Lungs Flashcards
Amphotericin B MOA
Complexes with ergosterol to disrupt fungal cell membrane
Spectrum of activity amphotericin B
Very broad
Amphotericin B and yeasts
Candida albicans
Cryptococcus neoformans
Amphotericin B and organisms causing endemic mycoses
Histoplasma capsulatum
Blastomyces dermatitidis
Coccidioides immitis
Amphotericin B and pathogenic molds
Asperigillus fumigatus
Agents of mucormycosis
Resistance amphotericin B
Alteration to ergosterol
Pharmacokinetics amphotericin B
Mainly IV
AE amphotericin B
Most common
Immediate-fever, chills, msucle spasm, vomiting, HA, and hypotension
Long term-renal toxicity
Flucytosine MOA
Converted to 5-fluorodeoxyuridine monophosphate (Fdump) and fluorouridine triphosphate (FUTP), which inhibit DNA and RNA synthesis, respectively
Spectrum of activity flucytosine
Narrow
C neoformans and some candida
Resistance flucytosine
Altered drug metabolism
Pharmacokinetics flucytosine
Water soluble oral formulation
AE flucytosine
Anemia, leukopenia, and thrombocytopenia
Soles MOA
Inhibiton of fungal cytochrome P450 enzymes
Spectrum of activity anoles
Broad
See individual drugsbelow for specific patterns
Resistance azoles
Upregulation of fungal cytochrome P450
Pharmacokinetis azoles
See below
AE azoles
Relatively non toxic
Minor GI issues
Abnormalities in liver enzymes
Ketoconazole
Greater propensity to inhibit mammalian cytochrome P450 enzymes
Itraconazole
Oral and IV
Potent antifungal
Poor penetration into CSF
Spectrum itraconazole
Dimorphic fungi histoplasma, blastomyces and sporothrix
Aspergillus
-largely replaced by voriconazole as the azole of choice for aspergillosis
Dermatophytoses and onychomycosis
Fluconazole
Good cerebral spinal fluid penetration
High oral bioavailability (can be given by IV as well)
Widest therapeutic index of all azoles
Spectrum fluconazole
Azole of choice for cryptococcal meningitis
Most commonly used for the treatment of mucocutaneous candidiasis
No activity against aspergillus spp or other filamentous fungi
Voriconazole
IV and oral formulations
Inhibitors of the mammalian CYP3A4
Visual disturbances are common (30%)
Spectrum voriconazole
Similar to itraconazole
Candida spp( including fluconazole-resistant species such as candida krusei) and the dimorphic fungi
Treatment of choice for invasive aspergillosis and some environmental molds
Enhanced activity against aspergillus spp. Versus other azoles.
Posaconazole
Available only as a liquid oral preparation
Spectrum posaconazole
Broadest spectrum member of azoles
Activity against most species of candida and aspergillus
Only azole with significant activity against the agents of mucormycosis
What is posaconazole currently licensed for
Salvage therapy in invasive aspergillosis
Prophylaxis of fungal infections during induction chemotherapy for leukemia
Allogeneic bone marrow transplant patients with graft versus host disease
Echinocandins
These are large cyclic peptides linked to a long chain FA
MOA echinocandina
Inhibit glucan synthase
Spectrum of activity echinocandins
Candida
Aspergillus
Not C neoformans or the agents of zygoma oasis and mucormycosis
What is echinocandina licensed for
Disseminated and mucocutaneous candida infections
Empiric antifungal therapy during febrile neutropenia
-replaced amphotericin B for this indication
Resistance echinocandins
Point mutations in glucan synthase
Pharmacokinetics echinocandina
Only IV
AE echinocandins
Well tolerated!
Caspofungin (echinocandin) specific spectrum
Invasive aspergillosis
Only as a salvage therapy in patients that don’t respond to amphotericin B
Not primary treatment
Half life aspofungin
9-11 hours
Micafungin (echinocandins) spectrum)
Mucocutaneous candidiasis
Candidemia
Prophylaxis of candida infections in bone marrow transplant patients
HL micafungin
11-15 hours
Andulafungin spectrum
Esophageal candidiasis and invasive candidiasis , including candidemia
HL anidulafungin (echinocandins)
24-48 horus
Antifungal
Amphotericin B
Flucytosine
Azoles
-ketoconazole, itraconazole, voriconazole, posaconazole
Echinocandins
-caspofungin, micafungin, anidulafungin
Anti viral
OK
LIFE CYCLE OF HIV
Virus binds to host cell and integrates into host genome
Gene transcription of viral proteins, cleavage, and maturation produces new visions
Resistance HIV
Resistance quickly develops, espicially with monotherapy
HAART-highly active antiretroviral therapy
CD4 T celll counts, viral load assays, and the patients clinical status must be monitored to assess effectiveness of chosen antiretroviral regimen
Goal of treating HIV
To decrease the circulating viral load
Spectrum of activity HIV
HIV-1 (focus on these notes)
Effectiveness to HIV2 varies
Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs)
Used in combination with other agents
NNRTIs, PIs, or integrate inhibitos
MOA NRTI
Competitive inhibition of HIV1 reverse transcriptase
Resistance NRTIs
Point mutations in HIV1 reverse transcriptase
AE NRTI
Mitochondrial toxicity
Abacavir (NRTI)
Guanosine analog
AE abacavir
Hypersensitivity (8%) first 6 weeks therapy
- fever, fatigue, nausea, vomiting, diarrhea, and abdominal pain
- respiratory symptoms-dyspnea, pharyngitis, cough
- skin rash
- do not reintroduce abacavir if hypersensitivity is observed. Reintroduce could result in severe outcomes including death
Didanosine (NRTI)
Synthetic analog of deoxyadenosine
AE didanosine
Dose dependent pancreatitis
- conditions or drugs that may cause pancreatitis are contraindicated
- alcohol abuse, hyperTG
Retinal changes and optic neutiris
- adults with high doses and children
- mandate periodic retinal examinations
Etricitabine (NRTI)
Fluoridated analog of lamivudine
AE emtricitabine
HA, diarrhea, nausea, and rash
-hyperpigmentation of the palms or soles may be observed particularly in african Americans (13%
Besides HIV, what does emtricitabine treat
HBV, s discontinuation could exacerbate HBV
Lamivudine
Cytosine analog
AE lamivudine
Uncommon, hypersensitivity rate
Besides HIV what does lamivudine treat
HBV so discontinuation could exacerbate HBV symptoms in a patient infected with both
Stavudine
Thymidine analog
AE stavudine
MAJOR-dose related peripheral sensory neuropathy
-increased by concomitant neurotoxic drug use or in patients with advanced immunosuppression
Tenofovir
An acyclic nucleoside phosphonate (nucleotide) analog of adenosine
Tenofovir dinoprostone fumarate
Water soluble prodrug of active tenofovir
Recommended for use during preg
AE tenofovir dinoprostone fumarate
GI complaints
-nausea, diarrhea, vomiting, flatulence
Tenofovir alafenamide
A phosphonoamidate prodrug of tenofovir
Less renal toxicity than tenofovir dinoprostone fumurate
AE tenofovir alafenamide
Uncommon
May include GI symptoms or HA
Besides HIV what does tenofovir alafenamide treat
HBX, discontinuation may exacerbated
Zidovudine (NRTI)
Deoxythymidine analog
Safe in preg
AE zidovudine
Microcytic anemia 1-4%
Neutropenia (2-8%)
GI intolerance, HA, insomnia may occur
-tend to resolve during therapy
Nucleoside reverse transcriptase inhibtiors (NNRTIs) MOA
Bind directly to HIV1 reverse transcriptase resulting in allosteric inhibiton of RNA and DNA dependent DNA polymerase activity
First generation NNRTI
Delaviridine, efacirenz, nevirapine
Second generation NNRTI
Etravirine, rilpivirine
Resistance NNRTI
Baseline genotypes testing is recommended to screen for resistant HIV1 reverse transcriptase mutants (point mutations that alert NNRTI binding )
AE NNRTI
GI intolerance
Skin rash
Metabolism NNRTI
Cyp450—many drug drug interaction
Delaviridine
Skin rash in 38%
Avoid in preg
CYP3A4 and 2D6
Efavirenz
Combined with tenofovir and emtricitabine in the conformation atrial as a once a day combination pill
Metabolism efavirenz
3a4 and 2B6
AE efavirenz
Main involve CNS 5-%
-dizzy, drowsy, insomnia, nightmares, HA
These dimish with continued therapy
Increase with alcohol and psychoactice drug use
Psychiatric symptoms may necessitate discontinuation
-depression, mania, psychosis
Skin rash 28%
Nauseas, vomiting, diarrhea, crystalluria, elevated liver enzymes, increases in total serum cholesterol by 10-20%
Efavirenz preg
Can be used in pregnancy but only after the first 8 weeks due to birth defects observed ina. Primate study
Etavirine
A diarylpyrimidine
AE etravirine
Most common-rash, nausea, diarrhea
Substrate as well as an inducer of CYP3a4 and an inhibitor of 2C9 and 2C19
Nevirapine
A single dose administered at the onset of labor followed by another dose to the neonate within 3 days of delivery is effective at preventing transmission of HIV from mother to newborn
AE nevirapine
Rash 2-%
- maculopapular eruption that spares palms and soles
- occurs in the first 4-6 weeks of therapy
- can be a dose limiting toxicity
Liver toxicity 4%
-more frequent with higher CD4 cell count, in women, and in those with HBV and HCV co infection
Rilpivirine
Co formulated with emtricitabine and tenofovir into a singe once daily tablet to increase compliance
