MP321 week 3 Flashcards
HIV viral replication steps
1- fusion of HIV to the host cell surface
2- HIV RNA reverse transcriptase , integrase and other viral proteins enter the host cell
3- viral DNA is formed by reverse transcription
4- viral DNA is transported across the nucleus and integrates into the host DNA
5- new viral RNA is used as genomic RNA and to make viral proteins
6- new viral RNA and proteins move to the cell surface and a new, immature, HIV forms
7- the virus matures by protease releasing individual HIV proteins
key HIV enzymes
protease
reverse transcriptase
integrase
inhibit these and stop HIV (viral) replication
define NRTIs
nucleoside reverse transcriptase inhibitors
how do NRTIs work
mimic the natural nucleosides that are incorporated into the double helix chain formation of DNA-RNA and DNA
NRTI prodrug and activated only viral kinase
target polymerase during transcription
prodrugs metabolised to give non-functional nucleosides
when NRTIs are incorporated into growing chain it causes chain termination
no more HIV can be made and CD4 cells not further compromised
to incorporate the nucleoside into the chain it needs to be converted to a nucleotide
the hydroxyl group enables the molecule to be seen and incorporated into the chain, the changes from hydroxyl to N3 in structure leads to chain termination
define prodrug
a biologically inactive compound which can be metabolized in the body to produce a drug
what is remdesivir used to treat
acute, severe covid-19, works differently to other NRTIs
chemistry of remdesivir
3’ hydroxyl group present - so a nonobligate chain terminator
although theoretically may bond to another nucleoside, it does not
note how others have this functional group removed to be active
it still works because it has a bulky group which hides and blocks the hydroxyl group
adenosine like most involved in base pairing with uracil
as this is very similar to how adenosine makes base pairs, this possibly is why it gets incorporated by viral polymerase - enables transcriptase to see and recognise
as it has a carbon - carbon bond it is more stable against nucleases as not a semi-aminal bond
define NNRTIs
non-nucleoside reverse transcriptase inhibitors
NNRTIs
Non-nucleoside reverse transcriptase inhibitors
Known as allosteric inhibitors (holy grail of inhibitor type)
Bind to a lipophilic pocket at the base of the “thumb” area of the RT enzyme
Conformationally prevents the enzyme from allowing the single strand of RNA to be transcribed
Prevents replication and protects CD4 cells
useful as they don’t block natural active site
targets polymerase during transcription as allosteric inhibitors
protease inhibitors (PI)
large proteins made following transcription and translation
proteases are inhibited by other small molecules
processed into smaller proteins to make virion
protease cleaves the larger proteins
hydrolysis of the protein peptide bond
HIV protease is a much smaller enzyme than the equivalent host aspartate proteases
Cleaves substrates N-terminal to proline residues unlike mammalian proteases (selectivity)
Tyr-Pro was identified as a cleavage site for the HIV protease
Rationale for inhibitor design was based on Phe-Pro or Tyr-Pro motif
mimic substrate with non hydrolysable functionality
hydrolysis of amide bond
split into amine and carboxylic acid and get rid of water
how does saquinavir work
when it is in the active site it won’t get cleaved and prevents the natural substrate binding, need to make the drug more favourable to get into site first
name 5 properties an ideal anti-microbial formulation should be
- effective against targeted infection
- able to reach (specifically) site of action
- rapid onset
- controllable duration
- free of side effects
name 2 things that will influence the route of administration and dosage form for antimicrobials
- site of infection
-severity of infection
topical administration- used for ?
mild infection
IV/IM administration- used for?
