin Flucloxacillin If penicillin allergic or MRSA  Prosthetic valve endocarditis caused by staphylococci vancomycin + rifampicin Flucloxacillin + rifampicin + lowdose gentamicin If penicillin allergic or MRSA  vancomycin + rifampicin + lowdose gentamicin Scenario Initial empirical therapy aged < months Initial empirical therapy aged months - 50 years Initial empirical therapy aged > 50 years Meningococcal meningitis Pneuomococcal meningitis Meningitis caused by Haemophilus influenzae Meningitis caused by Listeria Endocarditis caused by fullysensitive streptococci (e.g viridans) Benzylpenicillin Endocarditis caused by less sensitive streptococci Benzylpenicillin + low-dose gentamicin  If penicillin allergic  If penicillin allergic   vancomycin + low-dose gentamicin  severe valvular incompetence Intravenous cefotaxime + amoxicillin Intravenous benzylpenicillin or cefotaxime Intravenous cefotaxime Intravenous cefotaxime Intravenous amoxicillin + gentamicin Management of contacts vancomycin + low-dose gentamicin Indications for surgery BNF recommendation Intravenous cefotaxime + amoxicillin Intravenous cefotaxime If the patient has a history of immediate hypersensitivity reaction to penicillin or to cephalosporins the BNF recommends using chloramphenicol   aortic abscess (often indicated by a lengthening PR interval) infections resistant to antibiotics/fungal infections cardiac failure refractory to standard medical treatment recurrent emboli after antibiotic therapy all patients should be transferred to hospital urgently If patients are in a pre-hospital setting (for example a GP surgery) and meningococcal disease is suspected then intramuscular benzylpenicillin may be given, as long as this doesn't delay transit to hospital  Native valve endocarditis caused by staphylococci Antibiotics prophylaxis needs to be offered to household and close contacts of patients affected with meningococcal meningitis oral ciprofloxacin or rifampicin or may be used The Health Protection Agency (HPA) guidelines now state that whilst either may be used ciprofloxacin is the drug of choice as it is widely available and only requires one dose the risk is highest in the first days but persists for at least weeks meningococcal vaccination should be offered to close contacts when serotype results are available, including booster doses to those who had the vaccine in infancy Basic and clinical science for MRCP BY ALI AL-MANSOUR  for pneumococcal meninigitis no prophylaxis is generally needed There are however exceptions to this If a cluster of cases of pneumococcal meninigitis occur the HPA have a protocol for offering close contacts antibiotic prophylaxis Please see the link for more details Post-exposure prophylaxis Hepatitis A  Human Normal Immunoglobulin (HNIG) or hepatitis A vaccine may be used depending on the clinical situation Hepatitis B   HBsAg positive source: if the person exposed is a known responder to HBV vaccine then a booster dose should be given If they are in the process of being vaccinated or are a non-responder they need to have hepatitis B immune globulin (HBIG) and the vaccine unknown source: for known responders the green book advises considering a booster dose of HBV vaccine For known nonresponders HBIG + vaccine should be given whilst those in the process of being vaccinated should have an accelerated course of HBV vaccine Hepatitis C  monthly PCR - if seroconversion then interferon +/- ribavirin  a combination of oral antiretrovirals (e.g Tenofovir, emtricitabine, lopinavir and ritonavir) as soon as possible (i.e Within 12 hours, but may be started up to 72 hours following exposure) for weeks serological testing at 12 weeks following completion of post-exposure prophylaxis reduces risk of transmission by 80% HIV   Varicella zoster  Antibiotics VZIG for IgG negative pregnant women/immunosuppressed Estimates of transmission risk for single needlestick injury Hepatitis B Hepatitis C HIV 20-30% 0.5-2% 0.3% Basic and clinical science for MRCP BY ALI AL-MANSOUR  Drugs acting on common receptors Receptor Agonist Alpha  Alpha-1: Decongestants (e.g phenylephrine /oxymetazoline) also phenylephrine dilate the pupil  Alpha-2: Glaucoma (e.g topical brimonidine), clonidine (antihypertensive) Beta-1 Beta-2 Dopamine Inotropes (e.g dobutamine) Bronchodilators (e.g salbutamol)  Parkinson's disease (e.g ropinirole)  Prolactinoma (pituitary tumors)  Restless legs syndrome (RLS) E.g bromocriptine, ropinirole, cabergoline, apomorphine GABA Histamine-1 Producing typically sedative effects, anxiolytic, anticonvulsant, and muscle relaxant effects :  Benzodiazepines, Baclofen  Alcohols (e.g., ethanol, isopropanol),  Barbiturates (e.g., phenobarbital) Histamine produces increased vascular permeability, causing fluid to escape from capillaries into tissues, which leads to the classic symptoms of an allergic reaction — a runny nose and watery eyes Histamine also promotes angiogenesis Antagonist  Benign prostatic