oncology *
What is Primary Induction Chemotherapy
Chemotherapy administered in patients with advanced cancer for which no alternative treatment exists.
i.e. Hodgkin's and non-Hodgkin's Lymphoma.
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What is Neoadjuvant Chemotherapy
Use of chemotherapy in patients who present with localized cancer for which useful local therapies (surgery/ radiation) exist but may not be completely effective.
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What is Adjuvant Chemotherapy
Chemotherapy used as an adjuvant to local therapy such as surgery or radiation. It is effective in prolonging disease free and overall survival in patients
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What is the Therapeutic Index
Lethal Dose of a Drug for 50% of the Population divided by the minimum effective dose for 50% of the population
LD50 / ED50
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Why do Disseminated Cancers respond well to Chemotherapy
Disseminated Cancers generally have a high growth fraction.
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List examples of Cell Cycle Specific Drugs
- Antimetabolites (S Phases): Fludarabine, 5-Fluorouracil, Methotrexate
- Taxanes (M Phase)
- Vinca Alkaloids (M Phase)
- Antimicrotubule Inhibitor (M Phase)
- Antitumous Antibiotics (G2-M Phase)
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List Cell Cycle Nonspecific Drugs
- Alkylating Agents
- Antitumour Antibiotics
- Camptothecins
- Platinum Analogs
- Anthracyclines.
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Alkylating Agents are Cell Cycle Non Specific Chemotherapeutic Agents.
Describe how Alkylating Agents are Carcinogenic
Alkylating Agents cause abnormal base pairing therefore can be Carcinogenic and increase the risk of Secondary Malignancies
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Most adverse effects of Alkylating Agents are Generally Dose Related and Occur Primarily in Rapidly Growing Tissues.
Give Examples of Alkylating Agents Adverse Effects
1) Bone Marrow Depression
2) Nausea
3) Vomiting
Anti-emetics are often given prior and after alkylating dosing
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Cisplatin is a Platinum Analogue. What Cancers is it used to treat
Highly Bound to Plasma Protein and Highly Concentrated in Kidney, Intestines and Testes.
Treats Testicular, Ovarian and Solid Tumours.
It poorly penetrates the Blood Brain Barrier.
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Give Examples of Antimetabolites used in Chemotherapy
1) Folates Antagonists (Methotrexate)
2) Purine Antagonists (6 Mercaptopurine)
3) Pyrimidine Antagonists (5 Fluorouracile)
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Methotrexate is a Folic Acid Analogue. It is an Antimetabolite that is Cell Cycle Specific.
How does Methotrexate Work?
Binds to the Active Catalytic Site of Dihydofolate Reductase (DHFR)
This inhibits the synthesis of Tetrahydrofolate (THF)
Interfering with Formation of DNA, RNA and key cellular Proteins.
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What are the 3 actions of Methotrexate
1) Cytotoxic (mainly on bone marrow)
2) Immunosuppressive, preventing clonal expansion of B and T Cells
3) Anti-Inflammatory
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6 Mercaptopurine is a Purine Antagonist and an Antimetabolite that is Cell Cycle Specific.
How does 6 Mercaptopurine Work
It is Inactive in its parent form and must be metabolised in its active form.
It inhibits the synthesis of purine nucleotides, its metabolites alter the synthesis and function of RNA and DNA
It does not cross the blood brain barrier.
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How does 5 Fluorouracil work
It is inactive in its parent form, requires activation via a complex series of enzymatic reaction to ribosyl and deoxyribose nucleotide metabolites in order to interfere with DNA Synthesis
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How do Vinca Alkaloids work
Act by inhibiting tubulin proliferation, which disrupt assembly of
microtubules. This results in mitotic arrest in metaphase, bringing cell
division to a halt and ultimately leading to cell death.
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How do Antitumour Antibiotics work
Bind to DNA through intercalation between specific bases.