A diarylpyramidine (like etravirine)
Can use in preg
AE rilpivirine
Most common-rash, depression, HA, insomnia, increased serum aminotransferase
Protease inhibtors MOA
Block the HIV protease and prevent the maturation of the final structural proteins that make up the mature vision core
AE PI
IG intolerance (may be dos limiting)
Lipodystrophy
-metabolism-hyperglycemia, hyperlipidemia
Morphological-lipoatrophy, fat depression
Redistribution and accumulation of body fat
-central obesity, dorsocervical fat enlargement (buffalo hump), peripheral and facial wasting, breast enlargement , a cushingoid appearance
Metabolism PI
CYP3A4
-ritonavir has the most pronounced inhibitory effect and saquinavir the least
Name PI
Atazanavir Darunavir Fosamprenavir Indinavir Lopinavir Nelfinavir Ritonavir Saquinavir Tipranavir
Atazanavir
Boosted atazanavir is a recommended PI agent for use in pregnant women
AE atazanavir
Most common-diarrhea, nausea
Skin rash in 20%
Indirect hyperbilirubinemia with overt jaundice (10%)
Darunavir
Must be co administered with ritonavir or cobicistat
Boosted darunavir is a recommended PI agent for use in pregnant women
AE darunavir
Rash 2-7%
-occasionally severe
Darunavir contains a ulfonamide moiety
-may cause a hypersensitivity reaction in a patient with a sulfa allergy
Fosamprenavir
Prodrug of amprenavir, rapidly hydrolyzed by enxymes in the intestinal epithelium
AE fosamprenavir
Most common-HA, nausea, diarrhea, perior Ali paresthesia, depression
Contains a sulfonamide moiety
-may cause a hypersensitivity reaction in a patient with a sulfa allergy
Rash in 19%
Indinavir AE
Most common-unconjugated hyperbilirubinemia and nephrolithiasis due to urinary crystallization of the drug
- nephrolithiasis can occur days after initiating therapy
- incidence 10%
Consumption of 48 ounces of water a day is important to prevent kidney stones
Boosting indinavir with ritonavir
Allows for twice daily dosing (as opposed to 3 times a day) but this increases the chance for kidney stones so a higher fluid intake is required (1.5-2L)
Lopinavir
Available only in combination with low dose as a booster
Preferred treatment for pregnant women
AE lopinavir
Generally well tolerated
Nelfinavir AE
Diarrhea and flatulence
-diarrhea may be dose limiting
Ritonavir
No longer used as a sole PI agent due to its high rate of GU side effects at standard dose
-a lower dose used for inhibiton of CYP3A4
Very potent inhibitor of P450 system
-used primarily as a booster
Ritonavir
Used primarily as a booster
Prodrug
Saquinavir
Minimal amount of the drug absorbed when taken orally
AE saquinavir
GI discomfort
-nausea, diarrhea, abdominal discomfort, dyspepsia
When boosted with ritonavir, less dyslipidemia, of GI toxicity than with other boosted regimens
Hypersensitivity (rare)
Tipranaviir
Indicated for use in treatment -experienced patients who harbor strains resistant to other PI agents
Used in combination with ritonavir
Contains sulfonamide moiety and should not be Syed in a patient with a sulfa allergy
AE tipranavir
Most common-diarrhea, nausea, vomiting, ab pain
Urticaria or maculopapular rash 10-14%
Hypersensitivity rate
Fusion inhibitor
Viral attachment to host cell
Viral envelope glycoproteins complex gp160 (gp120+gp41) binds to its cellular receptor CD4
This binding changes the structure of gp120 which enables access to the chemokine receptors CCr5 or CxR4
Biding to chemokine receptors again leads to structural changes and exposes gp41
Gp41 leads to the fusion of the viral envelope with the host cell membrane and entry of the viral core into the host cell
Name fusion inhibitor
Enfuvitride
Enfuviritide
Synthetic 36 aa peptide
MOA enfuviritide
Binds to gp41 preventing the conformational and structural changes needed to allow fusion of the viral envelope with the host cell membrane
Pharmacokinetics enfuviritide
Must be administered with subcutaneous injection (2 x a day)
Resistance enfuviritide
Mutations in gp41
AE enfuviritide
Local injection site reactions
Drug drug enfuviritide
Not really
Entry inhibitor
Viral attachment to host cell
Viral envelope glycoproteins complex gp160 (gp120+gp41) binds to its cellular receptor CD4
This binding changes the structure of gp120 which enables access to the chemokine receptors CCR5 or CXCR4
Binding to chemokine receptors again leads to structural changes and exposes gp41
Gp41 leads to fusion of the viral envelope with the host cell membrane and entry of the viral core into the host cell
Maraviroc MOA
Binds specifically and selectively to CCR5 to prevent viral entry into the host cell
Pharmacokinetics maraviroc
Oral administration
Resistance maraviroc
Mutations in V3 loop of gp120
AE maraviroc
Generally well tolerated
Systemic allergic reaction followed by hepatotoxicity has been reported
-discontinue maraviroc if this occurs
Integrate strand transfer inhibtors (INSTIs) MOA
Inhibit strand transfer and prevent integration of reverse transcribed HIV DNA into the chromosomes of the host cell
AE INSTIs
Well tolerated
HA and GI effects most common
Dolutegravir
Preferred agent for treatment of treatment naive patients when combined:
Tenofovir/emtricitabine
Abacavir/lamivudine
Pharmacokinetics dolutegravir
14 hour
AE dolutegravir
Infrequent
Hypersensitivity (rash and systemic symptoms have been reported
-dolutegravir should be discontinued
Elvitagravir
Approved in 2012 only available as part of a combination pill
-s tri il4 (elvitegravir, cobicistat, emtricitabine, and tenofovir)
Requires boosting to be efficacious -combined with cobicistat
-inhibits CYP3A4
AE few
Raltegravir
Pyrimidinone analog
A preferred option for treatment naive persons beginning HAART
Recommended for use during pregnancy
HL raltegravir
9 hours
AE raltegravir
Uncommon
Oseltamivir MOA
Neuramindiase inhibitor
Interferes with release of progeny influenza A and B virus from infected host cells, thus halting the spread of infection within the respiratory tract. They competitively and reversible interact with the active enzyme site to inhibit viral neuraminidase activity at low nanomolar concentrations, resulting in clumping of newly released influenza virions to each other and to the membrane of the infected cell. Early administration is crucial bc replication of influenza peaks 24-72 hours after the onset of illness. Initiation of a 5 day course within 48 hours after the onset of illness modestly decreaseses the duration of TMP TOMS, as well as duration of viral shedding and viral titer. Once day prophylaxis is effective in preventing disease exposure
Oral prodrug that is activated by hepatic esterases and widely distributed through body. Oral available 80%, plasma protein binding is low and concentrations in the middle ear and sinus fluid are similar to plasma.
HL 6-10 hours
Excretion by kidney
Oseltamivir is active metabolite snow serum concentrations increase with declining renal function
Oseltamivir spectrum of activity
H1N1, H3N2, influenzae B
Influenza a and b
Oseltamivir resistance
May embrace and be transmissible >98% of H1N1 and H3N2 strains as well as 100% flu B retained susceptibility to both
Oseltamivir AE
N/V, HA (take with food)
Fatigue, diarrhea (more common prophylactic use)
Rash rare
Neuropsychiatric events (self injury and delirium), particularly in Japanese adolescent
Oseltamivir drugs and differences
Ok
Zanamivir MOA
Analog of sailing acid, interfere with release of progeny of influenza A and B virus from infected host cells, thus halting the spread of infection within the respiratory tract. These agents competitively and reversible interact with the active enzyme site to inhibit viral neuraminidase activity at low nanomolar concentrations, resulting in clumping of newly released influenza virions to each other and to the membrane of the infected cell. Early administration is crucial bc replication of influenza virus peaks at 24 -72 hours after the onset of illness. Initiation of a 5 day course of therapy within 48 hours after the onset of illness modestly decreases the duration of symptoms, as well as duration of viral shedding and viral titer; some studies have also shown a decrease in the incidence of complications. Once daily prophylaxis is 70-90% effective in preventing disease after exposure
Zanamivir spectrum
Influenza a and b
Zanamivir resistance
May emerge and be transmissible >98% of H1N1 and H3N2 strains as well as 100% if influenza B virus tested in 2015 retained susceptibility
Zanamivir ADME
Administered directly to the respiratory tract via inhalation. Of the active compound 10-20% reaches the lungs; the remainer is deposited in the oropharyngeal. The concentration of the drug in the respiratory tract is estimated to be more than 1000 times the 50% inhibitory concentration for neuraminidase, and the pulmonary half life is 2.8 hours. Of the total dose, 5015% is absorbed and excreted int he urine with minimal metabolis,.
