Pharmacology%20Study%20Guide%20-%20Infectious%20final.docx

Pharmacology Study Guide

Antibiotics Intro Classification of Antibiotics

  • Antibiotics can be classified in 3 different ways
    • Via their class and the spectrum of microorganisms they kill
    • Ex: If antibacterial, can be gram (-) or (+)
    • Broad spectrum vs Narrow spectrum
      • Broad – kills many different types of bacteria
      • Narrow – more selective targeting
    • Via the biochemical pathway they interfere with
    • Antibiotics target different parts of bacteria
      • Cell wall inhibitors (ex: Penicllins)
      • DNA synthesis inhibitors
    • Via the chemical structure of its pharmacophore
    • Do they have a beta lactam ring?
  • Bactericidal Vs. Bacteriostatic
    • Bactericidal
    • Bactericidal antibiotics either kill or lyse cells
    • If antibiotic targets cell wall, most likely bactericidal
    • What happens?
      • Antibiotics target different steps in the biochemical pathway of cell wall assembly
      • Leads to a compromised cell wall with missing components
      • Further divisions have weaker cell walls
      • Integrity of cell wall fails
      • Cells lyse and kill bacteria
    • Concentration-dependent kill vs Time-dependent kill
      • Concentration-dependent kill
      • Increase in concentration  kills more bacteria
      • Even bacteriostatic drugs can be considered bactericidal at very high concentrations
      • Ex: aminoglycosides, quinolones
      • Time-dependent kill
      • Based on threshold (MBC = minimum bactericidal concentration)
      • As long as plasma concentration is above a certain threshold, the antibiotic will keep killing bacteria

If it dips below threshold, bactericidal effects will be gone

  • Ex: Beta lactams, vancomycin
    • Bacteriostatic
    • Bacteriostatic antibiotics stop growth/interfere with growth of bacteria
    • May be reversible
    • Targets nucleic acid and protein synthesis
    • Need normal immune function in patients (can’t be immunocompromised)
    • Ex: Macrolides, tetracyclines
    • When would you choose bactericidal over bacteriostatic?
    • When the patient has a serious disease, such as meningitis
      • Use a bactericidal to obtain a quicker effect (bacteriostatic takes longer to act)
    • When the patient is immunocompromised (ex: older patients)
      • Can’t give bacteriostatic because it would suppress their immunity, making them more prone to infections
    • Bactrim (Sulfamethoxazole/Trimethoprim)
    • Both components are bacteriostatic, but because it’s a combination, it’s

bactericidal

  • Broad Spectrum vs Narrow spectrum
    • Broad Spectrum
    • Used when you don’t know the cause of infection
    • Treats many different types of infection (wide range)
    • Works by targeting structures or processes seen in many different bacteria
    • Can cause Superinfection
      • GI flora susceptible to broad spectrum antibiotics
      • Leads to unwanted bacteria growing
    • Stop giving once infectious agent is identified (switch to narrow spectrum)
    • Narrow Spectrum
    • Effective when infectious agent is known
    • Targets specific molecule involved in bacterial metabolism
    • Superinfection less likely
  • Post-antibiotic effect
    • PAE = T – C
    • T: how long the bacterial will take to grow 10-fold in the presence of drug
    • C: the time it will take to grow 10-fold if you weren’t taking the drug Antimicrobial Therapies
  • Empirical: given before the pathogen responsible or the susceptibility to a particular antimicrobial agent is known
  • Definitive: the pathogenic organism responsible for illness is identified
  • Combination Antimicrobial Therapy
    • Purpose:
    • Provide broad-spectrum empiric therapy in seriously ill patients
    • Treat polymicrobial infections
    • Decrease emergence of resistant strains
    • Decrease dose-related toxicity
    • More enhanced inhibition/killing

HIV

3 genes/proteins to remember

  • gag (Group-specific antigen)
    • Makes matric and core proteins
  • pol (Polymerase)
    • Makes reverse transcriptase, protease, integrase
  • env (Envelope)
    • Makes envelop proteins, glycoproteins
    • Gp120 (docking)
    • Gp42 (membrane)

NRTIs (nucleoside reverse transcriptase inhibitors)

