week 2. Antiviral, antifungal, intro to parasites Flashcards
what was the first antiretrovural drug produced and when?
AZT in 1987
explain the progression of HIV after infection?
you get primary infection –> where there is a rapid rise in viral load with a stark decrease in CD4 account.
However the immune system responds and there is a clinical latency where there the viral load is in balance.
However after some time the level of viral load increase while the CD4 count reduces –> opportunistic infection occurs
what are the two types of Virus?
ones based on RNA and ones with DNA
viruses that cause acute infection what are they based on?
RNA –> short lasting
give examples of acute infection caused by virus
Influenza, measles, mumps, hepatitis A virus
what are chronic infection based on?
DNA –> long lasting –> more stable and theredfore last a long time
what are the two types of chronic infection by a virus?
latent and persistant
give example of chronic latent virus’s?
Herpes simplex, Cytomegalovirus
give example of persistant virus?
HIV, Hepatitis B virus, Hepatitis C virus
what is a characteristic of persistant virus?
it replicates all the time
how does HIV convert its RNA to DNA?
using reverse transcriptase
what type of genetic information does Hep C have?
purerly RNA
how does Hep C overcome the immune system and cause chronic infection?
it affects the liver and therefore evades the immune system and constantly evolving –> beating the immune system
will you 100% die from hep B/C if you have it
no
what does a virus consist of?
Nucleic acid (DNA or RNA) Protein (coat - structural, enzymes-non-structural) \+/- Lipid envelope
HIV is Obligate intracellular parasites. What does this mean?
it cannot reproduce outside a host –> needs intracellular resources
what is important about envelope structural proteins of HIV?
it is what allows HIV to invade cells
what is the sequence of viral replication?
1) Virus attachment to cell (via receptor)
2) Cell Entry –> find the cell they can enter without harming it
3) Virus Uncoating ready for replication
4) Early proteins produced – viral enzymes
5) Replication
6) Late transcription/translation – viral structural proteins
7) Virus assembly
8) Virus release
9) Some virus kill the cell by lysis but not all do this and go and affect other cells
what do virus’s encode and why are they important for treatment?
viruses encode unique proteins that are vital for virus replication and infectivity –> antiviral drugs target this for molecular inhibition
what are the different types of polymerases involving VIrus’s?
DNA to DNA –>Eukaryotes , DNA viruses
DNA to RNA –> Eukaryotes ,DNA viruses
RNA to RNA–> RNA viruses
RNA to DNA –> Retroviruses (HIV), Hepatitis B virus
what is azidothymidine?
Nucleoside Reverse Transcriptase Inhibitor (NRTI
what does AZT do?
it inhibits reverse transcriptase in HIV and other retroviruses
what was AZT first used for?
as a cancer drug but was to toxic
what year was AZT used as a HIV treatment?
1985
what is AZT analogue of?
thymidine –> Oh is replace with 3 nitrogen atoms
what are the two types of NRTI analogue?
Purine analogue
Pyrimidine analogue
what are the pyrimidine?
thymine and cytosine
give examples of pyrimidine analogue?
Thymidine analogues –> Zidovudine
Cytosine analogues –>Lamivudine
what are the purines?
adenine and Guanidine
give example of purine analogue?
Abacavir
Tenofovir
why is NRTI effective for hep B virus?
The virus contains reverse transcriptase enzyme
what NRTI are effective against hep B infection?
Lamividine
Tenofovir
how does NRTI work?
by competing with reverse transcriptase for their interaction site with HIV genetic material
what is the difference between NRTI and NNRTI and how do NNRTI work?
NRTI looks similar to necleotides but NNRTI doesn’t look like anything like nucleotides.
NNRT block reverse transcriptase by binding to a different part of the protein
name all the different protease inhibitors for HIV treatment?
Atazanavir Darunavir Fospamprenavir Lopinavir Nelfinavir Ritonavir* Saquinavir
which of the protease inhibitors increase the affect of other drugs?
ritonavir
what is the importance of protease in HIV?