Zanamivir AE
Cough, bronchospasm (occasionally severe), reversible decrease in pulmonary function, and transient nasal and throat discomfort.
NOT recommended if have underlying airway disease
Peramivir MOA
Neuraminidase inhibitor, a cyclopentane analog,
Permavir spectrum
Influenza. A and b
Permivir resistance
Ok
Peramivir ADME
Treat within 48 hours
Less than 30% is protein bound. Is not significantly metabolized and major route of elimination is kidney. Dose adjustment is required for renal insuffiency. The elimination HL following IV is 20 hours
Peramivir AE
Serious skin or kypersensitivity reaction (Stevens johnson , erythema multiforme) have been rarely reported
Hallucinations, delirium, abnormal behavior in patients with influenza receiving it
Peramivir drug differences
Ok
Amantadine MOA
Tricyclic amines of the adamantane family that block the M2 proton ion channel of the virus particle and inhibit uncoating of the viral RNA within infected host cells, thus preventing its replication.
4-10 times less active than rimantadine.
Well absorbed and 67% bound to protein, HL 12-18 hours.
Excreted unchanged in urine
Dose reductions are required in elderly and in patients with renal insuffiency
Amantadine spectrum
Influenza a
70-90% protective in prevention when initiated before exposure and limit duration of clinical illness by 1-2 days
Amantadine resistance
Ok
Amantadine ADME
Amantadine AE
Amantadine resistance
High to H1N1 and H3N2, not recommended anymore for prevention
AE
Teratogenic and embryotoxic
GI
-nausea, anorexia
CNS-nervousness, difficulty in concentrations,, insomnia, light headed
Serious-behavioral changes, delirium, hallucinations, agitation, seizuresmay be due to alteration of dopamine neurotransmisssion )less frequent with R than A and associated with renal insuffiency, seizure disorders, LOF age and may increase with concomitant antihistamines, anticholinergics, hydrochlorothiazide and TMPSMX
Rimantadine MOA
Tricyclic amines of the adamantane family that block the M2 proton ion channel of the virus particle and inhibit uncoating of the viral RNA within infected host cells, thus preventing its replication
4-10 times more active than amantadine.
40% bound to protein HL 24-4 hours
Nasal mucus concentrations average 50% higher than those in plasma, and CSF levels are 52-96% of those in serum.
Extensive metabolism by hydroxylation, conjugation, and glucuronidation before urinary excretion
Dose reduction in elderly or renal insuffiency of with severe hepatic insuffiency
Rimantadine spectrum
Influenza a
70-90% protective in prevention when initiated before exposure and limit duration of clinical illness by 1-2
Rimantadine resistance
High to H1N1 and H3N2, not recommended anymore for prevention
Rimantadnine AE
Teratogenic and embryogenic
GI
-nausea, anorexia
CNS-nervousness, difficulty in concentrations,, insomnia, light headed
Serious-behavioral changes, delirium, hallucinations, agitation, seizuresmay be due to alteration of dopamine neurotransmisssion )less frequent with R than A and associated with renal insuffiency, seizure disorders, LOF age and may increase with concomitant antihistamines, anticholinergics, hydrochlorothiazide and TMPSMX.
Tuberculosis pharmacology
First line-isoniazid, rifampin, pyrazinamide, and ethambutol
Isoniazid and rifampin most active
Isoniazid-rifampin combo given for 9 months will cure 95-98% of Tb but a intensive phase of treatment is needed for first two months due to prevelance of resistance. Do this by adding pyrazinamide during intensive phase and puts treatment at 6 months will no less efficacy.
Usually use four drug regimen in practice-isoniazid, rifampin, pyrazinamide, and ethambutol until susceptibility is determined. If susceptible continue isoniazid and rifampin for four moths.
Neighbor ethambuto nor other streptomycin add substantially to overall activity of the regimen but the fourth drug provides additional coverage if the isolate proves to be resistant to isoniazid, rifampin or both. If therapy starts after it is known that strain is susceptible to isoniazid and rifampin, ethambutolol does not need to be added.
10% isoniazid resistance. Resistance to both isoniazid and rifampin 1%
Multi drug resistance is more preventlant in other parts of the world. Resistance to rifampin alone is rare
Isoniazid MOA
Most active drug for treatment of Tb caused by susceptible strains. Small molecule that is freely soluble in water.
Penetrates into macrophages and is active against extracellular and intracellular organisms
Inhibits synthesis of mycotic acids, which are essential components of mycobacteria cel walls. Prodrug that is activated by KatG, the mycobacteria catalase peroxidase. The activated form forms a covalent complex with an axel carrier protein (AcpM) and KasA, a beta ketoacidosis carrier protein synthetase, which blocks mycotic acid synthesis.
Isoniazid spectrrum
Tb
Isoniazid resistance
Associated with mutations resulting in overexpression on inhA, which encodes an NADH dependent acyl carrier protein reductase, mutation or deletion of the KatG gene; promoter mutations resulting in overexpression of ahpC, a gene involved in protection fo the cell from oxidative stress and mutations in kasA.
Overproducers of inhA express low level isoniazid resistance and cross resistance to ethionamide. KatG mutatnsts express high level isoniazid resistance and often are not cross reasistnt to ethionamide
Rare will be resistant to both so give both . At least two active agents should always be used to treat active Tb to prevent emergence of resistance during therapy
Isoniazid ADME
Readil absorbed from the GI tract, optimally on an empty stomach; peak concentrations may be decreased by up to 50% when taken with a fat meal.
Diffuses readily into all body fluids and tissues.
The concentration int he CNS and CSF ranges from 20 to 100% to serum
Metab-acetylation by liver N acetyltransferase, is genetically determined. Tumors rapid excretion by rapid acetylators
Metabolites Excreted in urine. Not need to adjust for renal failure or hepatic insuffiency .
Inhibits several P450 enzymes, leading to increased concentrations of such medications as phenytoin, carbamazepine, and benzodiazepines. However when used in combination with rifampin, a potent CYP enzyme inducer, the concentrations of these meds is decreased
Isoniazid AE
Immunologic
-fever, skin rash, drug induced SLE
Direct
-hepatitis, increase Aminotransferases (seen in 10-20% but don’t need to stop-stop if hepatitis, not increase in ALT AST).,
Clincial hepatitis with loss of appetite, nausea, vomiting, jaundice, RUQ pain , DEATH, hepatocellular damage and necrosis
Risk of hepatitis depends on age usually over 50. Also alcohol dependence and possible during pregnancy and postpartum…stop use
Peripheral neuropathy
-more likely in slow acetylators , malnutrition, alcohol, diabetes, AIDS< uremia, due to pyridoxine defiency. Isoniazid promotes excretion of pyridozine and this toxicity is readily reversed by administration of pyridoxine in a dosage as low as 01.
CNS_memory loss, psychosis, ataxia, seizures. May respond to pyridoxine
Tinnitus, GI discomfort, Hematologic issues
Rifampin MOA
Semisynthetic derivative of rifamycin
Binds to the B subunit of bacterial DNA dependent RNA polymerase and thereby inhibits I RNA synthesis . Resistanceresults from any one of several possible point mutations in rpoB, the gene for the B subunit of RNA polymerase. These mutations result in reduced binding of rifampin to RNA polymerase. Human RNA polymerase does not bind rifampin and is not inhibited by it. Rifampin is bactericidal for mycobacteria . It readily penetrates most tissues and penetrates into phagocytic cells. It can kill organisms that are poorly accessible to many other drugs, such as intracellular organisms and those sequestered in abscesses and lung cavities.
Rifampin spectrum
Gram + organisms, some gram negative such as Neisseria and haemophilus species, mycobacteria and chlamydia.
mycobacteria.