  • NRTIs are all nucleoside analogs
    • Thymine
    • Stavudine, Zidovudine
    • Adenine
    • Didanosine, Tenofovir
    • Cytosine
    • Emtricitabine, Lamivudine
    • Guanine
    • Abacavir
      • Aba, Ava, AVOcado makes GUAC (GUAnine)
  • MoA: blocks replication in 2 manners
    • Competitively inhibiting incorporation of native nucleotides
    • Terminating elongation due to lack of 3’-hydroxy group
  • Pillar of HIV therapy – most used drugs
  • Can be given with other drugs, also with other NRTIs
    • Don’t give 2 of the same nucleoside analogs!!! (ex: don’t give emtricitabine and lamivudine together)
  • Abacavir
    • Guanosine analog
    • Most potent
    • Alcohol increases serum levels
    • Undergoes hepatic metabolism (detoxification reaction)

HLA b5701 test

  • If patient tests positive, DO NOT give abacavir
    • Increased risk of myocardial infarction
  • Emtricitabine
    • Cytosine analog
    • Active against HIV and HBV
    • Don’t use with lamivudine (same nucleoside analog)
    • Contraindicated in young children and pregnant women (because propylene glycol in formulation)
    • CNS depression, hemolysis, lactic acidosis
  • Lamivudine
    • Cytosine analog
    • Recommended in pregnant women
  • Tenofovir
    • Acyclic nucleotide (adenosine)
    • Only 2 steps of phosphorylation needed because already has one phosphate

PRODRUG

  • Has ester groups that will get hydrolyzed
    • Can cause loss of renal function and Fonconi’s syndrome
  • Zidovudine
    • Deoxythymidine analog
    • Can give to pregnant women
    • Can cause myelosuppression
    • Lipoatrophy is another problem
    • Abacavir doesn’t have these liver issues NNRTIs (Non-nucleoside reverse transcriptase inhibitors)

Allosteric inhibitors

  • Non-competitive inhibitors
  • Even 1 mutation can make them inactive – never use as a single agent, always given in combination
    • Susceptible resistance by single mutation
  • Only active against HIV-1
  • Does not need to be phosphorylated
  • Does not target host DNA polymerase
  • MoA: binds directly to reverse transcriptase enzyme
  • High hepatic metabolism ( CYP3A4) thus considerable D-D interaction
  • Efavirenz
    • Give on empty stomach (FYI: Conry asked questions on which one’s you take with meals or on empty stomach, so should know these)
    • Metabolized by CYP2B6, CYP3A4
    • CNS psychiatric effects
    • SJS
    • Avoid in pregnant women
    • Increases serum cholesterol and liver enzymes
  • Etravirine
    • Better resistance profile
    • Take with meals
  • Nevirapine
    • Rash and hepatotoxicity
    • Causes opioid withdrawal
    • For pregnant
  • Rilpivirine
    • Only for treatment naïve patients -1st time
    • Take with meals
    • Do not take with antacids or H2 antagonists
    • Has to be separated with antacids by 2-6 hours
    • Causes fat redistribution and QT prolongation Protease inhibitors
  • All end in -navir
  • Protease cleaves between phenylalanine and proline
    • Blocking this affects viral protein maturation
  • Causes dyslipidemia, cardiac issues
  • Atazanavir
    • Needs acidic medium for absorption
    • Take with meals
    • Good for pregnant women
    • No dyslipidemia (unlike the other one’s)
  • Darunavir

Give with ritonavir

  • Take with meals
    • Hepatotoxicity and hypersensitivity
    • All protein inhibitors with sulfa has hypersensitivity potential
  • Fosamprenavir
    • Prodrug of amprenavir with phosphate group
    • Hypersensitivity (b/c sulfa)
    • Oral solution has propylene glycol so contraindicated in young children and pregnant women
  • Ritonavir
    • Good for pregnant women
    • Major use is to reduce pill burden of other drugs
    • Can increase theophylline and digoxin levels
    • Metabolized Cyp3a4 2d6, low dose
    • Do not give with saquinavir due to QT prolongation Entry Inhibitors (Maraviroc)
  • Glycoprotein is attached to CD4 receptor
  • That leads to the 2nd leg being attached to the CCR5 core receptor
  • Maraviroc binds to CCR5 (CCR5 receptor antagonist), preventing gp120 binding, fusion, and entry
    • This drug only works on patients who have CCR5 (some patients have CXCR4)
  • Resistance
    • V3 loop of gp120 protein
    • Virus changing to CXCR4 tropism Fusion inhibitors (enfuvirtide)
  • enFU (FUsion)
  • Blocks interaction between N36 and C34 sequences of gp41 glycoprotein by binding to N36 coil
  • Prevents formation of a six-helix bundle critical for membrane fusion and viral entry
  • Inhibits infection of CD4+ cells
  • Still works in viruses with RT mutations
  • Subcutaneous injection
  • Mutations in gp41 causes resistance Integrase strand transfer inhibitors (INSTI)
  • Both end with -gravir
  • dsRNA  genome (this happens by integrase)
    • INSTIs block from happening
    • Binds to HIV integrase, preventing DNA strand transfer
  • Active for HIV-1 and 2
  • Dolutegravir
    • Caution with antacids, laxatives, iron and calcium supplements
    • UGT1A1 (glucuronide formation) metabolism
    • Active against viruses resistant to other INSTIs
  • Raltegravir
    • UGT1A1
    • Single point mutation resistance
    • sjs
    • Don’t give with antacids Post-attachment inhibitors (ibalizumab)
  • Only give in patients that were treated with other drugs already
  • Multi-drug resistant HIV-1
  • Binds to CD4, similar mechanism as maraviroc
  • Prevents binding of gp120 to CD4 by binding to CD4
  • AE: immune reconstitution inflammatory syndrome
    • Excessive/exaggerated immune response to other infection patients get