They block synthesis of RNA, DNA or Both. Cause DNA strand Scission and Interfere with Cell Replication
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Antitumour Antibiotics are used in clinical practice against...
Streptomyces
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Give 3 examples of Hormones and Antagonists used in Chemotherapy
1) Glucocorticoids
- Used in acute leukemia and lymphomas due to their marked
lympholytic effect
2) Estrogens
- Physiological antagonists of androgens, so used to antagonize the effect
of androgens in androgen dependent prostate cancer
3) Estrogens Antagonists
- Used in breast cancer. Selective Estrogen Receptor (ER) Modulators, or
ER down regulator. Adverse effect, hot flushes, vomiting, menstrual
irregularities.
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What is Spread of Cancer to Bone associated with
1) Pain, Hypercalcaemia, Anaemia
2) Increased Risk of Infection
3) Compression of the Spinal Cord and/or Nerve Roots
4) Decreased Mobility and Skeletal Fracture (Catastrophic)
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Bisphosphonates cause Gastrointestinal Toxicities. Describe How.
they bind to calcium in the diet can cause gastrointestinal toxicities such as
nausea, vomiting, indigestion, oesophagitis, and diarrhea
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What does Drug Combination provide
Provides Maximal Cell Kill within a range of Toxicity tolerated by the host for each drug without compromising the dosing.
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What is Efficacy
maximal effect a drug can produce.
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What is Toxicity
the degree to which a substance is poisonous or can cause injury
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When do you suspect a Head & Neck cancer (11)
Suspect a Head & Neck Cancer when there is:
- Non Healing Ulcers (Undulated or Hard Margins)
- Red/White Patches
- Loose Teeth
- Spontaneous Jaw Pains
- Swelling or a Sore that does not heal
- Lump, Bump or Mass in the Head or Neck region with or without pain
- Persistent Sore Throat
- Foul Mouth Odour (not explained by oral hygiene)
- Hoarseness or Change in Voice for longer than 6 weeks
- Pain or Difficulty eating, swallowing or moving jaw/tongue
- Denture that no longer fit, could be due to growth of a mass.
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How many days prior to Radiotherapy should Extractions if needed be carried out
at least 10 days prior to the radiotherapy.
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What are the aims of Pre-Treatment Assessments (7)
1) Avoidance of Unscheduled Interruptions to primary treatment as a result of Dental Problems
2) Pre-prosthetic planning/treatment
3) Planning for extraction of teeth
4) Extractions be carried out as early as possible but at least 10 days prior to radiotherapy
5) Planning for restoration of remaining teeth as required
6) Preventive advice and treatment
7) Assess potential for post treatment access difficulties
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What are the short term Dental Implications of Oncology Treatment (4)
1) Mucositis
- Inflammation and Ulceration of the Mucosal Lining of the Oral Cavity
2) Infection
- Chemotherapy induced Neutropenia makes the patient susceptible to infections.
- Oral Candidiasis is common after chemotherapy or radiotherapy
3) Xerostomia
- Dry mouth resulting from decrease in saliva production as a result from radiotherapy
4) Taste Loss
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What are the long term Dental Implications of Oncology Treatment (6)
1) Altered Anatomy
- changes in oral anatomy can make prosthetic rehabilitation difficult
2) Rampant Dental Caries
- Radiogenic dental caries is thought to be the result of reduced saliva flow as well as direct radiogenic damage to ADJ
3) Trismus
- causes by surgical scarring or radiotherapy induced fibrosis of the masticatory muscles
4) Mastication Difficulties
- if opposing pairs of teeth are lost
5) Osteoradionecrosis
- Hypovascularity and Necrosis of bone followed by trauma induced or spontaneous mucosal breakdown leading to a non-healing wound
6) Xerostomia
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How can we prevent the Dental Implications of Oncology Treatment (6)
1) Maintain good Oral Hygiene
2) Dietary advice to prevent Caries
3) Daily Topical Fluoride Application and Mouthrinse
4) Daily use of GC Tooth Mousse containing free calcium
5) Saliva Replacement Therapies
- Get Sugar Free ones.
