Drugs for Final Flashcards
Methyldopa
Can initiate an autoimmune reaction
Blood pressure medication that is an alpha receptor drug and is used to tx HTN.
Causes hemolytic anemia-destruction of the RBC.
Monitor H&H and CBC
Hydralazine
Can initiate an autoimmune reaction
Lupus like syndrome
Notify and follow up
Isoniazid
Can initiate an autoimmune reaction
Lupus like syndrome
Notify and follow up
Procainamide
Can initiate an autoimmune reaction
Lupus like syndrome
Notify and follow up
Barbituates
Can cause a skin rash stevens-johnson in toxicity
Sulfonamides
Can cause a skin rash stevens-johnson in toxicity
Phenytoin
Can cause a skin rash stevens-johnson in toxicity
Carbamazepine
Can cause a skin rash stevens-johnson in toxicity
Allopurinal
Can cause a skin rash stevens-johnson in toxicity
NSAIDs
Can cause a skin rash stevens-johnson in toxicity
Penicillins
Can cause a skin rash stevens-johnson in toxicity
Gentamicin
Progressive renal failure- renal tubular injury reversible upon cessation
Amphotericin B
Progressive renal failure- high frequency of injury because mechanism for efficacy is shared by the mechanism responsible for toxicity
Contrast-Media
Progressive renal failure- dose related nephrotoxicity
Doxorubicin
Cardiovascular toxicity
Leads to production of reactive oxygen species
Bleomycin
Can result in pulmonary toxicity by pulmonary fibrosis
Amiodarone
Can result in pulmonary toxicity by pulmonary fibrosis
Vancomycin
Causes red-man syndrome
Flushing, pruritis, chest pain, muscle spasm, and hypotension during vancomycin infusion.
Pretreatment w/ IV antihistamines attenuates the sx of red-man syndrome.
Cromolyn
Blocks the release of histamine from mast cells.
Inhaled as a powder.
Stabalized mast cells preventing noncytolytic degranulation.
Decreases sx of allergic rhinitis
Prophylactic use to block asthmatic rxns but not useful in managing acute asthmatic attacks.
Poorly absorbed- with few adverse effects (irritation/taste)
Effective only if used BEFORE a challenge
Nedocromil
Blocks the release of histamine from mast cells.
Inhaled as a powder.
Stabalized mast cells preventing noncytolytic degranulation.
Decreases sx of allergic rhinitis
Prophylactic use to block asthmatic rxns but not useful in managing acute asthmatic attacks.
Poorly absorbed- with few adverse effects (irritation/taste)
Effective only if used BEFORE a challenge
Trirolidine, DIPHENHYDRAMINE (benydryl), PROMETHAZINE, HYDROXYZINE, chlorpheniramine
Histamine H1 receptor blockers
1st generation drugs that are widely used, effective and inexpensive.
Loratadine (claritin OTC), desloratadine (clarinex), azelastine (astelin), cetirizine (Zyrtec OTC), fexofenadine (allegra, OTC)
Less CNS toxicity or side effects compared to first generations since they do not cross the blood brain barrier or are excluded by p-glycoprotein (cause less drowsiness.
H1 blockers- active metabolites of the 2nd generation compounds are used therapeutically
Loratadine (Claritin) to desloratadine (clarinex)
terfenadine (seldane) to fexofenadine (Allegra)
Terfenadine (Seldane)- process
Terfenadine undergoes first-pass metabolism to fexofenadine.
Terfenadine blocks potassium channels in myocardium, which causes a prolonged QT interval and increases the risk of ventricular tachyarrhythmias. (torsades de pointes)
Terfenadine (Seldane)
Active metabolites of the 2nd generation compound that is used therapeutically is fexofenadine (allergra)
Loratadine (Claritin)
Active metabolites of the 2nd generation compound that is used therapeutically is desloratadine (clarinex)
Promethazine
The most effective antihistamine used to treat motion sickness.
Administered 1 hr before the anticipated motion.