Fostemavir = attachment inhibitor

Cobicistat

  • Inhibitor of CYP3A
  • Given in combination with HIV drugs so their concentration increases
  • Increased pill burden

Bictegravir

-IRIS, hepatomegaly with steatosis, lactic acidosis, nephrotoxicity, UGT1A1, CYP3A4

Antiviral

Treatment of Herpes Simplex Virus and Varicella Zoster Virus Acyclovir

  • Acyclic guanine nucleoside analog
  • Lacks 3’-hydroxyl
    • 5’ and 3’ are ends of DNA (5’ is start, 3’ is end)
    • Normally nucleosides have 2 hydroxyl groups
  • Mostly good for HSV1 and HSV2
  • Mechanism of action
    • Acyclovir gets phosphorylated by thymidine kinase
    • Once phosphate group is added, body’s enzymes adds 2 more phosphates (becomes acyclovir triphosphate)
    • Once converted to triphosphate, goes into cell nucleus, and participates as a nucleotide in nucleic acid synthase
    • Combine its phosphate with hydroxyl group of earlier nucleotide
    • Due to the lack of 2nd hydroxyl group in acyclovir structure, DNA synthesis stops
      • Like a chain of people holding hands, but last person missing an arm, so hand holding chain stops there (these are the types of analogies dukhande makes)
      • Called chain termination
    • Inhibits herpes DNA polymerase by binding to the pyrophosphate site
    • Pyrophosphate binds to herpes DNA polymerase, and is normally removed
      • When acyclovir binds, it doesn’t get removed, so acts as an inhibitor of herpes DNA polymerase
      • Competitive inhibitor at pyrophosphate site
    • So 2 actions: chain termination, and inhibiting DNA polymerase
  • Resistance:
    • Mutation in thymidine kinase
    • Mutation in DNA polymerase
    • Can use foscarnet, cidofovir, or trifluridine in these cases
    • Foscarnet looks like an organic phosphate
    • Cidofovir already has the first phosphate (so doesn’t need thymidine kinase)
    • Trifluridine is a pyrimidine, so inhibits a different enzyme
  • Oral: genital herpes, chicken pox, shingles
  • IV: serious herpes, immunocompromised patients
    • IV form nephrotoxic and or neurotoxic
  • Topical: cold sores
  • Prophylaxis: organ transplant patients to prevent symptoms Valacyclovir

Prodrug

  • 1-valyl ester of acyclovir
  • Only oral route Famciclovir and Penciclovir
  • Famciclovir is a prodrug of penciclovir
  • Acyclic guanine nucleoside analog
  • 2 hydroxyl groups
  • 1 MoA: inhibition of viral DNA polymerase
    • Cannot terminate chain because 2 hydroxyls
  • Not as good as acyclovir or valacyclovir
    • Only advantage is longer half life
  • Good for HSV1, HSV2, VZV

Docosanol

  • Prevents viral entry by inhibiting fusion of viral envelope to host plasma membrane
    • Useful in early stage, because once the virus is already inside, drug is useless
  • Used for cold sores (Abreva)
  • Used for recurrent herpes Trifluridine
  • Fluorinated pyrimidine nucleoside
  • Kills DNA synthesis, but also our DNA synthesis
  • Phosphorylated by host enzymes to triphosphate (does not need thymidine kinase) and incorporated by viral DNA polymerase
  • Monophosphate form blocks thymidine synthase
  • AE: hypersensitivity Idoxuridine
  • Iodinated thymidine analog
  • Too toxic for systemic, so given topically Foscarnet
  • Mimics inorganic-pyrophosphate
    • Blocks pyrophosphate binding site on viral DNA polymerase
  • Given in acyclovir resistance
  • Deposited in bones because it’s a phosphate
  • IV only
  • Resistance: point mutations in DNA polymerase
  • SE: nephrotoxicity (same like acyclovir) CMV Infection