With isoniazid or other antitb drugs to patients with active Tb
Meningococcal carriage. Staph carriage. Osteomyelitis (staph) prosthetic joint infections, prosthetic valve endocarditis
Rifampin resistance
Resistant mutants present in all microbial populations and readily selected out if rifampin is used as a single drug,
No cross resistance to other drug classes of antimicrobial drugs, but there is cross resistsance to other rifamycin derivatives rifabutin and rifapentine
Rifampin ADME
Well absorbed after oral administration and excreted mainly through the liver into bile. It then undergoes enterohepatic recirculating, with the bulk excreted as a deacylated metabolite in feces and a small amount excreted int he urine. Dosage adjustment for renal or hepatic insuffiency is not necessary. Usual doses result in serum levels 5-7 mcg/mL. Rifampin is distributed widely in body fluids and tissues . The drug is relatively highly protein bound, and adequate CSF concentrations are acheived onyl in presence of meningeal inflammation
Rifampin AE
Strong inducer P450, which increases the elimination of numerous other drugs
Co administration results in significantly lower serum levels of drugs
Harmless ORANGE URINE, SWEAT AND TEARS. Rash, thrombocytopenia, nephritis
Cholestatic jaundice and hepatitis, light chain proteinuria,
Flu like syndrome
Ethambutol MOA
Synthetic water soluble , heat stable compound ,
Inhibits mycobacteria arabinosyl transferase, which are encoded by the embCAB Operon. Arabinosyl transferase are involved in the polymerization reaction of arabinosyl an, an essential component of the mycobacteria cell wall.
Ethambutol spectrum
Tb and other mycobacteria
Mycobacterium avium complex -given with other agents
Ethambutol resistance
Mutations resulting in overexpression of emb gene products or within the embB structural gene.
Rapid when drug used alone. Always given with another antiTb drug. (Isnoazis, rifampin, pyrazinamide during intima treatment),
Ethambutol ADME
Well absorbed from gut.
HL 2-4 horus
20% excreted in feces 50% urine unchanged.
Accumulated INR enal failure, and does reduced 3x if creatine clearance less than 30 ml/min.
Crosses BBB only when meninges inflamed
Concentrations in CSF range depending on meningeal infallmmamtion
Ethambutol AE
Hypersensitivity rare
Common-retrobulbar neuritis, resulting in loss of visual acuity and red green color blindness. (Usually when used for several months)
Visual disturbances occur in 3% after at least 1 month.
Get baseline monthly visual acuity and color discrimination testing with attention if high doses or renal issues
CONTAINDCATED IN YOUNG BC OF VISION AND RED GREEN COLOR DISCRMINIAOTN
Pyrazinamide MOA
Relative nicotinamide, and it is used only for treatment of Tb. Stable and slightly water soluble. Inactive at neutral pH, but at 5.5 it inhibits Tb. Taken up by macrophages and exerts its activity against mycobacteria residing within the acidic environment
Converted to pyrazinamide acid-the active form of the drug-by mycobacteria pyrazinamide seems, which is encoded by pncA. Pyrazinamide acid disrupts mycobacteria cell membrane metabolism and transport function
Pyrazinamide spectrum
Ok
Pyrazinamide resistance
May be due to impaired uptake of pyrazinamide or mutations in pncA that impair conversion of PZa to its active form
Pyrazinamide ADME
well absorbed from the GI tract and widely distributed in body tissues, including inflamed meninges.
HL 8-11 hours. The parent compound is metabolized by the liver, but metabolites are really cleared; therefore, PZA should be administered at 25-35 mg/kg is unused for thrice weekly or twice weekly treatment regimens.
Pyrazinamide AE
Major adverse effects of PZA include hepatoxocity , nausea, vomiting, drug fever, photosensitivity, and hyperuricemia. The latter occurs uniformly and is not a reason to halt therapy if patients are asymptomatic.
Pyrazinamide resistance
Tubercle bacilli develop resistance to pyrazinamide fairly readily, But there is no cross resistance with isoniazid or other anti mycobacteria drugs
First line agents TB
Isoniazid, rifampin, ethambutol, pyrazinamide
Second line agents Tb
Streptomycin, ethionamide, capreomycin, cyclosporine, aminosalicylic acis, kanamycin and amikacin, fluoroquinolones, linezolid, rifabutin, rifapentine, bedauiline
Streptomycin MOA
Aminoglycosides. Lessen dose if on dialysis of creatinine clearance less than 30ml/min
Streptomycin spectrum
TB, MAC, mycobacterium kansassi
Others are resistant
Streptomycin resistance
All large populations of Tb contain some streptomycin resistant mutants. 1 in 10^9 are resistant .
Due to point mutation in either rpsL gene encoding the S12 ribosomal protein or the respiratory gene encoding 16S ribosomal RNA, which alters the ribosomal binding sit.
ADME streptomycin
Penetrates into cells poorly and is active mainly against extracellular tubercle bacilli. The drug crosses the bbb and achieves therapeutic concentrations with inflamed meninges
Clinical streptomycin
Streptomycin sulfate is used when an injectable drug is needed or desirable and in the treatment of infections resistant to other drugs.
AE streptomcin
Ototoxicity and nephrotoxicity.
Vertigo and hearing loss are the most common AE and may be permanent. Dose related. And increased in elderly.
Adjust with renal prob.
Reduce to no more than 6 months
Ethionamide
Chemically related to isoniazid and similarly blocks the synthesis of mycotic acids. It is poorly water soluble and available only for oral use. Metabolized by liver
Spectrum ethionamide
Tubercle bacilli
-CSF equal to serum
ADME ethionamide
CSF same as serum
Administered at an intima dose which is increased
Hepatotoxicity. Neurologic symptoms may be alleviated by pyridoxine
Resistance ethionamide
Rapidly in vitro in Vito. There can be low level cross resistance between isoniazid and ethionamide
Capreomycin
Peptide protein synthesis inhibitor antibiotic obtained from strep capreomycin.
Capreomycin spectrum
Mycobacteria, including multidrug resistant strains of M tuberculosis (when resistant to streptomycin)
Resistance capreomycin
Some cross resistance with amikacin and kanamycin.
Associated with rss , EUS, or tlyA gene mutations
AE capreomycin
Nephrotoxicity and ototoxicity
Tinnitus, deafness, vestibular disturbances
Injection pain and sterile abscess
How minimize ris of toxicity of capreomycin
Intermittent dissing
Cyclosporine
Structural analog of D alanine-inhibits cell wall synthesis
Two oral doses,
ADEM cyclosporine
Two oral doses
Cleared renally, and the dose should be reduced by half if creatinine clearances is less than
Widely distributed to tissues, including the CNS
AE cycloserine
Peripheral neuropathy and CNS dysfunction, including depression and psychoses.
Pyridoxine should be given with cycloserine bc this ameliorates neurologic toxicity.
Most common first 2 weeks of therapy,
Aminosalicyclic acid (PAS)
Folate synthesis antagonist that is active almost exclusively against M tuberculosis. Structurally similar to PABA and is thought to have a similar MOA to the sulfonamides.
must be administered sprinkled over applesauce or yogurts or fruit
Spectrum aminosalicycic acid
Tubercle bacilli
ADME aminosalicyclic acid
Granule formulation results in improved absorption from GI
Widely distributed in tissues and body fluids except the CSF
Rapidly excreted in urine, in part as active PAs and in part as the acetylated compound and other metabolic products. To avoid accumulation in renal impairment lessen with creatine clearance less than 30
Very high in urine can give crystsalluria
Aminosalicylic acid infrequently used in USA
Other oral drugs are better tolerated . GI symptoms are common but occur less frequently with the delayed release granules; they ma be dimished by giving the drug with meals and with antacids. Peptic ulceration hemorrhage may occur. Hypersensitivity reactions manifested by fever, joint pains, skin rashes, hepatosplenomegaly, hepatitis, adenopathy, and granulocytes Elia often occur after 3-8 weeks of PAS therapy. Making it necessary to stop administration temporarily or permanently
Kanamycin and amikacin
Aminoglycoside antibiotics .
Kanamycin has been used for treatment of Tb caused by streptomycin resistant strains but is no longer available in USA and less toxic alternatives taken its place (capreomycina nd amikacin)
Amikacin
Treat Tb due to prevelance of multidrug resistant strains. Prevelance of amikacin resistant strains is low and most multidrug resistant strains remain amikacin susceptible. M Tb is inhibited at concentrations 1mcg or less
Active against atypical mycobacteria.
Resistance amikaricin
No cross resistance between streptomycin and mikacin, but kanamycin resistance often indicated resistance o amikacin as well.
Spectrum amikacin
Tb suspected or known to be caused by streptomycin resistant or multidrug resistant strains. This drug must be used in combination with at least one a preferably two or three other drugs to which the isolate is susceptible for treatment of drug resistant cases.