severe infections
name one advantage of topical administration onto the skin
local action- drug retained in the skin
to be suitable for topical drug delivery the drug should be (3)
- low MW (less than 500 Da)
- moderately lipophilic (log P between 1 and 4)
- effective at low dose (less than 10mg/day)
name the three formulation types for skin
- liquid
- semi-solid
- solid
name the 2 principles of formulation for the skin
- formulation should be stable but allowing drug to be released after application
- vehicle should allow some solubility of the drug but should not retain the drug by being a very good solvent
name one advantage and 2 disadvantages of a liquid formulation for the skin
ad- rapid short term input of permeant into the skin
dis- low drug delivery
dis- treatment of surface infection only
name 2 advantages and one disadvantage of ointments
ad- increase of transdermal drug flux (the number of molecules moving through a given cross- sectional area during a given period of time)
ad- prolonged drug delivery
dis- messy to use due to greasy nature
name 2 advantages and one disadvantage of creams
ad- easier to apply than ointments
ad- can be washed off skin surface
dis- less occlusive than ointments, therefore less beneficial in dry skin conditions
name an example of a solid formulation for skin application
spray powder
name one of the challenges with topical application to the nail
nail has a hard keratinised structure- need keratolytic components to increase diffusion of drug through nail plate
name one important must have property of topical formulae for the eyes
formulation must be sterile
one average what is the range (%) of drug in topical formulations that reaches the aqueous humour in the eye
1-5%
name 2 advantages and one disadvantage of eye drops
ad- easy to administer
ad- homogenous (better dose uniformity)
dis- rapidly drained out of the eye (90% in first 30s)
name 3 advantages and 3 disadvantages of eye ointment formulations
ad- reduced drug drainage caused by tear flow
ad- sustained drug release (2-4h)
ad- incorporation of drugs with poor aqueous solubility
dis- more difficult to administer than drops
dis- more variation in dosing
dis- blurs the vision
name 2 advantages of ear drop formulations
ad- easy to administer
ad- dose uniformity
name 2 considerations for topical applications for the nose
-need of increasing nasal residence time (bioadhesion, increased formulation viscosity
-mucocilliary clearance
define mucocilliary clearance
removal of the drug from the nasal cavity
name 4 oropharyngeal formulations
-solutions
-gels
-suspensions
-mucoadhesive buccal tablets
name 4 vaginal formulations
gels
creams
pessaries
ovules
define pessary
vaginal suppository- solid, single-dose formulations of ovoid shape
define ovules
vaginal capsules, shell pessaries- solid, single dose formulations similar to oral soft capsules but shape is often elongated and larger
name 2 advantages and 1 disadvatange of topical formulations for the vagina
ad- treatment of local infections with a much lower dose than with oral administration
ad- no need of absorption of the drugs for local action
dis- release of the drugs influenced by varying volumes of vaginal fluid
oral administration types (2)
solid
liquid
parenteral administration types (2)
injections and infusions
liposomes
name one advantage and one disadvantage of oral administration (general)
ad- the simplest, most convenient and safest means of drug administration
dis- possibility of irregular absorption of certain drugs
name 4 advantages and 2 disadvantages of tablet formualtions
ad- accurate dosing
ad-convenient to handle and carry
ad- easy to take
ad- controlled release of the drug
dis- poor bioavailability of some drugs
dis- local irritant effects to GI mucosa
name 3 advantages and 3 disadvantages of capsule formulations
ad- accurate dosing
ad- drug release faster than tablets
ad- shell masks taste of unpleasant drugs
dis- bulky materials can result in a large capsule
dis- susceptible to moisture
dis- not suitable for drugs that are inactivated in the stomach
name 2 advantages and 2 disadvantages of powder formulations
ad- reconstituted just before use to avoid chemical degredation
ad- fast drug release compared to tablets and capsules
dis- not suitable for drugs that are inactivated in the stomach
dis- less convenient to carry and self-administer
name 2 advantages and 1 disadvantage of suspensions
ad- drug absorption fast than tablets or capsules
ad- convenient when drug is not soluble in water and when non-aqueous solvent cannot be used
dis- risk of sedimentation
can a suspension with caking be redispersed ?
no
can a suspension with settling at the bottom be redispersed
yes
name 2 advantages and 2 disadvantages of syrup formulations
ad- drug already dissolved
ad- easy to a just dose for Childs weight
dis- risk of deterioration fast than solid dosage forms
dis- inaccuracy with patients measuring doses
name 2 advantages and 2 disadvantages of suppositories
ad- good route when vomiting
ad- indicated for drugs inactivated in the liver after oral administration
dis- patient acceptability (cultural influence)
dis- irregular drug absorption
name 2 advantages and 2 disadvantages of suppositories
ad- good route when vomiting
ad- indicated for drugs inactivated in the liver after oral administration
dis- patient acceptability (cultural influence)
dis- irregular drug absorption
principles of parenteral administration
Administration by injection
- Intramuscular and intravenous administrations of anti-microbials (only solutions injected IV !)