hyperplasia (e.g tamsulosin, doxazosin)  Hypertension (e.g doxazosin)  Caution should be exercised in patients who are having cataract surgery due to the risk of intra-operative floppy iris syndrome  Alpha-2: yohimbine  Non-selective: phenoxybenzamine (previously used in peripheral arterial disease) Non-selective & selective beta-blockers (e.g atenolol, Bisoprolol) Non-selective beta-blockers (e.g propranolol, labetalol - vasodilatory properties)  Schizophernia (antipsychotics e.g haloperidol) & bipolar disorder  Anti-emetics (e.g metoclopramide/domperidone)  Antidopaminergics such as haloperidol can be an antidote for poisoning with cocaine, amphetamines and dopamine agonists such as Bromocriptine and/or Ropinirole  Agents such as Atypical antipsychotics (coupled with serotonin antagonist effects): paliperidone, clozapine, risperidone, olanzapine, quetiapine, and ziprasidone  Used as tricyclic antidepressants: amoxapine, clomipramine, trimipramine  Control the symptoms of hypersexuality and increased orgasmic activity Flumazenil: used for counteracting overdoses of sedative drugs NOTE: There are three receptors: GABA-α and GABA-ρ are ion channels The GABA-β receptor belongs to the class of G-Protein coupled receptors Are of value in the treatment of allergic rhinitis and urticaria  Examples of sedating antihistamines: chlorpheniramine As well as being sedating these antihistamines have some antimuscarinic properties (e.g urinary retention, dry mouth)  Examples of non-sedating antihistamines: loratidine, cetirizine They act on H2 histamine receptors found mainly in the parietal cells of the gastric mucosa Antacids (e.g Cimetidine, Famotidine, Ranitidine) Histamine-2 Muscarinic Drugs & Receptor ACh can stimulate postganglionic receptors to produce effects such as: (SLUD) Salivation, Lacrimation, Defecation, Micturition, Sweating, Miosis, Bradycardia, and Bronchospasm   Glaucoma (e.g pilocarpine) An acetylcholinesterase inhibitor or anticholinesterase is a chemical that inhibits the cholinesterase enzyme from breaking down acetylcholine (ACh), so increasing both the level and duration of action of the neurotransmitter acetylcholine (Donepezil, galantamine and rivastigmine) & pyridostigmine  Atropine (e.g for bradycardia)  Bronchodilator (e.g ipratropium bromide, tiotropium)  Urge incontinence (e.g oxybutynin) S/E: dry mouth, blurred vision, urinary retention, constipation, dilation of the pupils with difficulty accommodating and sensitivity to light - i.e blurred vision, increased intraocular pressure Nicotinic  Nicotine  Varenicline (used for smoking cessation)  Depolarising muscle relaxant (e.g suxamethonium) Non-depolarising muscle relaxants (e.g atracurium) Oxytocin Serotonin Inducing labour (e.g Syntocinon) Agonists are used in the acute treatment of migraine whilst 5-HT antagonists are used in prophylaxis  Triptans: sumatriptan is a 5-HT1D agonist which is used in the acute treatment of migraine (zolmitriptan)  Ergotamine is a partial agonist of 5-HT1 receptors Tocolysis (e.g atosiban) Vasopressin Desmopressin, Therapeutic uses include: •  Diabetes insipidus, nephrogenic and cranial •  In the management of bleeding diatheses, particularly von Willebrands disease and haemophillia •  in the short term management of some nocturnal enuresis and post-operative polyuria and polydipsia  It may also be used in the assessment of polydipsia in the water deprivation test  pizotifen is a 5-HT2 receptor antagonist used in the prophylaxis of migraine attacks  Methysergide is another antagonist of the 5-HT2 receptor but is rarely used due to the risk of retroperitoneal fibrosis  Cyproheptadine is a 5-HT2 receptor antagonist which is used to control diarrhoea in patients with carcinoid syndrome  Ondansetron is a 5-HT3 receptor antagonist and is used as an antiemetic  Antagonists of the 5-HT2A receptor are sometimes used as atypical antipsychotics (contrast with typical antipsychotics, which are purely dopamine antagonists) A vasopressin receptor antagonist (VRA): Most commonly VRAs are used in the treatment of hyponatremia, especially in patients with congestive heart failure, liver cirrhosis or SIADH  Demeclocycline, a tetracycline antibiotic, is sometimes used to block the action of vasopressin in the kidney in hyponatremia due to inappropriately high secretion of vasopressin (SIADH), when fluid restriction has failed  lithium Basic and clinical science for MRCP BY ALI AL-MANSOUR Arachidonic acid metabolism The diagram below shows the metabolism of arachidonic acid: Leukotrienes   LTB4: B4 (before) leukocytes comes LTB4 the rest A, C, D & E constrict the lungs Endoperoxides  THROMBOxane think THROMBOSIS: platelets aggregated and vasoconstriction Prostacyclin is the opposite Drugs & Receptor Basic and clinical science for MRCP BY ALI AL-MANSOUR Contraception Contraception: mode of action Advantages of combined oral contraceptive pill The table below is based on documents produced by the