Ganciclovir

  • Acyclic guanosine analog
  • Triphosphorylated by viral UL97 and host kinases
  • 2 hydroxyl groups so only 1 mechanism of action (inhibition of DNA polymerase)
  • Resistance: mutations in UL97 kinase; UL54 mutation in DNA polymerase
  • AE: myelosuppression Valgancyclovir
  • L-valyl ester prodrug of ganciclovir
  • Given orally
  • Take with food Cidofovir
  • Cytosine analog
    • Both start with C
  • Already has 1 phosphate so doesn’t need thymidine kinase
  • 2 hydroxyl groups so no chain termination
  • Only MoA: DNA polymerase inhibition
  • AE: nephrotoxicity (should know which ones are nephrotoxic Influenza

Pandemic – outbreak of disease that has spread throughout a large region or globally Epidemic – a disease that appears as new cases at a rate that substantially exceeds what is expected

  • Ex: when flu comes and it’s more resistant Endemic – restricted to particular region
  • Ex: Malaria restricted to topical areas Antigenic Drift
  • Small changes in genes of influenza virus
  • Produces viruses that are closely related to each other
  • Small changes accumulate over time and can become drastically different from original gene
  • Main reason why people can get flu more than one time, and why flu vaccination always updating

Antigenic Shift

  • Abrupt major change in virus, resulting in new proteins that infect humans
  • Recombination leads to totally different flu HA and NA
  • HA (Hemagglutinin)
    • Needed for viral attachment and membrane fusion
  • NA (Neuraminidase)
    • Helps virus to escape
    • Cleaves sialic acid from cell surface
    • When we get flu, body develops huge amount of mucous
    • Mucous is very sticky due to sialic acid
    • Virus breaks sialic acid so it can infect other cells, otherwise it gets trapped

Oseltamivir

  • Analog of sialic acid
  • Instead of NA cleaving sialic acid, it will cleave oseltamivir instead
  • Virus can’t escape and gets trapped
  • Resistance: mutation in HA and NA
  • Active for Influenza A and B
    • Other drug class (Amantadine one) only good for influenza A
  • Active against amantadine-resistant influenza
  • Early administration is crucial (Etzel emphasizes this more later)
    • Need to give within 48 hours
  • Neuropsychiatric events in Japan Zanamivir
  • Can be given via inhalation
  • Mostly for adults, do not give if <8 y.o Peramivir
  • 18 years or older
  • Same MoA
  • Neuropsychiatric events Amantadine and Rimantadine
  • Prevents the drug from growing inside the cell
  • Binds to the M2 channel (proton channel)
  • Virus goes in the cell through endosomes and undergoes uncoating
    • After uncoating, it goes in the nucleus and makes more copies
    • For uncoating, pH has to be acidic
    • Acidic pH maintained by using proton pump
  • Amantadine binds to the proton pump, prevent its actions, preventing endosomes from being acidic, and preventing uncoating

Do not give in pregnant women

  • Influenza A only
  • CNS issues

Antifungals

  • 2 drugs that don’t act on the cell wall: Flucytosine and tavaborole
  • Squalene  squalene epoxide  lanosterol
    • Terbinafine blocks squalene into squalene epoxide
    • Lanosterol turns into ergosterol, and is blocked by azoles
  • Amphotericn B, nystatin act on membrane and form pores through the fungal membrane
  • Beta glucan synthase blocked by enchinocandins Amphotericin B
  • Given IV
  • Has affinity for ergosterol and cholesterol
    • Binding activity: Cholesterol < Liposomal vehicle < Ergosterol
  • Binds to ergosterol and produces disorganization of membrane by formation of pores
    • Depolarizes cell membrane and increases permeability
  • Resistance: ergosterol medication
  • AE: Nephrotoxicity

Flucytosine

  • Used in combination with amphotericin B or fluconazole
  • Taken up by fungal cells via cytosine permease
  • Converted into 5-FU, and then FdUMP and FUTP
    • FdUMP inhibits DNA synthesis (both have D)
    • FUTP inhibits RNA synthesis
  • AE: bone marrow toxicity Azoles
  • Decrease ergosterol biosynthesis by inhibiting CYP450 enzyme: 14-a-sterol demethylase
  • Triazoles more selective
  • Resistance: mutation in ERG11, increased azole efflux, mutation in ERG3 Ketoconazole
  • Only used topically Itraconazole
  • Oral, IV
  • AE: Hepatotoxicity Fluconazole
  • Can be used for streptococcal meningitis
  • Start with amphotericin B, then give fluconazole Voriconazole and Posaconazole
  • Good for aspergillosis and molds
  • Visual disturbance
  • Posaconazole covers mucormycosis Isavuconazole
  • Invasive aspergillosis
  • Invasive mucormycosis