HIV virus cuts proteins–> to form specific enzymes needed for it to function and replicate
what three parts of the HIV genome can be targeted in treatment?
core structural protein, envelope structural protein and viral enzymes
give example of the newer HIV drugs?
Fusion inhibitor
Integrase Inhibitors
Chemokine receptor antagonsits (
give an example foa fusion ihibitor and how it functions in respect to HIV treatment?
Enfuviritide (T20, given by IM injection as it is a peptide
give an example foa Integrase Inhibitors in respect to HIV treatment?
Raltegravir
how does Chemokine receptor antagonsits work?
it blocks the ability for HIV to bind to co receptors such as CCR-5 and CXCR4 –> which prevents the HIV virus to bind to CD4
what are the different combinations of Highly Active Antiretroviral Therapy (HAART)?
2 NRTIs + NNRTI
2 NRTIs + boosted PI
when is HAART given?
Started when CD4 falls
Aim to switch off virus replication
Taken life long
Suppression >10yrs achieved
what toxicity can be caused by HAART?
liver and kidney toxicity
in HAART why is 3 drugs used?
reduce the chance of the virus to become resistant –> very highly unlikely that the virus will mutate in such a way to become resistant to 3 different drugs
what mutation takes place in HIV to become resistant to Lamivudine?
M184V mutation
how many nucleotides does HIV contain?
9000
what mutation can make someone more resistant to HIV infection?
having a mutation to the gene that codes for CCR5 and CxCr4 will give someone greater resistance to HIV
what are inteferons?
are naturally occurring antivirals that are within the human body
what is the treatment of Hep C?
use of exogenous interferon –> can boost peoples antiviral affect
for howlong do you have to give interferons to treat Hep c?
3 to 12 months
what are the side effects of interferons?
make you feel depressed, flu like and is a injection
when will antivirals work on acute infection?
only if given very soon after infection –> as the bodies own immune system will start to kick in
what is Aciclovir used for?
For Rx of Herpes Simplex Virus (HSV) and Varicella Zoster Virus (VZV)
what is the structure of Aciclovir
Nucleoside analogue (phosphorylated by herpesvirus thymidine kinase)
what is Ganciclovir used for?
treatment of Cytomegalovirus (CMV)?
what is the treatment of influenza?
Oseltamivir and Zanamavir (neuraminidase inhibitors)
what is Ribavirin used for?
Hepatitis C virus and RSV
what is Interferons used for?
Hep B and C
what is a parasite?
An organism which lives in or on another organism (its host) and benefits by deriving nutrients at the other’s expense.
DOES A PARASITE always cause disease?
no
what does Symbiosis mean?
living together; close, long term interaction between two different species
what does Mutualism mean?
an association in which both species benefit from the interaction
what does parisitism mean?
an association in which the parasite derives benefit and the host gets nothing in return but always suffers some injury
what does Commensalism mean?
an association in which the parasite only is deriving benefit without causing injury to the host
what is a definitve host in parasites?
Either harbours the adult stage of the parasite or where the parasite utilizes the sexual method of reproduction
what is the intermediate host in parasites?
Harbours the larval or asexual stages of the parasite
what is teh Paratenic host in parasites?
Host where the parasite remains viable without further development
what are the two types of parasites?
Protozoa –> Micro-parasites
Helminths –>Macro-parasites
what does P.Falciparum cause and where is it found?
cause malaria and found in blood smears
what are the two types of helminths?
Platyhelminths–>(Flatworms)
Nematodes –> (Round worms)
give example of Cestode and what is causes?
Taenia sp and it is tapeworm
what does Tissue nematode cause?
found in the bowel cause elephantiasis inflammation of the lymphatic system extreme swelling of arm and leg
what are the two types of parasite life cycle?
direct and indirect
what is direct life cycle?
invoves one type of species –> transmission through same species
how does indirect cycle work?
involves more than one specie –> there is a intermediate host
what is a complex indirect life cycle?
where there is more than one intermediate host
What type of parasite is Ascaris?
Macro-parasite (Helminth) - intestinal nematode
in what area is Ascaris most prevelant and what age group?
between ages of 3-8yr olds and also in areas of poor sanitation
how is Ascaris transmitted?