FLUOROQUINOLONES
In addition to their activity against many gram positive and gram negative bacteria, ciprofloxacin, levofloxacin, gatofloxacin and moxifloxacin inhibit strains of M Tb .
Alsoactive against atypical mycobacteri
Moxifloxacin
Most active against M Tb
Levofloxacin
Slightly more active than ciprofloxacin against M Tb, whereas ciprofloxacin is slightly more active against atypical mycobacteria
Spectrum fluoroquinolones
When strains are resistant to first line.
Use moxifloxacin or levofloxacin
Resistance fluoroquinolones
Point mutations in grade A subunit, develops rapidly if a fluoroquinolones is used as a single agent; thus the drug must be used in combination with two or more additional active agents
Resistance to one indicates resistant to all
However moxifloxacin may retain some activity in strains resistant to ofloxacin
Linezolid
Inhibits strains of Mtb
Good intracellular concentrations and is active in murine models of Tb
In combo with other second and third line drugs to treat multidrug resistant Tb . Conversion of sputum cultures to negative was associated with it
AE linezolid
Bone marrow suppression and irreversible peripheral and optic neuropathy, have been reported with the prolonged courses of therapy that are necessary for treatment of Tb.
Low -prevent AE and supplement pyridoxine
When use linezolid
Only multidrug resistant
Who should not have linezolid
Patients on concomitant serotonergic agents due to concern for serotonin syndrome
Rifabutin
Derived from rifamycin and is related to rifampin.
Rifabutin spectrum
M tuberculosis, MAC, and mycobacterium fortuitous.
Resistance in rifabutin
Cross resistance with rifampin is virtually complete
Some resistant strains may appear susceptible to rifabutin in vitro but a clincal response is unlikely bc the molecular basis of resistance, rpoB mutation, is the same
ADME rifabutin
Both subrate and inducer of cytochrome p450 enzymes. Because it is a less potent inducer, rifabutin is often used in place of rifampin for treatment of Tb in patients with HIV infection who are receiving antiretroviral therapy with a protease inhibition, a nonnucleoside reverse transcriptase inhibitor or an integrate strand transfer inhibit, drugs that also cytochrome p450 or UDP glucuronosyltransferases substrates
AE rifabutin
May accumulate in severe renal impairment, and the dose should be reduced by half if creatinine clearance is less than 30ml.min. Rifabutin is associated with similar rates of hepatotoxicity or rash compared to rifampin; it can also cause leukopenia, thrombocytopenia, andoptic neuritis
Rifapentine MOA
Another analog of rifampin.
As with all rifamycin, it is a bacterial RNA polymerase inhibitor, and cross resistance between rifampin and rifapentine is complete.
Spectrum rifapentine
M Tb and MAC
ADME rifapentine
Potent inducer of P450 enzymes, and it has the same drug interaction profile; however when is given intermittently, induction of metabolism of other medications is less pronounced compared to rifampin.
HL 13 hours
Not given at high risk of failure patients or positive cultures at the end of the intensive treatment phase and those with evidence of cavitation on chest radiographs.
DONT use to treat active Tb in patients with HIV bc unacceptable high relapse rate with rifampin resistant organisms.
Combined with isoniazid
Effective for latent Tb
AE rifapentine
Similar to rifampin.
Bedaquiline
Diarylquioline-first drug with a novel mechanism of action against M Tb to be approved since 1971.
Inhibits adenosine 5-triphosphate synthase in mycobacteria, has in vitro activity against both replicating and nonreplicating bacilli, and has bactericidal and sterilizing activity in the murkiness model of Tb .
Resistance bedaquiline
Cross resistance has been reported between bedaquiline and clofazimine, likely via upregulation of the multisubstrate efflux pump, mmpL5
ADME bedaquiline
Peak plasma concentration and plasma exposure increase twofold when given with high fat foot.
Highly protein bound>99%, is metabolized chiefly through the cytochrome p450 system, and is excreted primarily via the feces.
HL bedaquiline -5.5 months
Long elimination phase probably reflects slow release of bedaquiline and M2 (major metabolite) from peripheral tissues
3a4 is major isoenzymes involved int he metabolism and potent inhibitors or inducers of this enzyme cause CLINCIALLY significant drug interactions
When use bedaquiline
In combination with at least three other active medications, may be used for 24 weeks of treatment in adults with laboratory confirmed pulmonary Tb if the isolate is resistant to both isoniazid and rifampin .
AE bedaquiline
25% or more
Nausea, arthralgias, and headache.
Hepatotoxicity and cardiac toxicity.
Black box warning related to QT prolongation and mortality .
Reversed for patients who do no have other treatment options and used with caution in patients with other risk factors for cardiac conduction abnormalities
Pharmacology of asthma and COPD drugs
Ok
Components of asthma management
Routine monitoring of symptoms and lung function
Patient education to create a partnership between clinical and patient
Controlling environmental factors (trigger factors) and comorbid conditions that contribute to asthma severity
Pharmacological therapy
Goals of asthma management
Reduction in impairment and reduction of risk
How manage asthma
Can usually be managed with rescue inhalers to treat symptoms and controller inhalers that prevent symptoms. Severe cases may require longer acting inhalers that keep the airways open, as well as oral steroids.
Air of asthma therapy
Minimal chronic symptoms, including nocturnal
Minimal exacerbations
No emergency visits
Minimal use of a required B2 agonist
No limitations on activities, including exercise
Peak expirations flow circadian variation<20%
Near normal peak expirations flow
Minimal AR from medicine
Treat mild intermittent asthma
SABA
Mild persistent asthma
ICS low dose
SABA
Moderate persistent asthma
SABA
LABA ICS low dose
Severe persistent asthma
LABA
ICS high dose
SABA
Treat very persistent asthma
OCS, LABA, ICS high dose, SABA
Step 1 persistent asthma
Rescue inhaler
Persistent asthma step 2
Low dose inhaled corticosteroid plus LABA
Rescue inhaler
Persistent asthma step 3
Low dose inhaled corticosteroid plus a LABA
Rescue inhaler as needed
Consider seeing an asthma specialist
Step 4 persistent asthma
Medium dose inhaled corticosteroid plas a LABA
Rescue inhaler as needed
See an asthma specialist
Step 5 persistent asthma
High dose inhaled corticosteroid plus a LABA
Consider amalizumab
Rescue inhaler as needed
See an asthma specialist
Step 6 persistent asthma
High dose inhaled corticosteroid plus a LABA plus oral corticosteroid and consider amalizumab
Rescue inhaler as needed
See an asthma specialist
Drugs for asthma
Bronchodilators
Anti inflammatory drugs
Leukotriene antagonist
Monoclonal antibody
Bronchodilators
B2 agonists
Anticholinergic drugs
Methylxanthines
Anti inflammatory drugs
Inhaled corticosteroids
Bronchodilators therapy
Bronchodilators act primarily on airway smooth muscle to reverse the bronchoconstriction of asthma. This gives rapid relief of symptoms but has little or no effect on the underlying inflammatory process. Thus, bronchodilators are not sufficient to control asthma in patients with persistent symptoms. There are three classes of bronchodilator in currentt use:
B2 adrenergic agonists, anticholinergics, and theophylline of these, B2 agonists are by far the most effective.
2 agonists
B2 agonsits activate B2 adrenergic receptors, which are Woden expressed int he airways. B2 receptors are coupled through a stimulators G protein to adenylyl cyclase, resulting in increased intracellular cyclic adenosine monophosphate (AMP), which relaxes smooth muscle cells and inhibits certain inflammatory cells, particularly mast cells. The primary action of b2 agonists is to relax airway smooth muscle cells of all airways, where they act as functional antagonsits, reversing and preventing contraction of airway smooth muscle cells by all known bronchoconstrictors. This generalized action is likely to account for their great efficacy as bronchodilators in asthma. There are also additional non bronchodilator effects that may be CLINCIALLY useful , including inhibition of mast cell mediator release, reduction in plasma exudation, and inhibition of sensory nerve activation. Inflammatory cells express small numbers of B2 receptors but these are rapidly down regulated with B2 agonist activation so that, in contrast to corticosteroids, there are no effects on inflammatory cells in the airways and there is no reduction in airway hyper responsiveness.