Prevention of nausea and vomiting by blockage of dopamine D2 receptors
Phenothiazine class
Promethazine and timeprazine
Blockade of dopamine D2 receptors to prevent nausea and vomiting
Diphenhydramine
OTC tx of hyposomnia
Antimuscarinic actions
Magic Mouthwash
Formulated from prescription
Used to treat oral ulcers, infections, inflammation, pain
Contains diphenhydramine
Syrup of Ipecac
Onset 15-20 minutes
95% vomit in 20 mins, 30% reduction in bioavailability at 1 hour
Side effects- acute- diarrhea, drowsiness, chronic- cardiac arrhythmia’s, neuropathy, muscle weakness.
cathartics
activated charchol
Promote movement of AC bound drug through GI tract, may cause hypovolemia and electrolyte imbalance
Activated Charcol
Absorbant 1gm/kg
Will NOT bind- low molecular weight, charge compounds; cyanide, bromide, potassium, ethanol, methanol, iron, lithium, alkaline corrosives, mineral acids, highly concentrated solutions such as gasoline, kerosene, and ETOH
Efficacy 40% reduced bioavailability at 1 hour
ADR- Vomiting, constipation, aspiration, GI obstruction, charcoal empyema, GI perforation.
Golytely
Used in whole bowel irrigation
Used prior to colonoscopy.
Dimercaprol (BAL)
Chelator used for metal poisonings because they bind to metal
uses for As, Hg, Pb, Cd and toxicities include HTN and tachycardia
Penicillamine
Chelator used for metal poisonings because they bind to metal
uses for Cu, Pb, Hg, As, toxicities include allergic rxns
DSMA (succimer)
Chelator used for metal poisonings because they bind to metal
used for Pb, As, Hg, toxicities include Gas and ABD pain
Edetate calcium disodium (EDTA)
Chelator used for metal poisonings because they bind to metal
used for Pb and toxicities include nephrotoxicity
Deferoxamine
Chelator used for metal poisonings because they bind to metal
used for Fe, toxicities include hypotension, anaphyactoid rxn and ARDS
Crotalidae Antivenin
Antivenins/biologics
rattle snake envenomation
Lactrodectus Antivenin
Antivenins/biologics
black widow spider envenomation
Elapidae Antivenin
Antivenins/biologics
eastern and texas coral snake envenomation
Trivalent botulinum
Antivenins/biologics
botulisms type A, B, and E
Digoxin immune fab
Antivenins/biologics
digoxin and digitoxin
N-acetylcysteine
Pharmacologic Antagonists
poisoning is acetaminophen and mechanism is prevents NAPQI binding at hepatocyte.
Naloxone
Pharmacologic Antagonists
poisoning is opioids and mechanisms is opioid receptor antagonist
Flumazenil
Pharmacologic Antagonists
poisoning is benzodiazepines and mechanism is benzodiazepine receptor antagonist
Atropine
Pharmacologic Antagonists
poisoning is organophosphates and pesticides and mechanism is muscarinic receptor antagonist
Fomepizole
Pharmacologic Antagonists
poisoning is methanol and ethylene glycol and mechanism is blocks metabolite formation.