Faculty for Sexual and Reproductive Health (FSRH)  Standard contraceptives:   Contraceptive COCP Progestogen-only pill (excluding desogestrel) Desogestrel-only pill Injectable contraceptive (medroxyprogesterone acetate) Implantable contraceptive (etonogestrel) Intrauterine contraceptive device Intrauterine system (levonorgestrel) Mode of action Inhibits ovulation Thickens cervical mucus Primary: Inhibits ovulation Also: thickens cervical mucus Primary: Inhibits ovulation Also: thickens cervical mucus Primary: Inhibits ovulation Also: thickens cervical mucus Decreases sperm motility and survival Primary: Prevents endometrial proliferation Also: Thickens cervical mucus Combined oral contraceptive pill: overview     Highly effective (failure rate < per 100 woman years) Doesn’t interfere with sex Contraceptive effects reversible upon stopping Usually makes periods regular, lighter and less painful Reduced risk of ovarian, endometrial and colorectal cancer May protect against pelvic inflammatory disease May reduce ovarian cysts, benign breast disease, acne vulgaris Disadvantages of combined oral contraceptive pill       People may forget to take it Offers no protection against sexually transmitted infections Increased risk of venous thromboembolic disease Increased risk of breast and cervical cancer Increased risk of stroke and ischaemic heart disease (especially in smokers) Temporary side-effects such as headache, nausea, breast tenderness may be seen Whilst some users report weight gain whilst taking the combined oral contraceptive pill a Cochrane review did not support a causal relationship Is one of the most popular methods of contraception currently used in the UK Mode of action:   Main: stops ovulation Also: thickens cervical mucus (reducing chance of semen entering uterus) and thins endometrial lining (reducing chance of implantation) All contain synthetic:   Oestrogen A progestogen COCP: contraindications COCP: advantages/disadvantages Basic and clinical science for MRCP BY ALI AL-MANSOUR The decision of whether to start a women on the combined oral contraceptive pill is now guided by the UK Medical Eligibility Criteria (UKMEC) This scale categorises the potential cautions and contraindications according to a four-point scale, as detailed below:     UKMEC 1: a condition for which there is no restriction for the use of the contraceptive method UKMEC 2: advantages generally outweigh the disadvantages UKMEC 3: disadvantages generally outweigh the advantages UKMEC 4: represents an unacceptable health risk Concurrent antibiotic use     Examples of UKMEC conditions include        More than 35 years old and smoking less than 15 cigarettes/day Migraine without aura and more than 35 years old Family history of thromboembolic disease in first degree relatives < 45 years Controlled hypertension Immobility e.g wheel chair use Breast feeding weeks - months postpartum BMI > 35 kg/m^2* For many years doctors in the UK have advised that the concurrent use of antibiotics may interfere with the enterohepatic circulation of oestrogen and thus make the combined oral contraceptive pill ineffective - 'extra- precautions' were advised for the duration of antibiotic treatment and for days afterwards no such precautions are taken in the US or the majority of mainland Europe in 2011 the Faculty of Sexual & Reproductive Healthcare produced new guidelines abandoning this approach The latest edition of the BNF has been updated in line with this guidance precautions should still be taken with enzyme inducing antibiotics such as rifampicin Switching combined oral contraceptive pills  the BNF and Faculty of Sexual & Reproductive Healthcare (FSRH) appear to give contradictory advice The Clinical Effectiveness Unit of the FSRH have stated in the Combined Oral Contraception guidelines that the pill free interval does not need to be omitted (please see link) The BNF however advises missing the pill free interval if the progesterone changes Given the uncertainty it is best to follow the BNF Examples of UKMEC conditions include         More than 35 years old and smoking more than 15 cigarettes/day Migraine with aura History of thromboembolic disease or thrombogenic mutation History of stroke or ischaemic heart disease Uncontrolled hypertension Major surgery with prolonged immobilisation Breast feeding < weeks post-partum Breast cancer Diabetes mellitus diagnosed > 20 years ago is classified as UKMEC or depending on severity *The UKMEC rating for a BMI > 40 kg/m^2 was removed in 2009 COCP: special situations Contraception Progestogen only pill: types Basic and clinical science for MRCP BY ALI AL-MANSOUR Second generation    norethisterone levonorgestrel ethynodiol diacetate Third generation  desogestrel (Cerazette) The decision of whether to start a women a particular type of contraceptive is now guided by the UK Medical Eligibility Criteria (UKMEC) This scale categorises the potential cautions and contraindications