6) Jaw Exercises to reduce Trismus
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What is the objectives of Obturators (4)
1) Restore the partition between the oral and nasal cavities to enable normal swallowing and speech
2) Restore palatal contours
3) Replace needed dentition and restore occlusion
4) Provide retention, stability and support for the complete denture/obturator prosthesis
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What are the haematological issues with Chemotherapy (3)
1) Decreased Red Blood Cells i.e. Anaemia (Fatigue, Dizziness, Shortness of Breath)
2) Decreased White Blood Cells i.e. Leukopenia (Increased risk of acquired infections)
3) Decreased Platelet Count (Thrombocytopenia)
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Which patients are more at risk of developing MRONJ
1) Patients taking Bisphosphonates
2) Patients taking Denosumab in last 9 months
3) Anti-angiogenic Biological Therapies
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What prognostic markers are used to determine Treatment Pathways of Cancers
- Oestrogen Receptor (ER) in breast cancer
- HER2 receptor in Breast and Gastric Cancers
- BRAF Mutation in Melanoma
- HPV association in Head & Neck Cancers
- EGFR & ALK expression in Lung Cancers
- PSA Level in Prostate Cancers
- HCG Levels in Choriocarcinoma
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Why is Chemotherapy given as an Adjuvant Treatment
To Reduce the Risk of Recurrence
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What are the General Side effects of Chemotherapy
1) Nausea & Vomiting
2) Fatigue
3) Change in Taste
4) Bowel Disturbance
5) Infertility & Premature Menopause
6) Renal & Liver Dysfunction
7) Allergic Reactions
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What is the interval for Chemotherapy
Chemotherapy is given at 3 weekly cycles. Patients get 4 to 6 cycles.
Every cycle has pre assessment and blood tests done so that the patient is coping with the side effects and that the blood levels are up to the mark.
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Describe the patterns in Blood Levels following Chemotherapy
After Day 1 Chemotherapy, Blood Cells Drop and gradually pick up Automatically.
However if one catches an infection when blood levels are low then they may not fight the infection adequately
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At what point in the Chemotherapy Cycle is the Maximum Risk
Risk between 7-14 days, Week 2.
Second Week should be avoided for Dental Extractions & Treatment.
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When is the best time to give Dental Treatment to patients on Chemotherapy
Just before the next cycle. Usually counts are recovering in week 3.
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What Targeted Therapy can be used in treatment of Cancers
Oral Tyrosine Kinase Inhibitors
- Dabrafenib, Gefitnib, Imatinib, Sunitinib
IV Monoclonal Antibodies
- Trastuzumab
- Cetuximab
- Bevacuizumab
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What is Immunotherapy
Using drugs to stimulate the body's immune response to disease
Now in use for most of the cancers in different settings
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List Drugs used in Immunotherapy
PDL1 Inhibitors: Pembrolizumab
Immune Checkpoint Inhibitors: Nivolumab
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What do Drugs in Immunotherapy do?
Cause an 'itis' of any organ that can be fatal but they can also be effective in controlling cancers.
Melting away the cancers.
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Why are Bone Treatments used in Cancers
Reduce risk of Skeletal Related Events (SREs) or decrease the symptoms of SREs
i.e.
Bisphosphonates
RANK ligand Inhibitors
Radium 223
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Which Cancers are Osteoblastic
Prostate & Breast
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Which cancers are Osteolytic
Myeloma
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What are the Clinical Consequences of Bone Metastases (4)
What are the 4 Skeletal Related Events
1) Pathologic Fracture
2) Radiotherapy to Bone
3) Surgery to Bone
4) Spinal Cord Compression
4 Consequences collectively called Skeletal Related Events
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How do Tumour Cells Damage the Bone with Osteoclastic Effect
They release Growth Factors and Cytokine Stimulating Osteoclasts which stimulate Peptides to resorb bone.