- All parenteral products must be sterile
- Preferred route when rapid absorption is essential (emergency, unconscious patients)
- Generally sterile solutions or suspensions of drugs in water
difference between injections and infusions
- Injections
= sterile solutions, emulsions or suspensions, in water or non-aqueous liquid - Injected in less than 15 min
- Infusions
- Aqueous solutions
- Large volumes: 100 ml -1000 ml
- Injected in more than 15 min
depot parenteral administration
- Depot preparation
- Dispersion of the drug in an oily vehicle
Slow release of the drug - IM injection deep into skeletal muscles
- Viscous formulation, large volume (5 mL maximum) injected
Need to be injected in large muscles to decrease pain and swelling - Slow release of the antibiotic for weeks
name one advantage and one disadvantage of depot injection
ad- long lasting effects- 2-4 weeks
dis- negative patient acceptance- very painful
what are liposomes
spherical vesicles in which a lipid bilayer membrane delimitates a central aqueous compartment
can carry hydrophilic and lipophilic drugs
liposomes form when the phospholipids are exposed to an aqueous environment
downfall of fungizone
not specific - releases drug too quickly which is toxic on mammalian cells
can cause renal toxicity, haematological toxicity and cardiovascular toxicity
name the 2 branches of antibiotic resistance
intrinsic and acquired
define intrinsic antibiotic resistance
nothing we can do about it- natural
name the 2 branches of resistance within acquired resistance
horizontal and vertical transfer
how many cytoplasmic membranes do gram negative bacteria have
2
how many cytoplasmic membranes do gram positive bacteria have
1
can vancomycin be used against gram negative bacteria ?
no- it is too big to fit through porins in the membrane
can vancomycin be used against gram positive bacteria?
yes it works well on these but is only used as a last resort
explain why vancomycin cannot be used on gram negative bacteria
vancomycin is very large and very hydrophilic (due to sugars, OH and carbonyl groups)
even though porins let through hydrophilic molecules - only small ones this is too big to fit
all gram negative bacteria are intrinsically resistant to vancomycin
explain acquired resistance - vertical transfer
bacteria have small genetic mutations
these are passed from parent cell to daughter cell- this is also true for mutations that make then resistant to antibiotics
because bacteria divide and multiply so quickly these are passed down many generations very quickly
natural selection also plays a part here- only bacteria resistant to the antibiotic survive to pass on their genetic material
explain acquired resistance- horizontal transfer
this is where genetic material is transferred between bacteria of the same generation
it can even be transferred between bacterial species
name and explain the three possible ways of horizontal transfer
conjugation
- close contact
-facilitated by pili
- genetic material transferred from one plasmid to another
transduction
-done by a virus
-virus incorporates genetic material from bacteria into its own, then leaves that bacterium and enters a new cell- this infects the new bacteria with the old bacterias genetic information
transformation
-bacteria die, then through lysis cell opens up and genetic information is then loose, other near by bacteria can then pick this up
what do efflux pumps do
efflux pumps are proteins synthesised by bacteria
these want to eject anything that goes into the cell
antibiotics are ejected out of the cell by these profile pumps
can target these pumps by using an inhibitor although there is nothing on the market for this yet
AMR- how does it translate
efflux pumps
antibiotic altering enzyme
change in structure of porins
- some small molecules which normally work through porins on gram negative no longer work
change in ribosomes
- if ribosomes are changed even 1 or 2 amino acids, the antibiotic no longer works
penicilli binding protein
how does antibiotic altering enzyme work
antibiotic is changed (not degraded) functionalities change and it no longer functions in the same way
why is AMR a global health issue
- antimicrobial misuse/ over use leads to a high AMR
- resistant microbes increase severity and duration of infection (high costs)
- rapid spread (ease of transfer between species)
-decline in antibiotic research
what percentage of S.aureus roughly are now resistant to benzylpenicilin
90%
what is MRSA
methicillin resistance to staphylococcus aureus