1 worm produces 200,000 eggs -> feaces of humans that contains eggs that contaminate water and ground.
how does Ascaris worm develop from a egg into a worm?
THe life cycle
Has a direct life cycle Worm in human intestine, eggs shed into the environment in faeces, eggs are then ingested, they travel in the portal circulation to the lungs where they then hatch and the worms are they swallowed and enter the intestine
what are the 2 different clinical stages of Ascaris?
lung migration and intestinal phase
In the lung migration of Ascaris what are the syptoms? (6)
Loefflers syndrome- dry cough, dyspnea, wheeze, haemoptysis, eosinophilic pneumonitis
what does eosinophilic pneumonitis mean?
is a disease in which a certain type of white blood cell called an eosinophil accumulates in the lung
what symptoms are present in the intestinal phase of AScaris?
Malnutrition
Migration – into hepatobiliary tree and pancreas
Intestinal obstruction
Worm burden
what is the treatment of Ascaris?
Albendazole and Benzimidazole
Prevents glucose absorption by worm
what are the controls for AScaris?
Improve sanitation
Education
Community targeted deworming
what type of parasite are Schistosomiasis?
macro-parasites –> worms
where does Schistosomiasis occur and why?
predominantly in Africa because of the presence of Fresh water snails
What are the 4 stages of disease following schistosomiasis infection?
1) Swimmers itch (at sight of entry) 2) Katayama fever (can last a couple of weeks) 3) Chronic schistosomiasis (can persist for years) 4) Effects of eggs in distant sites: spine, lung
what does Schistosomiasis cause?
Causes chronic disease resulting in bladder cancer and liver cirrhosis
what is the intermediate host of Schistosomiasis ?
fresh water snails
what is the life cycle of Schistosomiasis ?
Eggs are shed in human stools or urine, the eggs hatch and the organism infects freshwater snails by penetrating snail tissue, organism matures in snail then released into water and penetrates human skin.
Pass into human circulation, migrate to portal blood in liver and mature into adults which migrate to the mesenteric venules of the bowel/rectum (laying eggs that circulate to the liver and shed in stools) and venous plexus of the bladder.
what is Katayama fever?
infection of the unirary tract and intestines –> through the blood –> weight loss –> loss of appetite
what specie of schistosomiasis affects the unirary tract and what is the symptoms?
S. haematobium
Haematuria
Bladder fibrosis and dysfunction
Squamous cell CA bladder
what specie of schistosomiasis affects the intestinal tract and what is the symptoms?
Hepatic/Intestinal (S. mansoni; S. intercallatum, S. japonicum; S. mekongi)
Portal Hypertension
Liver cirrhosis
how do you diagnose schistosomiasis that affects the urinary tract?
Terminal Stream Microscopy
Serology
how do you diagnose schistosomiasis that affects the intestinal tract?
Stool Microscopy
Rectal Snip Microscopy
Serology
what is the treatment for schistosomiasis ?
Praziquantel (parazinoisoquinoline derivative) and treatment of long term complications
how does Praziquantel work?
40-60 mg/kg with food 3 doses 8-hourly
Mechanism unknown- increased ionic permeability tetanic contraction, detachment, death
Well absorbed, extensive 1st pass metabolism, inactive metabolites excreted in urine
how is schistosomiasis controlled?
Chemical treatment to kill snail intermediate hosts
Chemoprophylaxis
Avoidance of snail infested waters
Community targeted treatment, education and improved sanitation
what type of parasite causes Hydatid ?
Macro-parasite (Platyhelminth- Cestode-Tapeworm
what is the host of Hydatid?
human are accidental hosts
usual host are sheep and dog
what causes Hydatid?
Echinococcus sp. (E. granulosus- cystic and E. multilocularis- alveolar)
what are the main point in the life cycle of Hydatid?
Dog has adult worm in intestines and sheds eggs in faeces These are ingested by a sheep, they hatch and the organism penetrates the sheep intestinal wall and travels to the liver or lungs where it forms a hyatid cyst. Cyst in sheep is ingested by a dog and cycle continues
what is the clinical signs of Hydatid?