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What does Radiopharmaceutical's do
Bone Targeted Agent that binds onto bone surface and causes local damage to cancer cells
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Bisphosphonates are made up of R1 and R2 chains. What do R1 and R2 chains do
R1 chain has an affinity to bone calcium material. R2 chain has anti-resorptive potency
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What is the Half Life of Bisphosphonates
0.5-2 hours in humans
50% of circulating bisphosphonate is taken up by skeleton. It can remain in bone from 1-10 years
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How does Denosumab work
blocks interaction between RANKL and Rank receptor on osteoclasts that prevents formation
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Compare Denosumab over Bisphosphonates
Given S/C which is more convenient than IV Bisphosphonates
No concerns about renal safety, so no need to monitor Denosumab
Fewer Acute Phase Reactions
HOWEVER
Still causes Osteonecrosis of the Jaw
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What is the general rule to dentists in managing patients with ONJ
Suspend or Stop Treatment Immediately
If no ONJ, restart after 6 weeks.
Suspend Treatment until dental assessment to exclude suspicion of ONJ
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What are the sources of Radiation used in Radiotherapy
Linear Accelerators
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What are the General Principles of Radiotherapy when it is used for a Curative Treatment
Complex Planning with Accurate Localisation
Longer Course of Treatment with more early Side Effects
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What are the 3 Radiotherapy Treatment Modalities
1) X-Rays
- Superficial Radiotherapy 100KV Pantac
- Megavoltage Radiotherapy 6 to 20MV
2) Electron Treatment
- 6-20 MeV
3) Brachytherapy
- Insertion of Isotopes into Tumour
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Which Gender do Head & Neck Cancers commonly affect
Males
2:1 Ratio Male to Female.
Peak Incidence 60-75 Years of Age
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What is the most common type of HPV involved with Cervical and Oropharyngeal Squamous Cell Carcinomas
Type 16
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What percentage of Head and Neck Cancers are HPV Positive
25%
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What is the correlation between HPV Positive Cancers and their response to Chemotherapy
HPV positive Cancers respond well to chemotherapy. In their staging, they are down staged considerably.
They have a better prognosis when they are HPV positive.
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Why is Non Surgical Oncology Treatment advantageous
Organ preservation.
Oropharyngeal Cancers treated by Surgery have high risk of extreme morbidity.
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What are the Late Side Effects of Radiotherapy (8)
- Xerostomia
- Altered Taste
- Osteoradionecrosis
- Alopecia
- Hypothyroidism
- Subcutaneous Fibrosis
- Second Malignancy
- Altered Pigmentation of Skin
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What dose of Radiotherapy is given to Target Areas of Cancer
High Dose of 70Gy
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What dose of Radiotherapy are given to Areas at Risk to Develop Cancer (Elective Dose)
57Gy
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What is Osteoradionecrosis
Death of the Bone due to Damage to Blood Vessels from Radiotherapy.
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What drug is Used in Concurrent Chemoradiotherapy of Head & Neck Cancers
Cisplatin, every 3 weeks during Radiotherapy.
Radiotherapy commonly lasts 7 weeks, so Chemotherapy is given concurrently 3 times during the 7 weeks, 1st Week, 4th Week and 7th Week.
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What drugs are used in Palliative Chemotherapy
Cisplatin & 5FU every 4 weeks.
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What is Selective Toxicity
Ability of drug to kill or inhibit pathogen while damaging host as little as possible
An agent must be highly effective against microbes but have minimal or no toxicity to humans
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Explain the Disc Diffusion Test for Antibiotics
- Bacteria is grown on an Agar Dish.
- Discs are soaked in different antibiotics or different concentrations of the same antibiotics and placed on the agar dish.
- If the bacteria are sensitive to the antibiotic then you will get a clear zone surrounding the disc.