methicillin-type drugs (like flucloxacillin) developed target B-lactasmase resistant bacteria
but MRSA can produce a new penicillin binding protein that is not inhibited by flucloxacillin
what do we use to treat MRSA
vancomycin
B-lactamases-producing gram negative bacteria
Extended Spectrum Beta Lactamases degrade penicillins (except temocillin) + cephalosporins + monobactams
Metallo-b-lactamase (NDM 1) degrades penicillins + cephalosporins + carbapenems
Metallo-b-lactamase (KPC) degrades penicillins + cephalosporins + monobactams +carbapenems
Some metallo-b-lactamases are neither inhibited by clavulanic acid nor tazobactam
how can we tackle AMR
-Use antibiotics in the right way (right drug/right dose/right time/right duration. As prescribed and full course completion
-Don’t keep/share antibiotics
-Never use antibiotics for viral sore throats
-Select most appropriate antibiotic (narrow vs broad-spectrum)
-Reserve highly effective antibiotics for severe infections
-Provide appropriate advice on management of ATB use (e.g. AMR clinical surveillance)
-Develop local antimicrobial guidelines/policies (e.g. SAPG & antimicrobials pharmacists) to encourage wise/prudent use of antibiotics
-Prevent transmission (infection control)
-Develop quicker diagnostics
-Support drug discovery efforts
-Develop further education/training
-Raise awareness
-Be PROACTIVE
define clinical governance
a framework which the NHS have in place for improving the quality of their services and safeguarding high standard of care
name the three components of the healthcare quality strategy for Scotland
person-centred
clinically effective
safe
name the four components of the medication process
prescribing
dispensing/ preparation
administration
monitoring
name some ways to create a safe and reliable system
simplify
standardise
use protocols and checklists
access to information at point of need
effective communication
what kind of molecules can liposomes carry
hydrophilic and lipophilic
how do liposomes form
when phospholipids are exposed to a aqueous environment
which of fungizone and ambizome are specific
ambizome
what is the main barrier to topical application to the skin
stratum corneum
types of patients at higher risk of infection
- immune compromised (drug or disease)
- patients in intensive care or post op
-malnourished - patient with cancer(chemo drugs)
-diabetics
-elderly or infirm
-infants and neonates
appropriate use of antibiotics
Correct diagnosis
Known or presumed site of infection
Likely causative organism
Antibiotic culture & sensitivity
May take 2 – 3 days to get this
Local variations in sensitivity
Patient factors
Site and severity
SIRS, MEWS, SEWS
Route of administration
Serious infection cannot wait for culture and sensitivity results
Antibiotic sensitivity is different in different areas ie what works in Edinburgh may not work in glasgow
selection and use of antibiotics
Pharmaceutical
Clinical efficacy
Route of administration
Oral / IV / IM / topical / inhaled
Absorption, distribution, metabolism, excretion (ADME)
Toxicity
Knowledge of drug properties
Drug interactions
With other treatments or with foods / fluids
Cost of treatment
oral easiest most common
IV reliable- 100% bioavailability, however breaching skin, this poses its own risks
IM- less predictable, may not work
Topical- minor- not systemic infection, hard to reach high enough concentration to kill microbe
ADME- important for antimicrobials too
Tetracycline- cant have with milk- interactions
pharmaceutical assessment (antibiotics)
Check patient factors
Contraindications
Interactions
Medicines, food, fluids
Allergies
Renal function
Hepatic function
Double check any other meds- OTC, prescription, herbal etc
Allergies- lactose intolerance,
Excretion- liver, kidney function
choice of route for antibiotics
oral administration with adequate doses is preferred if possible
topical should be avoided where suitable oral alternatives- exceptions- cold sores, athletes foot etc
Intravenous therapy
Required for
Clinical symptoms / signs of infection and deteriorating clinical condition; febrile with neutropenia / immunosuppression; meningitis / CNS infection; infective endocarditis; bronchiectasis; bone / joint infection; deep abscess; cystic fibrosis; Staphylococcus aureus bacteraemia; skin and soft tissue infection; IV therapy if sepsis or 2 or more of heat, erythema or induration / swelling; oral route compromised - vomiting, nil-by-mouth, reduced gastrointestinal absorption; mechanical swallowing disorder; unconscious; no oral formulation available; initial therapy for biliary sepsis / intra-abdominal infection.