according to a four point scale, as detailed below:    Cerazette     new third generation type of progestogen only pill (POP) containing desogestrel inhibits ovulation in the majority of women users can take the pill up to 12 hours late rather than hours like other POPs Progestogen only pill: advantages/disadvantages Advantages      highly effective (failure rate = per 100 woman years) doesn't interfere with sex contraceptive effects reversible upon stopping can be used whilst breast-feeding can be used in situations where the combined oral contraceptive pill is contraindicated e.g in smokers > 35 years of age and women with a history of venous thromboembolic disease UKMEC 1: a condition for which there is no restriction for the use of the contraceptive method UKMEC 2: advantages generally outweigh the disadvantages UKMEC 3: disadvantages generally outweigh the advantages UKMEC 4: represents an unacceptable health risk Examples of UKMEC conditions include     active liver disease or past tumour liver enzyme inducers breast cancer more than years ago undiagnosed vaginal bleeding Examples of UKMEC conditions include   pregnancy breast cancer within the last years Disadvantages     irregular periods: some users may not have periods whilst others may have irregular or light periods This is the most common adverse effect doesn't protect against sexually transmitted infections increased incidence of functional ovarian cysts common side-effects include breast tenderness, weight gain, acne and headaches These symptoms generally subside after the first few months Progestogen only pill: contraindications Contraception Menopause: management Basic and clinical science for MRCP BY ALI AL-MANSOUR Many women have little or no symptoms around the menopause not require any specific treatment other than advice and reassurance Hormone replacement therapy (HRT) should be used primarily for the treatment of menopausal symptoms It should no longer be given in an attempt to modify cardiovascular risk (following the Women's Health Initiative Study) but may be beneficial in the prevention and treatment of osteoporosis   Contraception Vasomotor symptoms such as flushing, insomnia and headaches Premature menopause: should be continued until the age of 50 years Most important reason is preventing the development of osteoporosis Lifestyle advice should be given including regular exercise, avoiding caffeine/spicy foods and lighter clothing The main indication is the control of vasomotor symptoms The other indications such as reversal of vaginal atrophy should be treated with other agents as first-line therapies other benefits include a reduced incidence of colorectal cancer Hormonal methods Hormone replacement therapy: adverse effects   Hormone replacement therapy: most effective tibolone: unsuitable for use within 12 months of last menstrual period as may cause irregular bleeding Non-hormonal methods may help vasomotor symptoms    Selective serotonin reuptake inhibitors Clonidine: use is often limited by sideeffects such as dry mouth, dizziness and nausea A progestogen such as norethisterone Vaginal symptoms   Vaginal atrophy may be helped by topical oestrogens if the symptoms are predominately vaginal dryness then a vaginal lubricant or moisturizer Involves the use of a small dose of oestrogen (combined with a progestogen in women with a uterus) to help alleviate menopausal symptoms Side-effects    Potential complications      Hormone replacement therapy: indications Its involves the use of a small dose of oestrogen, combined with a progestogen (in women with a uterus), to help alleviate menopausal symptoms The indications for HRT have changed significantly over the past ten years as the long-term risks became apparent, primarily as a result of the Women's Health Initiative (WHI) study Hormone replacement therapy (HRT) may be used to replace decreasing oestrogen levels around the perimenopausal period Indications Nausea Breast tenderness Fluid retention and weight gain Increased risk of breast cancer: increased by the addition of a progestogen Increased risk of endometrial cancer: reduced by the addition of a progestogen but not eliminated completely The BNF states that the additional risk is eliminated if a progestogen is given continuously Increased risk of venous thromboembolism: increased by the addition of a progestogen Increased risk of stroke Increased risk of ischaemic heart disease if taken more than 10 years after menopause Breast cancer     In the Women's Health Initiative (WHI) study there was a relative risk of 1.26 at years of developing breast cancer The increased risk relates to duration of use Breast cancer incidence is higher in women using combined preparations compared to oestrogen-only preparations The risk of breast cancer begins to decline when HRT is stopped and by years it reaches the same level as in women who have never taken HRT
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