Echinocandins (Caspofungin, Micafungin, Anidulafungin)

  • Non-competitive inhibitors of Beta 1,3-glucan synthase
  • Causes disruption of fungal cell wall and death
  • Therapy against invasive candidiasis and invasive aspergillosis
  • Resistance: mutation in Beta 1,3-glucan synthase
  • Given IV Griseofulvin
  • Fungistatic drug
  • Inhibits fungal mitosis by inhibiting spindle formation Terbinafine
  • Fungicidal drug
  • Inhibits fungal squalene epoxidase

Antiprotozoal

What happens in Malaria (maybe just watch a video tbh)

  • Infected female mosquito bite (something called a sporozoite is initially injected, and nothing can kill this)
  • Entry into hepatocytes via cell surface receptors
  • Exoerythrocytic stage (1 week)  asexual reproduction  liver schiznts (AKA hyponozoites)
    • Latent phase
  • Hepatocyte rupture, merozoites released in blood
  • Asexual erythrocytic stage  erythrocytic schizonts  replicated  release and infect other erythrocytes
  • Cyclic fever pattern
  • Erythrocytic form  gametocytes -> ingested by mosquito  sexual reproduction in mosquito  repeat

Categories of Anti-malarials

  • Erythrocytic schizonts
  • Erythrocytic and hepatocyte schizonts
  • Primary and latent liver stage and gametocytes
    • Only Primaquine active in this stage
  • No agent targets all stages, so combination therapy needed Artemisinins
  • Sesquiterpene lactone endoperoxide
  • Iron from heme reacts with peroxide moiety
  • Generates ROS and alters cellular redox cycle
  • Blocks Pf proteins that have role in calcium transport
  • Blood schizonticide
  • AE: neutropenia, anemia, hemolysis
  • Can be given in late pregnancy (2nd and 3rd trimester, NOT FIRST) Chloroquine
  • Passes membrane, accumulates in lysosomes
  • Binds heme, changes osmotic properties of lysosomes and prevents heme detoxification
    • Causes iron toxicity, and parasite gets killed
  • Blood schizonticide, gametocide
  • AE: patients with G6PDH deficiency – hemolysis
  • Do not take with antacids
  • Safe in pregnant women Amodiaquine
  • MoA similar to chloroquine Piperaquine
  • Long half life Quinine and Quinidine
  • Blood schizonticide against all 4
  • Gametocidal against vivax and ovale but not falciparum
  • Not active against hepatic
  • Resistance: PfMDR1
  • More toxic and less effective than chloroquine
  • AE: cinchonism, babeosis, blackwater fever
  • Don’t give with mefloquine Mefloquine
  • Prophylaxis and combination with artesunate
  • MoA similar to chloroquine
  • Safe in pregnancy
  • Resistance: PfMDR1
  • Recommended in chloroquine-resistant regions
  • Black-box warning for neurologic and psychiatric toxicities
  • Don’t give in pregnancy
  • Don’t co-administer with quinines Primaquine
  • Used to eradicate dormant forms of vivax and ovale
  • Active against hepatic forms, gametocidal
  • Weak activity against blood schizonts
  • Causes oxidative stress, which kills parasites
  • G6PD deficiency causes hemolysis (same with chloroquine) Atovaquone
  • Disrupts mitochondrial ETC of parasite
  • Active against tissue and blood schizonts Halofantrine
  • MoA unknown, related to heme solubilization disruption

Cardiac conduction problems

Lumefantrine

  • No cardiac problems like halofantrine of quinidine Amebiasis
  • Extraluminal (liver parasite)
  • Luminal (GI parasite) Metronidazole and Tinidazole
  • Nitroimidazole
  • Drug of choice for extraluminal amebiasis
  • Inhibits nucleic acid synthesis
    • Disrupts DNA and causes strand breakage
  • Action dependent on reduction of nitro group
  • AE: pancreatitis, severe CNS toxicity Iodoquinol
  • Luminal amebicide
  • Not active against trophozoites or extraintestinal Paromomycin Sulfate
  • Aminoglycoside antibiotic
  • Luminal amebicide
  • Antiamebic luminal agent of choice in USA