AE B2 agonists
Usually associated with b agonists are not problematic when given by inhalation. The most common-muscle tremor and palpitations, which are seen more commonly in elderly patients. There is a small fall in plasma K due to increased uptake by skeletal muscle cells, but this effect does not usually cause any clincial proble,. Tolerance is a potential problem with any agonist given chronically, but while there is down regulation of b2 receptors, this does not reduce the bronchodilator response as there is a large receptor reserve in airway smooth msucle cells. By contrast mast cells become rapidly tolerant, but their tolerance may be prevented by concomitant administration of inhaled corticosteroids
Albuterol
SABA
Indications albuterol
Asthma, acute bronchitis, COPD, bronchiolitis
AE albuterol
HA, dizziness, insomnia, dry mouth, cough
Interactions albuterol
BB, digoxin, diuretics, monoamine oxidase inhibtiors, tricyclic antidepressants
Contraindications albuterol
Paradoxical bronchospasm, deterioration of asthma, use of anti inflammatory agents, cardiovascular effects, do not exceed recommended dose, immediate hypersensitivity reactions
Terbutaline
Beta adrenergic agonist with preferential effects on the beta 2 receptos resulting in smooth muscle relaxation. Only b2 drug available by subcutaneous injection (terbutaline sulfate inj» patients with sulfur allergy, not recommended)
Indications terbutaline
FDA approved for the treatment or prophylaxis of bronchospasm associated with asthma, bronchitis and emphysema in patients 12 years old and older
AE terbutaline
HA, nausea, tachycardia and palpitations. However, more serious maternal AE that can occur include cardiac ischemia, hypotension and tachycardia
Cautions terbutaline
BBW (black box warning) not recommended as a medication for tocolysis
Metaproterenol indications
Used as a bronchodilator for bronchial asthma and for reversible bronchospasm which may occur in association with bronchitis and copd
AE metaproterenol
Nervousness, HA, dizziness, palpitations, GI distress, tremor, throat irritation, nausea, vomiting, cough and asthma exacerbation
Interactions metaproterenol
Beta adrenergic aerosol bronchodilators should not be used concomitantly with metaproterenol bc they may have additive effects. Beta adrenergic agonists should be administered with caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, since the action of beta adrenergic agonists on the vascular system may be potentiated
Cautioned/warning metaproterenol
Can produce a significant cardiovascular effect in some patients , as measured by pulse rate, bp, symptoms, and/or ECG changes. As with other beta adrenergic aerosols, metaproterenol can produce paradoxical bronchospasm (which can be life threatening0
Pirbuterol indications
Used int he prevention and reversal of bronchospasm in patients 12 years of age and older with reversible bronchospasm including asthma. It may be used with or without concurrent theophylline and/or corticosteroids
AE pirbuterol
CNS: nervousness, tremor, HA, dizzy,
Cardio: palpitations, tachycardia
Respiratory: cough
GI: nausea
Interactions pirbuterol
Other short acting beta adrenergic aerosol bronchodilators should not be used concomitantly with pirbuterol bc they may have additive effects
Cautions warnings pirbuterol
Cardiovascular: like other inhaled beta adrenergic agonists, can produce a CLINCIALLY significant cardiovascular effect in some patients, as measured by pulse rate, bp and/or symptoms
Levalbuterol indications
Used in treatment or prevention of bronchospasm in patients 4 years of age and older with reversible obstructive airwaydisease
AE levalbuterol
Accidental injury, bronchitis, dizzy, pain, pharyngitis, rhinitis, vomiting
Interactions levalbuterol
Potentiation the effect of other SABA drugs
Cautions warnings levalbuterol
Life threatening paradoxical bronchospasm may occur
Fomoterol
LABA
Indications fomoterol
Treatment of asthma in patients>5 years as an add on to long term asthma control medication such as an inhaled corticosteroid. Prevention of exercise induced bronchospasm (EIB) in patients > 5 years. Maintence treatment of bronchoconstriction in patients with chronic obstructive pulmonary disease
AE fomoterol
Asthma: viral infection, bronchitis, chest infection, dyspnea, chest pain, tremor, dizzy, insomnia, tonsillitis, rash, dysphagia, and serious asthma exacerbation
COPD: upper respiratory tract infection, back pain, pharyngitis, chest pain, sinusitis, fever, leg cramps, muscle cramps, anxiety, pruritis, increased sputum and dry mouth
Interactions fomoterol
Adrenergic agents: use with caution. Additional adrenergic drugs may potentiation sympathetic effects
Canthine derivatives, systemic, corticosteroids, and non K sparing diuretics: use with caution. May potentiation hypoK or ECG changes
mAO inhibits, tricyclic antidepressants, macrolides, and drugs that prolong QT: use with extreme caution. May potentiation effect on CVD
BB: use with caution and only when medically necessary. May decrease effectiveness and produce severe bronchospasm.
Contraindications/warning fomoterol
CVD: like other inhaled beta adrenergic agonsits, can produce a CLINCIALLY significant cardiovascular effect in some patients, as measured by pulse rate, bp and/or symptoms
Levalbuterol indications
Used in treatment or prevention of bronchospasm in patients 4 years of age and older with reversible obstruction=Clive airway disease
AE levalbuterol
Accidental injury, bronchitis, dizzy, pain pharyngitis, rhinitis, and vomiting
Interactions levalbuterol
May potentiation and effect of other Saba drugs
Cautions/warning levalbuterol
Life threatening paradoxical bronchospasm may occur
Salmeterol
LABA
Indication LABA
Treatment of asthma in patients aged 4 years and older. Prevention of exercise induced bronchospasm in patients aged 4 years and older. Maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease
AE salmeterol
Asthma: HA, influenza, nasal/sinus congestion, pharyngitis, rhinitis, trachietis/bronchitis.
COPD: cough, HA, musculoskeletal pain, throat irritation, viralrespiratory infection
Salmeterol LABA interactions
Strong cytochrome P450 3a4 inhibtors : use not recommended. May increase risk of cardiovascular effects
Monoamine oxidase inhibitors and tricyclic antidepressants: use with extreme caution. May potentiation effect of salmeterol on vascular system
BB: use with caution. May block bronchodilators effects of beta agonists and produce severe bronchospasm.
Diuretics: use with caution. ECG changes and/or hypokalemia associated with non K sparing diuretics may worsen with concomitant beta agonists
Contraindicationswarning salmeterol
Asthma: without concomitant use of a long term asthma control medication such as an inhaled corticosteroid. Primary treatment of status asthmaticus or acute episodes of asthma or COPD requiring intensive measures
Severe hypersensitivity to milk proteins
*LABA increase the risk of asthma related death and asthma related hospitalizations.
Prescribe for asthma only as concomitant therapy with an inhaled corticosteroid. Do not initiate in acutely deteriorating asthma or COPD
Do not use to treat acute symptoms.
Not a substitute for corticosteroids
Patients with asthma must take a concomitant inhaled corticosteroid.
Do not use in combination with an additional medicine containing a LABA bc of risk of overdose. If paradoxical bronchospasm occurs, discontinue and institute alternative therapy
Indacaterol indications
LABA used to treat breathing problems caused by COPD including chronic bronchitis and emphysema
AE indacaterol
Most common adverse reactions are cough, oropharyngeal pain, nasopharyngitis, HA, nausea
Interactions indacaterol
Other adrenergic drugs may potentiation effect. Xanthing derivatives, steroids, diuretics or non K sparing diuretics may potentiation hypoK or ecg changes
Cautions/warning
BBW long acting beta 2 adrenergic agonists (LABA) increase the risk of asthma related death
Olodaterol (LABA) indications
Used in the long term once daily maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema
AE olodaterol
Most common AE reactions are nasopharyngitis, Upper respiratory tract infection, bronchitis, urinary tract infection, cough, dizzy, rash, diarrhea, back pain and arthralgias
Interactions olodaterol
Other adrenergic drugs may potentiation effect. Xanthine derivatives , steroids, diuretics or non K sparing diuretics may potentiate effect on cardiovascular system. Use with extreme caution. Bb may decrease effectiveness
Cautions/warning olodaterol
BBW, long acting beta 2 adrenergic agonists increase the risk of asthma related death
Anticholinergic agents
Anticholinergics block acetylcholine from binding to it receptors on certain nerve cells. They inhibit parasympathetic nerve impulses. These nerve impulses are responsible for involuntary msucle movements in the GI tract, lungs, urinary tract, and other parts of your body
Anti muscarinic agents most widely used in asthma/COPD
Atropine
Ipratropium
Tiotropium
Aclidinium
ATROPINE INDICATIONS
ATROPINE IS A MUSCARINIC ANTAGONIST INDICATED FOR TEMPORARY BLOCKADE OF SEVERE OR LIFE THREATENING MUSCARINIC EFFECTS
AE ATROPINE
MOST ADVERSE REACTIONS ARE DIRECTLY RELATED ATROPINES ANTIMUSCARINIC ACTION. DRYNESS OF THE MOUTH, BLURRED VISION, PHOTOPHOBIA AND TACHYCARDIA COMMONLY OCCUR WITH CHRONIC ADMINISTRATION OF THERAPEUTIC DOSES
INTERACTIOSN ATROPINE
ATROPINE DECREASES THE RATE OF MEXILETINE ABSORPTION WITHOUT ALTERING THE RELATIVE ORAL BIOAVAILABILITY; THIS EDLAY IN MEXILETINE ABSORPTION WAS REVERSED BY THE COMBINATION OF ATROPINE AND IV METOCLOPRAMIDE DURING PRETREATMENT FOR ANESTHESIA
CAUTION.WARNSING ATROPINE
When the recurrent use of atropine is essential in patients with CAD. The total dose should be restricted to 2-3 mg to avoid the detrimental effects of atropine induced tachycardia on myocardial oxygen demand
Ipratopium indications
Used as a bronchodilator for maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease, including chronic bronchitis and emphysema
AE ipratropium
As an anticholinergic drug, cases of precipitation or worsening of narrow angle glaucoma, mydriasis, acute eye pain, hypotension, urinary retention, tachycardia, constipation, bronchospasm, including paradoxical bronchospasm have been reported
Caution/warning ipratropium
Caution is advised in the co administration of ipratropium with other anticholinergic containing drugs
Tiotropium indications
Is an anticholinergic indicated for long term, once daily, maintenance treatment of bronchospasm associated with COPD, and for reducing COPD exacerbations
AE tiotropium
The most common adverse reactions were upper respiratory tract infection, dry mouth, sinusitis, pharyngitis, and rhinitis.