Cysts: 70% liver, 20% lungs May remain asymptomatic for years Secondary bacterial infection Cyst rupture- hypersensitivity Aliphatic shock Can see death
how is Hydatid diagnosed?
imaging and serology?
how to control Hydatid?
Regularly worm dogs to reduce egg production
Hand hygiene
Safe disposal of animal carcasses/products of conception
what type of parasite causes malaria?
Micro-parasite (protozoa- sporozoan
what are the species that cause malaria?
P. falciparum
P. vivax
P. ovale
P. malariae
which specie caues the most severe type of malaria?
P. falciparum
how is malaria transmitted?
by Anopheles (mosquito) as a vector
What is the life cycle of malaria?
Organism infected mosquito takes a blood meal from a human injecting the organism This travels to liver cells where it replicates until the cell bursts and the organism then infects RBCs, it can continue in a cycle in which it replicates in RBCs causing them to burst and release further organisms to infect further RBCs. It can also form gametocytes in RBCs which are ingested by another aedes mosquito when it takes a blood meal to form a new organism
what is the clinical presentation of malaria?
Fever & Rigors (alt. days with falciparum malaria, every 48hrs or 72hrs with benign malaria)
Cerebral malaria (confusion, headache, coma)
Renal failure (black water fever)
Hypoglycaemia
Pulmonary oedema
Circulatory collapse
Anaemia, Bleeding and DIC
what does the malaria parasite affect?
rupture red cells, block capillaries and cause inflammatory reaction
how do you diagnose malaria?
Thick and Thin Microscopy –> at least 3 to rule it out
Serology- detection of antigen in blood
PCR- detection of malarial DNA
what are the controls for malaria?
Insecticide spraying in homes Larvicidal spraying on breeding pools Filling in of breeding pools Larvivorous species introduced in to mosquito breeding areas Use of insecticide impregnated bed nets Chemoprophylaxis
what is Cryptosporidiosis caused by?
Caused by Cryptosporidium parvum and hominis (micro-parasite, sporozoan)
what does Cryptosporidiosis cause?
diarrhoeal disease
how is Cryptosporidiosis spread?
human to human transimission –> faecal-oral spread.
what animals act as reservoir of Cryptosporidiosis?
cattle, sheep, goats
what conditions promote Cryptosporidiosis?
warm and tropical places
what is the clinical presentation of Cryptosporidiosis?
Watery diarrhoea with mucus (no blood)
Bloating, cramps, fever, nausea, vomiting
how long does Cryptosporidiosis last for and when is it severe?
Usually self-limiting (last up to 2 weeks)
Can be severe in:
very young
very old
Immuno-compromised (60% HIV patients infected go on to chronic infection- can loose up to 25 litres fluid/day)
who are at risk of human to human spread of Cryptosporidiosis ?
Regular users of swimming pools (can be resistant to chlorine) Child care workers and parents Nursing Home residents/carers Healthcare workers Travellers
who are at risk of animal to human spread of Cryptosporidiosis ?
Backpackers, Campers, Hikers
Farm workers
Visitors to farms/petting zoos
Consumers of infected dairy products
what is the diagnosis of Cryptosporidiosis- ?
Faeces sample:
Acid fast staining
Antigen detection by EIA Enzyme Immunoassays
what are the treatments for Cryptosporidiosis?
Symptomatic:
Rehydration etc.
Nitazoxanide
For immunocompromised:
Paromomycin (to kill parasite)
Nitazoxanide (effectiveness is unclear)
Octreotide (reduce cramps and frequency)
HIV patients, HAART should be quickly initiated
how can Cryptosporidiosis be controlled?
Human-Human:
Hand hygiene
Filter or boil drinking water (cf. chlorination)
Isolate symptomatic patients in healthcare setting
Ensure symptomatic children are kept away from school
Animal-Human:
Pasteurise milk and dairy products
Boil or filter drinking water if camping
what are the two main types of fungi?