- If the bacteria are not sensitive to the antibiotic then you will not get a clear zone.
This is the Disc Diffusion Test as the Antibiotic Diffuses into the Agar where bacteria are growing
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Define MIC
Minimum Inhibitory Concentration
- The minimum concentration of antimicrobial needed to stop the bacteria from growing
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Define MBC
Minimum Bactericidal Concentration
- The minimum concentration of antimicrobial needed to kill the bacteria
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Describe in Liquid Testing of Antibiotics
- Same amount of bacteria is placed in each test tube and suspended in broth
- Antibiotics are added to the test tubes but in decreasing concentrations and incubated over night.
- Look to see which point the bacteria had stopped growing. The tubes become less cloudy if the bacteria have stopped growing. This is the MIC
- Then put the Test Tube samples onto agar plates. Incubate over night and then see the concentration at which the bacteria stop growing. This is the MBC.
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What are the main targets for Antibiotics (6)
1) Cell Wall (Peptidogylcan Synthesis)
2) Protein Synthesis (Ribosomes or Enzymes)
3) Metabolic Pathways
4) Bacterial DNA
5) Membranes
6) Bacterial Enzymes
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Describe the Structure of Peptidoglycan
•NAG-NAM repeating chains
•Tetrapeptide side chains
•Peptide cross-links between chains
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Name the Amino Acids used to form the Peptide Crosslinks between NAM and NAG repeating chains in the Peptidoglycan Structure (2)
1) D-Alanine
2) D-Glutamate
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Which Antibiotics inhibit peptidoglycan synthesis (3)
1) Beta Lactams i.e. Penicillin and Cephalosporins
2) Glycopeptides (Vancomycin, Teicoplanin)
3) Cycloserine (inhibits alanine racemase and D-Alanine Ligase)
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What are Beta Lactam Antibiotics
- Bactericidal Compounds that contain a Beta Lactam Ring and Inhibit Bacterial Cell Wall Formation
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List Beta Lactam Antibiotics
- Penicillin
- Cephalosporins
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What are PBPs
Penicillin Binding Proteins.
These are a group of proteins present in bacteria that are involved in Peptidoglycan Synthesis
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Where do Beta Lactam Antibiotics Bind to
Beta Lactam Antibiotics bind to Penicillin Binding Proteins (PBPs) and inhibit Peptidoglycan Synthesis
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How do Cycloserines inhibit Peptidoglycan Formation
- Cycloserines are an analogue of Alanine. They bind in the crosslinking between NAM and NAG chains of Peptidoglycan. They do not function as Alanine therefore break up the crosslinking and inhibit peptidoglycan function
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Compare the Structures of Penicillin and D-alanyl-D-alanine
Penicillin and D-Ala-D-Ala are structural analogues.
D-Ala-D-Ala is part of the Amino Acid Crosslinking Structure in Peptidoglycan Synthesis.
PBP Transpeptidase binds naturally to D-Ala-D-Ala.
Therefore Penicillin can bind to the PBP Transpeptidase and prevent crosslinkages from forming leading to Cell Death.
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Describe the difference in how Penicillin Work in comparison to Vancomycin
Vancomycin binds to D-Ala-D-Ala and blocks the binding site of PBPs
Penicillin binds to PBPs preventing it binding to D-ala-D-ala.
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List Antibiotics that affect Bacterial Protein Synthesis
1) Aminoglycosides
2) Tetracyclines
3) Erythromycin
4) Fusidic Acid
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How do Bacterial Ribosomes differ from Mammalian Ribosomes
Bacterial Ribosomes have 30s and 50s
Mamallian Ribosomes have 40s and 60s.