Defuroxamine
Metal antidote for iron
Deferasirox
Metal antidote for iron
Oral option
Penicillamine
Metal Antidote for copper
Trientine
Metal antidote for copper
Parathion
Pesticide
Organophosphate
Acetylcholinesterase inhibitors producing muscarinic and nicotinic toxicity
Malathion
Pesticide
Organophosphate
Acetylcholinesterase inhibitors producing muscarinic and nicotinic toxicity
Diazinon
Pesticide
Organophosphate
Acetylcholinesterase inhibitors producing muscarinic and nicotinic toxicity
Atropine
Pesticide treatment
Muscarinic antagonist
Pralidoxime
Pesticide treatment
Regenerated ACHE
Classifications of ABX- Agents that inhibit cell wall synthesis
Penicillins Cephalosporins Cycloserine Vancomycin Bacitracin
Classifications of ABX- Agents that act directly on the cell membrane of the microorganism affecting permeability and leading to leakage of intracellular compounds
Detergents
- polymyxin
Classifications of ABX- Agents that interfere with protein synthesis by interaction with bacterial ribosomes
Chloramphenicol Tertracyclines Macrolides Clindamycin Streptogramins Ketolides
Classifications of ABX- Agents that interfere with protein synthesis by blocking initiation
Oxazolidinoses (linezolid)
Classifications of ABX- Agents that interfere with protein synthesis by inhibition of tRNA synthesis
Mupirocin
Classifications of ABX- Agents that interfere with protein synthesis by multiple mechanisms leading to disruption of RNA processing
Aminoglycosides
Classifications of ABX- Agents that inhibit DNA processing by
Inhibition of DNA topoisonerases
Quinolones
Inhibition of DNA-dependent RNA polymerase (Directly-rifampin and indirectly- nitrofurantoin)
Classifications of ABX- The antimetabolites- blocking bacterial folic acid pathway
Trimethoprim
Sulfonamides
Methicillin-resistant Staphylococcus aureus (MRSA) and Mycobacteria tuberculosis
Multiple drug-resistance bacteria
Beta Lactam Compounds
Penicillins Cephalosporins Cabapenems Monobactams Beta lactamase inhibitors
Beta Lactam Compounds- Penicillins
Natural penicillin
Aminopenicillins
Penicillinase Resistanct Penicillins
Extended spectrum penicillins (Anti-psuedomonal)
Beta Lactam Compounds- Cephalosporin
First generation- fifth generation
Penicillins Mechanism of Action
Interfere with the last step in bacterial cell wall growth
Works best on rapidly proliferating organisms
No effect on organisms without a cell wall (protozoa, mycoplasma, mycobacteria, fungi, and viruses)
Penicillin resistance
Inactivated by beta-lactamase
Modification of PBP target (mechanisms of MRSA and penicillin resistant to pneumococci)
Impaired penetration of drug to target PBP
Penicillin classification- Natural Penicillins
Penicilling G or V
Narrow spectrum, PCN G acid labile, penicillinase sensitive.
Highly active against sensitive stains of gram positive cocci (Not staphylococcus)
Anaerobes
Some gram negative
Penicillin G or V
Tx infections of upper and lower respiratory tract, throat, skin, and GU tract.
Prophylaxis in rheumatic fever, dental procedure for those at risk of endocarditis, gonorrhea or syphilis expose.
Penicillin G or V- gram positive cocci
Streptococcus, enterococcus faecalis, listeria morlocytogenes
Penicillin G or V- Anaerobes
Bacteroides species and fusebacterium species
Penicillin G or V- gram negative
E. coli, H. influenzae, N. gonorrhoeae, Treponema be, and suspectible psuedomonas species.
Amniopenicillins
Ampicillin and amoxicillin
Ampicillin and Amoxicillin
Activity of PCN G plus improved coverage of gram negative cocci adn Enterobacteriaceae
Not active against treponema or actinomyces
Ampicillin and Amoxicillin- therapeutic uses
URI (Otitis, sinusitis), uncomplicated UTI, meningitis, salmonella infections
Ampicillin and amoxicillin- resistance leading to combinatins with beta-lactamase inhibitors
Augmentin = Amoxicillin + Clavulanic acid
Ampicillin + sulbactam (unasyn)
Better coverage against H. Influenzae and Klebsiella sp.