Filamentous fungi
Yeasts
what characterstic does Dimorphic fungi have?
can be a in a yeast form or the filmanetous form depending on the environment they are in
what does Pneumocystis jiroveci cause?
it causes pneumonia in immunesupressed patients
what are all the possible targets of antifungals?
cell wall DNA synthesis mitosis cell membrane protein synthesis
what is the cell membrane of a fungus made up of and why is this key to antifungal agents?
it is made up of Ergosterol –> human cell mebrane contain cholesterol. Therefore antifungal agents can target Ergosterol without damaging human cells
what is the cell wall of antifungals made up of?
ß-1,3 glucan
where is Ergosterol found and what does it regulate?
Forms clusters within the phospholipid bilayer of the cell membrane
Has a role in the regulation of membrane permeability
what is the importance of ergosterol?
Required for normal growth and function of the fungal cell wall, hence fungal viability
what is the route of the formation of ergosterol?
squalene –> lanosterol –> ergosterol
what are the two main enzymes involved in the formation of ergosterol? At what point do they act?
Squalene epoxidase –> involved in squalene converting to lanosterol
Lanosterol 14a demethylase –> involved in lanosterol converting to ergosterol
what is ß-1,3 glucan mae up of?
large polymer of UDP glucos
how much of the cell wall is made up of ß-1,3 glucan
50-60% of the dry weight of fungal cell wall is made up of ß-1,3 glucan
what synthesises ß-1,3 glucan?
ß-1,3 glucan synthase
what does ß-1,3 glucan form?
forms a fibrous network on the inner surface of the cell wall
what are the antifungal classes?
Polyenes
Allylamines
Azoles
Echinocandins
what is the mode of action of polyenes?
Association with ergosterol in a physical way
Formation of pore-like molecular aggregates
Loss of membrane integrity and leakage of K+
Cell death –> don’t have a proper cell membrane integrity
give exampls of polyenes?
Amphotericin B
Nystatin
what is the problem of Nystatin ?
it is very toxic and can’t be given by Iv –> only orally and small amounts
what is the spectrum of activity of Amphotericin B?
Most fungi of medical importance
Aspergillus spp., Candida spp., Cryptococcus spp.
what are the adverse affects of Amphotericin B?
allergic reaction and nephrotoxicity
It is not 100% selective to fungal cells can affect human cells –> if patient is ill then can also damage the kidneys
why is the Lipid-associated AmB?
it is less toxic to kidney cells
what are the different formations of AmB?
Liposomal AmB (L-AmB)
AmB lipid complex (ABLC)
AmB colloidal dispersion (ABCD)
how is AmB used clinically? How is it administrated?
Not absorbed orally so it is administered parenterally IV
Used for Serious/systemic infections
e.g. aspergillosis, candidiasis, cryptococcosis
Not used, if possible, in patients with existing nephrotoxicity
what is Nystatin used for?
Superficial infections
e.g. oral/vaginal candidiasis
tropical administration
how does Allylamines work? Give a example of Allylamines.
Mode of action –> Inhibit ergosterol synthesis (Squalene epoxidase)
Examples
Terbinafine
what is the spectrum of terbinafine?
Broad spectrum of activity in vitro but in practice only one type of infection
what is the adverse affects of terbinafine?
Liver toxicity
Jaundice, hepatitis – rarely fatal
what is the clinical use of terbinafine?
Dermatophyte infections (superficial fungal infections)
what is the tropical use of terbinafine?
Athletes foot (tinea pedis), tinea corporis, tinea cruris
what is the systemic (oral) use of terbinafine?
Scalp ringworm (tinea capitis), onychomycosis
what is onychomycosis?
nail infection
what is 1)tinea corporis, 2)tinea cruris?
1) infection of the arms and legs
2) infection of the groin
what is the structure of azoles?
Synthetic compounds containing a 5-membered azole ring
what are the two types of azoles and state how many nigrtogen atoms they have
Imidazoles –> Two nitrogen atoms
Triazoles –> Three nitrogen atoms
which azoles type is the new one?
imidazoles –> is old one
Triazoles –> new one
how dos azoles work?
Inhibit ergosterol synthesis
Lanosterol 14α-demethylase –>inhibit this enzyme
Build up of non-ergosterol 14α-sterols in cell membrane –> don’t function properly and therefore fungus can’t become functioning fungal
what is the spectrum of azoles?