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How do Aminoglycosides inhibit Protein Synthesis
Aminoglycosides act on the 30s subunit of the Bacterial Ribosome which results in misreading of the genetic code and inhibits proteins synthesis
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Give Examples of Aminoglycosides
- Gentamicin
- Streptomycin
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Which microorganisms are Aminoglycosides effective against
Effective against Aerobes and Facultative Anaerobes
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How are Aminoglycosides administered
IV or IM
These antibiotics are not absorbed from the gut
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How do Tetracylines inhibit Protein Synthesis of Bacteria
Tetracylines inhibit tRNA binding to the 50s subunit of the Bacterial Ribosome. This inhibits protein synthesis
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When is Erythromycin used
- Used for Penicillin Allergic Patients
It penetrates mammalian cells to reach intracellular organisms along with Tetracyclines
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List Antimicrobial Agents that affect Bacterial DNA (3)
1) Quinolones
2) Rifamycins
3) Metronidazole
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How do Quinolones affect Bacterial DNA
Inhibit DNA Gyrase. Mechanism is not fully deduced.
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How do Rifamycins affect Bacterial DNA
- Act on DNA-Dependent RNA Polyemrases.
- Rifamycin affect Bacterial Polymerases (enzymes) which form mRNA from the bacterial DNA strands
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How do Metronidazole affect Bacterial DNA
- Directly damage Bacterial DNA by causing Strand Breakage
Metronidazole is active only which organisms
Anaerobic Organisms.
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Which antibiotics affect Metabolic Pathways and Folic Acid Synthesis
Sulfonamides such as Sulfanilamide intrupt Folic Acid enzymes needed for Amino Acid synthesis
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Sulfonamides are active against which organisms
Gram Positive and Gram Negative Bacteria
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How do Sulfonamides affect Folic Acid Synthesis
PABA is a precursor for Amino Acid Synthesis. Sulfonamides are structural analogues of PABA
Therefore Sulfonamide and PABA act in competition to bind to the enzyme Dihydropteroate Synthetase.
This enzyme converts PABA to amino acids. However is Sulfonamide binds to Dihydropteroate Synthetase this reaction is inhibited.
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What do Sulfonamides bind to
Enzyme Dihydropteroate Synthetase (which normally would convert PABA to amino acids)
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Antibiotic Resistance can be due to...
- Chromosomal Mutation
- Some is coded for by Plasmid DNA
- Transposons can carry resistance genes and jump between chromosome and plasmid DNA
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How do PBP develop Antimicrobial Resistance
Target is structurally altered by mutation. PBP can change their structure so they are no longer complementary to penicillin anymore
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Antimicrobial Resistance can be due to...
- Target is structurally altered by mutation
- Target is overproduced
- The drug is not activated i.e. Aerobes will not activate Metronidazole
- The drug may be removed
- The drug cannot gain entry to the cell.
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How does Beta Lactamase remove the Antibiotic
Beta Lactamase is an enzyme produced by bacteria. They break down the Beta Lactam Ring in Antibiotics and prevent the antibiotic from working
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How can bacteria remove the antibiotic
- via Enzyme Destruction i.e. Beta Lactamase
- Aminoglycoside Resistance, 3 modifying enzymes can modify the antibiotic by changing its structure i.e. Phosphorylation
- Efflux pumps pump the antibiotic out the cell for example in Tetracyclines and Quinolones
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Properties of Antivirals
- Few in Number
- Narrow in Spectrum
- Virustatic
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How do Antivirals work? (3)
1) Target the Penetration and Uncoating Step of the Lytic Life Cycle of Viruses
2) Taking over cell machinery i.e. Transcription and Translation
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How does Amantadine work
Antiviral that prevents the fusion of viral envelope with cell membrane.
Affects the penetration and uncoating steps of the Lytic Life Cycle of the Virus
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How do Protease Inhibitors prevent Post Translation Inhibition of Viruses.
- Protease Inhibitors prevent post translation inhibition
Proteases cleave viral polyproteins into structural proteins required for Viral Replication however Protease Inhibitors prevent these resulting in immature defective viral particles.
HAART is a protease inhibitor