Use until there is clinical control of the infection
Indicators of infection returning to reference range
IM is less reliable than IV
IV to oral switch therapy
In patients who have been on IV for 24 – 48 hours and who have
Settling temperature
Falling indicators of infection
Able to take oral therapy
Oral therapy available
review patient after 24 hours
If they are improving or now able(ie stopped vomiting, feeding tube removed etc)- switch to oral
general penicillin dose
500mg-1g four times daily
general gentamicin dose
5-7mg per kg once daily
management of infection
Suggested empirical therapy
Should be modified based on
Patient factors
Results of culture & sensitivity (if taken)
Patient response to therapy
Therapeutic drug monitoring
pharyngitis
upper respiratory tract infection
majority viral – no antibiotic or antiviral recommended
<20% bacterial
Streptococcus pyogenes
Narrow spectrum penicillin
Macrolide
otitis media
upper respiratory tract infection
Usually viral or self limiting
Haemophilus influenzae
Penicillin
Macrolide
- delayed prescribing to see cultures
exacerbation of COPD
lower respiratory tract infection
Diagnostic criteria
Increased wheeze, increased shortness of breath, increased sputum volume and purulence
Strep pneumoniae
Haemophilus influenzae
Moraxella catarrhalis
Penicillin
Tetracycline
Macrolide
IV therapy if severe infection
Patient factors
Possibility of a recurrent infection due to underlying condition
Previous therapy likely to be effective
Route of therapy – orally normally
Patient age – likely to be older: has ADME been affected
Other diseases – possibility of drug interactions
what is the minimum age for tetracyclines
12
name one common interactant of tetracyclines
milk
community acquired pneumonia (CAP)
lower respiratory tract infection
Strep pneumoniae
Haemophillus influenzae
Non-severe CAP (C(U)RB-65 score 0 or 1)
Penicillin such as amoxicillin
tetracycline
macrolide
Moderate CAP (C(U)RB-65 score = 2 and no sepsis syndrome)
Ask about foreign travel
Possibility of Legionella (especially if the patient is confused)
Penicillin such as amoxicillin and either
Tetracycline or macrolide
Still water or showers that haven’t been used for a while - legionella is they are confused- need to use macrolide best for legionella infections
severe community acquired pneumonia
lower respiratory tract infections
Severe Community Acquired Pneumonia (CURB-65 > 3 or any C(U)RB-65 score and sepsis syndrome)
Consider Legionella especially if patient confused
Macrolide (oral or IV as appropriate) and either
Penicillin or penicillin with beta lactamase inhibitor.