Complex, varies between drugs
Essentially broad spectrum
Yeasts and filamentous fungi
what azole is ineffective against Aspergillus?
Fluconazole
what type of drug is Ketoconazole and why was it stopped?
it is a imidazoles –> very toxic and causes hepatitis
give examples of imidazoles –> state the most common one?
Clotrimazole–> most common and used for vaginal thrush
Miconazole
Ketoconazole –> shampoo format
give examples of Triazoles–> state the most common one?
Fluconazole --> common Itraconazole--> common Voriconazole --> common Posaconazole Isavuconazole
what is the adverse effect of azoles?
Hepatotoxicity liver problem
Mild liver enzyme abnormalities (e.g. 7% with fluconazole)
Life-threatening hepatitis (e.g. 1/10 000 patients with ketoconazole)
what drug interaction does azole have?
Inhibition of cytochrome P-450 enzymes
Increases concentration of all drugs metabolised by Cy P-450 enzymes
what is the antifungal spectrum for triazoles drugs?
Fluconazole –> only yeast
Itraconazole/ voriconazole –> yeast and Aspergillus spp.
Posaconazole/isavuconazole –> yeast, Aspergillus spp and Mucoraceous moulds
what is the clinical use of Imidazoles?
Superficial infections (topical administration)
Candidiasis –> vaginal thrush ( treatment –>Clotrimazole)
Dermatophyte infections
what is the clinical use of triazole?
Systemic infections (oral/parenteral administration)
Aspergillosis (used in treatment and occasionally as prophylaxis)
Candidiasis (fluconazole)
what is the mode of action of Echinocandins ?
Inhibition of β-1,3-glucan synthase
Construction of severely abnormal cell wall
give examples of Echinocandins ?
Anidulafungin –> most common
Caspofungin
Micafungin
what is the spectrum of actiity of Echinocandins?
Aspergillus and Candida spp.
what are the adverse affects of Echinocandins?
Minimal
e.g. skin rash, nausea, vomiting, headache, diarrhoea in common with any other drug
what is the clinical use of Echinocandins?
Parenteral formulations only –> only IV
only treat serious fungal infection –> so really only treat Aspergillus
and Candida spp
what is 5-fluorocytosine (5-FC)?
Synthetic analogue of cytosine (nucleotide) –> initially anti cancer drug but now used as a antifungal agent
Pyrimidine nucleoside
what is the mode of action of 5-fluorocytosine (5-FC)?
Entry into cell requires fungal cytosine permease–> selective toxicity
Converted to 5-fluorouracil and 5-fluorodeoxyuridine monophosphate –> Inhibit RNA/protein synthesis and DNA synthesis
spectrum of activity of 5-fluorocytosine (5-FC)?
yeast only –> Candida and Cryptococcus spp.
what is the adverse affect of 5-fluorocytosine (5-FC)?
Bone marrow suppression
Selective toxicity is incomplete ( gets to human a bit)
5-fluorouracil (5FU) is an anti-cancer drug
clinical use of 5-fluorocytosine 5-FC?
clinical use is exteremly limited --> Cryptococcal meningitis (in combination with AmB)
what is the mode of action, spectrum of activity, adverse affect and clinical use of Griseofulvin?
Mode of action –>Inhibition of fungal mitosis
Spectrum of activity –> Dermatophytes
Adverse effects –>Minimal
Clinical use –> Dermatophyte infections in children requiring systemic treatment –> e.g. kerion, onychomycosis
what are the reasons for therapeutic drug monitoring
To minimize toxicity –>Level should remain below a threshold value
To maximize efficacy –> Level should exceed a threshold value
what are the antifungal agents that need therapeutic drug monitoring TDM?
Itraconazole
5-fluorocytosine
Voriconazole
why does Itraconazole, 5-fluorocytosine and Voriconazole needs TDM?
itraconazole –> if given to low of a dose then won’t have a affect
5-fluorocytosine –> V. toxic if have a build up
Voriconazole –> liver toxicity but also a level of use beneath it which it is not effective