Interactions tiotropium
May interact additively with concomitantly used anticholinergic medications. Avoid administration fo tiotropium with other anticholinergic containing drugs
Cautions/warning tiotropium
Not for acute use. Not a rescue medication. Immediate hypersensitivity reactions may include; angioedema, urticaria, rash, bronchospasm, or anaphylaxis can occur. Use with caution in patients with severe hypersensitivity to milk proteins
Aclidinium indication
Indicated for the long term maintenance treatment of bronchospasm associated with COPD, including chronic bronchitis and emphysema
AE aclidinium
Include but are not limited to paradoxical bronchospasm, worsening of narrow angle glaucoma, worsening of urinary retention
Interactions aclidinium
In vitro studies suggest limited potential for CYP450 related metabolic drug interactions, thus no formal interaction studies have been performed. Drug performance is still highly monitored since the drug was approved in 2012.
Caution/warning aclidinium
Not for acute use. This drug is intended as a twice daily maintenance treatment for COPD and is not indicated for the initial treatment of bronchospasm
Methylxanthines
Methylxanthines are a unique class of drug that are derived from the purine base xanthine. Xanthine is produced naturally by both plants and animals. The methylxanthines, theophylline, and dyphylline are used int he treatment of airways obstruction caused by conditions such as asthma, chronic bronchitis, or emphysema. Caffeine and theobromine (in chocolate) are also methylxanthines
Theophylline
Has two distinct actions in the airways of patients with reversible obstruction; smooth muscle relaxation (bronchodilator) and suppression of the response of airways to stimuli (non bronchodilator prophylactic effects)
Indications theophylline
Used in the treatment of asthma and other lung problems, such as emphysema and chronic bronchitis
AE theophylline
cNS excitement, hAA, insomnia, irritability, restlessness, seizure, diarrhea, nausea, vomiting, urinary retention
Interactions theophylline
Theophylline interacts with a wide variety of drugs. The interaction is increased or decreased based on serum theophylline concentrations. Theophylline only rarely alters the pharmacokinetics of other drugs
Caution/warning theophylline
Theophylline should be used with extreme caution in patients with the following clinical conditions due to the increased risk of exacerbation of the concurrent condition: active PUD, seizure disorder cardiac arrhythmias (not including Brady arrhythmia)
Inhaled corticosteroids
By far most effective controllers for asthma, and their early use has revolutionized asthma therapy. Most effective anti inflammatory agents used in asthma therapy, reducing inflammatory cell numbers and their activation in the airways.
What do ICS do
Reduce eosinophils int he airways and sputum, and numbers of activated T lymphocytes and surface mast cells in the airway mucosa. These effects may account for the reduction in AHR that is seen with chronic ICS therapy.
MOA ICS
Several effects both einflammatory process
The major effect-corticosteroids is to switch off the transcription of multiple activated genes that encode inflammatory proteins such as cytokines, chemokines, adhesion molecules, and inflammatory enzymes.
This effect involves several mechanisms, including inhibiton of the transcription factors NF KB but an important mechanism is recruitment of histone deacetyation 2 inhibitor to the inflammatory gene complex, which reverses the histone acetylation associated with increased gene complex, which reverses the histone acetylation associated with increased gene transcription.
Also activated anti inflammatory genes such as nitrogen-activated protein kinase phosphatase 1, and increase the expression of B2 receptors.
Side effects ICS
Most metabolic and endocrine side effects of corticosteroids are also mediated through transcriptional activation.
Most effective controllers in asthma
ICS
Beneficial in treating asthma of any severity and age. Usually given twice daily but some may be effective once daily in mildly symptomatic patients.
ICS rapidly improve symptoms of asthma, and lung function improves over several days.
They are effective in preventing asthma symptoms, such as exercise induced asthma and nocturnal exacerbations, but also prevent severe exacerbations
ICS reduce AHR, but maximal improvement may take several months of therapy.
Early treatment with ICS appears to prevent irreversible changes in airway function that occur with chronic asthma.
Withdrawal ICS
Results in slow deterioration of asthma control, indicating that they suppress inflammation and symptoms, but do not cure the underlying condition.
Who gets ICS
First line for patients with persistent asthma, but if they do not control symptoms at low doses, it si usual to add a LAB as the next step
Inhaled corticosteroids
Beclomethasone
Budesonide
Ciclesonide
Flunisolide
Fluticasone
Mometasone
Triamcinolone
Beclomethasone indications
Prescribed as a maintenance treatment for asthma and as prophylactic therapy in patients 5 years of age and older. Also used in the treatment of asthma in patients who require oral corticosteroid therapy to reduce or eliminate the need for the systemic corticosteroids
AE beclomethasone
Most common AE include HA, pharyngitis, oral symptoms (inhalation route) and sinusitis
AE beclomethasone
Most common AE include HA, pharyngitis, oral symptoms(inhalation route) and sinutisit
Interactions beclomethasone
Other drugs may interact with beclomethasone inhalation, including prescription and OTC medicines, vitamins and herbal products
Cautions/warning beclomethasone
Particular care is needed in patients who are transferred from systemically active corticosteroids to beclomethasone bc deaths due to adrenal insuffiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic pituitary function
Budesonide indications
Maintenance treatment of asthma as prophylactic therapy in adult and pediatric patients six years of age or older
AE budesonide
Most common AE are nasopharyngitis, nasal congestion, pharyngitis, rhinitis allergic, viral URI, nausea, viral gastroenteritis, otitis media, oral candidiasis
Interactions budesonide
The main route of metabolism of corticosteroids ,including budesonide, is via 3a4
Cautions/warning budesonide
This drug should not be used where primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required. Severe hypersensitivity to milk proteins and any of the ingredients in budesonide is contraindicated
Ciclesonide indications
Prescribed as an inhaled corticosteroid indicated for maintenance treatment of asthma as prophylactic therapy in adult and adolescent patients 12 years of age and older
AE ciclesonide
Most common are HA< nasopharyngitis, sinusitis, pharyngolaryngeal pain, upper respiratory infection, arthralgia, nasal congestion, pain in extremity and back pain
Interactions ciclesonide
In clincial studies, concurrent administration of ciclesonide and other drugs commonly used in the treatment of asthma (albuterol, formoterol) had no effect on pharmacokinetics of desciclesonide
Cautions/warning ciclesonide
Ciclesonide is not indicated for the relief of acute bronchospasm. Use is not recommended in presence of Candida albicans infection of the mouth and pharynx, tb, fungal , bacterial , viral, or parasitic infection
Fluniolide indications
Indicated for the maintenance treatment of asthma as prophylactic therapy in adult and pediatric patients 6 years of age and older. Also indicated for asthma patients requiring oral corticosteroid therapy where adding flunisolide therapy may reduce or eliminate the need for oral corticosteroids
AE flunisolide
The most common are pharyngitis, rhinitis, HA, sinusitis, and increased cough
Flunisolide interactions
No significant drug interactions with other drugs used in asthma therapy. However the effects of some other drugs can change if you take other drugs or herbal products at the same time
Caution/warning flunisolide
Contraindications in patients for primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required
Fluticasone indications
Maintenance treatment of asthma as prophylactic therapy in patients aged 4 and older. Not indicated for relief of acute bronchospasm
AE fluticasone
Most common adverse reactions are upper respiratory tract infections or inflammation , throat irritation, sinusitis, dysphagia, candidiasis, cough, bronchitis, and HA
Interactions fluticasone
Strong p450 3a4 inhibtiors use not recommended. May increase risk of systemic corticosteroid effects
Caution/warning fluticasone
Candida albicans infection of the mouth and pharynx may occur monitor patients periodically. Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk
Mometasone indications
Maintenance treatment of asthma as prophylactic therapy in patients 4 years of age and older
AE mometasone
The most common adverse reactions are HA< allergic rhinitis, pharyngitis, URI, sinusitis, oral candidiasis, dysmenorrhea, musculoskeletal pain, back pain, and dyspepsia
Interactions mometasone
In clincial studies, the concurrent administration of mometasone and other drugs commonly used int he treatment of asthma was not associated with any unusual adverse reactions