Quinolone may be used in a patient with true penicillin allergy
hospital acquired pneumonia (HAP)
Within four days of hospital admission – treat as CAP
Within 7 days of discharge or after 5 days of hospital admission and CURB-65 less than 2
Penicillin with beta lactamase inhibitor
Tetracycline
Within 7 days of discharge or after 5 days of hospital admission and CURB-65 less than 3 or more
Penicillin and aminoglycoside
Extended spectrum penicillin
pneumonia patient factors
Patient age – adult or child
Severity of infection – need for IV therapy
Severe infection may affect absorption
Comorbidities – other medicines may interact
May need to withhold other meds while the patient has sepsis (eg antihypertensives if the patient is hypotensive)
UTI
Uncomplicated UTI in men and non-pregnant women
E coli
Proteus spp
Enterococci
trimethoprim
nitrofurantoin
Pregnant women
nitrofurantoin
penicillin
upper UTI without sepsis
Women
trimethoprim
nitrofurantoin
Men
trimethoprim
Penicillin with beta lactamase inhibitor
Pregnant women
Penicillin with beta lactamase inhibitor
trimethoprim last trimester only can cause teratogenicity
upper UTI with sepsis
Women and men
Penicillin with beta lactamase inhibitor and aminoglycoside
Pregnant women
Penicillin with beta lactamase inhibitor and aminoglycoside
most likely IV
aminoglycosides- very good at treating UTIs but can only be given via IV
UTI patient factors
Anatomy
Length of urinary tract (men have longer)
Pregnancy
Possibility of teratogenicity
Which trimester of pregnancy?
Severity of infection
May need IV therapy
Does the patient have a catheter?
Difficult to eradicate infection
Length of treatment
3 days may be enough
Additional counselling
Avoid perfumed wipes, hygiene, post coital infections, fluids, avoid coffee, etc
3 days of treatment in women= 5 days in men
skin and soft tissue infections
Cellulitis
Staph aureus, Strep pyogenes
Mild cellulitis /erysipelas
Narrow spectrum penicillin
tetracycline
macrolide
Moderate cellulitis
Narrow spectrum penicillin
glycopeptide IV
Human or animal bite
Penicillin with beta lactamase inhibitor
tetracycline and metronidazole
skin and soft tissue patient factors
Site of infection
Comorbidities eg diabetes
Age of the patient
Is it a bacterial infection only?
Possibility of viral or fungal infection at the same time
Is topical treatment possible – some mild infections
Necrotising fasciitis
Rapidly spreading infection
Strep pyogenes
benzylpenicillin 2.4g every six hours and flucloxacillin 2 g every four to six hours and gentamicin IV and clindamycin IV 600mg every six hours and metronidazole IV 500mg every eight hours
Surgical treatment may be needed
could need amputation
pyrexia of unknown origin (PUO)
Sepsis or severe sepsis
Broad spectrum cover required
Penicillin and aminoglycoside IV
metronidazole
Glycopeptide IV and aminoglycoside IV
Patient factors
Age
Other treatments eg steroids, chemotherapy
Comorbidities
IV access may be difficult if hypotensive
Clostridium difficle
Antibiotic associated diarrhoea
Related to broad spectrum antibacterial therapy
Non-severe
metronidazole 400mg every eight hours
vancomycin 125mg every six hours
Severe
vancomycin 125mg every six hours
Severe / complicated
vancomycin 125mg every six hours +/- metronidazole 400mg every eight hours
Relapsing – consider faecal transplant, re-establishing the microbiome
only time we use oral vancomycin but needs to be capsules
common viral infections
Herpes simplex (cold sores)
aciclovir topically
Herpes zoster (chickenpox, shingles)
aciclovir 800mg five times a day
valaciclovir 1g every eight hours
Patient factors
Age
Time of onset of symptoms
Formulation of treatment – topical, eye ointment, tablets, liquids, IV
Immunocompromised or very serious infection need treatment
Most people with viral infection will get better on their own
If shinges rash for less than 72 hours- treat- if more than 72 hours- don’t treat- it makes no difference to recovery time
common fungal infections
Tinea
athletes foot
Antifungal powders / ointment
Ringworm (anywhere on the body including scalp and groin)
Topical antifungal
Patient advice – sharing towels,
Candida
Oral infections
Vaginal infections
Azole antifungals – usually oral
Patient factors, age, other treatments eg inhaled or oral steroids,
prescribing factors
Allergies
Sensitivities
Under dosing
Over dosing
Resistance local differences
Side effects
name one counselling point on using tetracyclines
cause sun sensitivity