Caution/warning mometasone
Use of this drug is contraindicated in patients with status asthmaticus or other acute episodes of asthma where intensive measures are required. Also contraindicated in patients with a known hypersensitivity to milk proteins or any ingredients of mometasone
Triamcinolone indications
Indicated in the maintenance treatment of asthma patients who require systemic corticosteroids administration , where adding this agent may reduce or eliminate the need for the systemic corticosteroids. Not indicated for the relief of acute bronchospasm
AE triamcinolone
Diarrhea, oral minilia, toothache, vomiting , weight gain, bursitis, myalgia, dry mouth, rash, chest congestion, voice alteration
Triamcinolone interactions
The concurrent administration of triamcinolone and other drugs commonly used in the treatment of asthma was not associated with any unusual adverse reactions
Caution/warning triamcinolone
Contraindications in the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required. Particular care is needed in patients who are transferred from systemically active corticosteroids to triamcinolone bc deaths due to adrenal insuffiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to aesolized steroids in recommended doses
Combination ICS and LABA drugs
Fluticasone+salmeterol
Budesonide+fomoterol
Oral and parenteral corticosteroid
Oral corticosteroids are used in combination with SABA to treat moderate to severe asthma flare ups. Oral corticosteroids are more likely to cause side effects than inhaled corticosteroids
Prednisone indications
Used as an antiinflammatory or immunosuppressive agent for certain allergic, Dermatologic, GI, hematologic, ophthalmologist, nervous system, renal respiratory, rheumatologist, specific infectious diseases or conditions and organ transplatation. Also used for the treatment of certain endocrine conditions and for palliation of certain neoplastic conditions
AE prednisone
Common include fluid retention, alteration in glucose tolerance, elevation in bp, behavioral and mood changes, increased appetite and weight gain
Interactions prednisone
Anticoagulant agents may enhance or dimish anticoagulant effects. May increase blood glucose concentrations. Use of NSAIDS including aspirin and salicylate increased the risk of GI side effects
Caution/warning prednisone
May lead to hypothalamic pituitary adrenal axis suppression. Monitor patients for Cushing syndrome and hyperglycemia with chronic use and taper doses gradually for withdrawal after chronic use
Leukotriene antagonists
Among most prescribed drugs for the management of asthma, used both for treatment and prevention of acute asthmatic attacks. This class of drugs acts by binding to cysteine leukotriene (CysL T) receptors and blocking their activation and the subsequent inflammatory cascade which cause the symptoms commonly associated with asthma and allergic rhinitis. This cysteinyl leukotrienes (LTC4, LTD4, LTE4) are products of arachidonic acid metabolism and are released from various cells, including mast cells and eosinophils. These eicosanoids bind to cysteinyl leukotriene (CysL T) receptors. THe CysL T type 1 receptor is found in the human airway (including airway SM cells and macrophages) and on other pro inflammatory cells (including eosinophils and certain myeloid stem cells). CysLts have been correlated with the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene mediated effects include airway edema, smooth msucles contraction, and altered cellular activity associated with the inflammatory process)
Montelukast
Orally active compound that binds with high affinity and selectivity to the CysLT1 receptor (in preference to other pharmacologically important airway receptors, such as the prostatis, cholinergic, or B adrenergic receptor). Montelukast inhibits physiologic actions of LTD4 at the cysLT1 receptor without any agonist activity. More specifically, montelukast causes inhibition of airway cysteinyl leukotriene receptors as demonstrated by the ability to inhibit bronchoconstriction due to inhaled LTD4 in asthmatics
Indications montelukast
Primaryily prescribed to treat allergies and prevent asthma attacks
AE montelukast
URI, fever, HA, sore throat, cough, stomach pain, diarrhea, earache, ear infection, flu, runny nose, sinus infection
Interaction montelukast
The concurrent administration of montelukast and other drugs commonly used int he treatment of asthma was not associated with any unusual adverse reactions
Caution/warning montelukast
Not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus. Therapy with montelukast can be continued during acute exacerbations of asthma. Patients who have exacerbations of asthma after exercise should have available for rescue a short acting inhaled B agonist
Zafirlukast
Selective and competitive receptor antagonist of leukotriene D4 and E4 (LTD4 and LTE4) components of slow reacting substance of anaphylaxis (srsa0 cysteinyl leukotriene production and receptor occupation have been correlated with the pathophysiology of asthma, including airway edema, smooth msucle constriction and altered cellular activity associated with the inflammatory process, which contribute to the signs and symptoms of asthma
Indications zafirlukast
Prophylaxis and chronic treatment of asthma in adults and children 5 years of age and older.
AE zafirlukast
Coadminstration with warfarin results in a CLINCIALLY significant increase in prothrombin time. Patients on oral warfarin anticoagulant therapy and zafirlukast should have their prothrombin times monitored closely and anticoagulant dose adjusted accordingly
Cautions/warning zafirlukast
Hepatotoxicity: cases of life threatening hepatic failure have been reported in patients treated with safirlukast. Cases of liver. Injury without other attributable cause have bee reported from ost marketing adverse event surveillance zafirlukast
Sileuton
Immediate relase tablts were withdrawn from US market in 2008
Controlled release still avail early a
Inhibitor of 5 lipoxygenase and thus inhibits leukotriene (LTB4, LTC4, LTD4, and LTE4) formation
Zileuton indicatiosn
Leukotriene synthesis inhibitor indicated for the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older and not used to treat an acute asthma
AE zileuton
Most common AE include sinusitis, nausea, and pharyngolaryngeal pain
Interactions zileuton
Increases theophylline evils and increases warfarin levels. Monitor prothrombin time and adjust warfarin dose accordingly. Zileuton increases propranolol levels and bb activity
Cautions/warning zileuton
Not recommended in cases where active liver disease or persistent hepatic function enzyme elevations are over 3 times the upper limit of normal
Monoclonal antibody
Omalizumab
Indications for omalizumab
Anti IgE antibody indicated for moderate to severe persistent asthma in patients 6 yers of age and older with a positive stint est or in vitro reactivity to a perennial aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids. Also, indicated in the treatment for chronic idiopathic urticaria in adults and adolescents 12 years of age and older who remain symptomatic despite H1 antihistamine treatment
AE omalizumab
The most common adverse reactions in clincial studies with adult and adolescent patients>12 with arthralgia, pain, leg pain, fatigue, dizzy, fracture, arm pain, pruritis, dermatitis, and earache
Interactions omalizumab
No formal drug interaction studies have been performed with omalizumab. In patients with asthma the concomitant use of this agent and allergen immunotherapy has not been evaluated
Caution warning omalizumab
BBQ anaphylaxis: administer only in a healthcare setting prepared to manage anaphylaxis that can be life threatening and observe patients for an appropriate period of time after administration
Asthma COPD overlap
Although distinct syndromes , some patients with asthm have features of COPD and some patients with COPD have features of asthma with more reversibility and increased airway and blood eosinophils. This may represent to coincidence of two common diseases, or these may be distinct phenotypes. ACO patients tend to have more symptoms and exacerbations. They may benefit from triple therapy with ICS, LABA and LAMA
Goal of chronic asthma management
Reduction in impairment
Reduction risk
Precipitating or aggravating factors of asthma
Viral respiratory infections
Exercise
Endocrine factors
Drugs: asprin, bb
Weather changes: cold air
Allergens
Emotional expression: anger, laughing
Food additives: sulfite
Environmental changes
Exposure to irritant and occupational chemicals
Comorbid conditions and asthma
Hormonal changes
COPD
Upper airway
Rhinitis
GERD
Fat
Sleep apnea
What are the 2 categories of asthma therapy
Anti inflammatory drugs
Bronchodilators
Muscarinic antagonist and theophylline
Decrease acetylcholine (muscarinic) and adenosine (theophylline) which increase bronchial tone
Beta agonist
Increase AC and cAMP for bronchodilator
Theophylline
Decrease PDE which increase cAMP and increase bronchodilation
Zafirlukast and montelukast
Selective reversible antagonsits of CysLT1 receptors)
Taken orally
Are bronchodilators
Have antiinflammatory action
Less effective than ICS
Have glucocorticoids sparing effect(potentiate corticosteroids)