Penicillinase-Resistance Penicillins (antistaphylococcal penicillins)
Nafcillin, oxacillin, dicloxacillin
Methicillin and cloxacillin no longer available in US
Penicillinase resistance, narrow spectrum
Staph resistant to this class is called MRSA
Penicillinase-Resistance Penicillins (antistaphylococcal penicillins)- tx
Used in treatment of staphylococcal infection with high beta-lactamase production (cellulitis and endocarditis)
Not active against gram-negative or anaerobic organisms
Antipseudomonal penicillins
Piperacillin, ticarcillin, carbenicillin (PO)
Maintains activity of PCN G but gain great gram negative coverage including psuedomonas
Coverage against H. influenzae and kelbsiella sp
No coverage against treponema palladium or actinomyces
Gram negative infections in combo with aminoglycosides (bacteremias, pneumonias, resistant UTIs, infections in burn patients)
Antipseudomonal penicillins- resistance issues and are paired with beta-lactamase inhibitors
Piperacillin + tazobactam = zosyn
Ticarcillin + clavulanic acid= timentin
Beta-lactamase inhibitors
Clavulanic acid, sulbactam, tazobactam
Structurally similar but lack antibacterial activity
Act as suicide inhibitors -> potent, irreversible inhibitors of many lactamases.
Extends the spectrum of the ABX its paired with
Addition of Beta-lacamase inhibitors- Aminopenicillins
Amoxicillin + clavulanic acid (augementen)
Ampicillin + sulbactam (unasyn)
Addition of Beta-lacamase inhibitors- Antipseudomonal penicillins
Piperacillin + tazobactam (Zosyn)
Addition of Beta-lacamase inhibitors
Increased coverage against H. flu, staph, moraxella catarrhailis
Variable coverage against gram (-) bacteria- pseudomonas, enterobacter, E. coli, klebsiella, serratia due to resistance to these beta-lactamase inhibitors.
Penicillin pharmacokinetics-absorption
Many cannot be administered orally (due to destruction in acid)
Food may decrease the absorption of available oral penicillins
IV route bypasses absorption considerations and is preferred for serious infections.
Penicillin pharmacokinetics- Distribution
Widely distributed with tissue level=to serum
Poorly penetrate the eyes, CNS, and prostate
ONLY PENETRATE THE CNS WHEN MENINGES ARE INFLAMED.
Penicillin pharmacokinetics- metabolism
Most penicillins are not metabolized by dependent on the kidney for elimination
Penicillin pharmacokinetics- elimination
Kidney excretion is the main route of elimination (except antipseudomonal PCN and nafcillin via billiary excretion)
Penicillins are filtered (10%) and actively secreted (90%) into the urine
Active secretion can be blocked by probenecid
Doses need to be adjusted in renal insufficiency
Penicillins Adverse Effects
Hypersensitivity
Allergic responses develop in respinse to beta-lactam ring and derivatives (Cross rxn)
Anaphylactic shock is rare
Serum sickness- urticaria, rash, fever, angioedema
Interstitial nephritis and hemolytic anemia
Desensitization protocols are available.
Penicillins adverse effects
GI upset with oral agents
Diarrhea
Secondary infections- vaginal candidiasis
Hepatitis w/ oxacillin
Neutropenia w/ nafcillin
Abnormal platelet aggregation with ticarcillin and carbenicillin
Cephalosporins Intro
Discovered 1948 by Guisepee Brotzu
Similar to penicillins chemically, MOA, and toxicity
Bactericidal
Inhibit bacterial-cell wall synthesis similar to PCNS
Structurally contain a dihydrothiazine ring connected to the B-lactam ring making them more resistant to hydrolysis by B-lactamase (Broader spectrum of activity)
Classified by 5 generations
Category B in pregnancy
Cephalosporin Resistance
Mutations or carried on plasmids
Mutations in PBP
Production of Beta-lactamases
Alteration in cell-membrane porins in gram negative bacteria
1st Generation Cephalosporins Spectrum
Good aerobic gram-positive, above the diaphragm anaerobes and community acquired gram negative coverage.
Stable against staph produced penicillinase
IV= Cefazolin (Ancef)
PO= Cephalexin (keflex)
1st Generation Cephalosporins - Use
Used for septic arthritis in adults, skin infections, acute otitis media, prophylaxis for clean surgeries, and gram (+) infections in pts that cannot take penicillin
2nd Generation Cephalosporins- Spectrum
Two classes w/in second generation Added gram (-) coverage (ie moraxella, neisseria, salmonella, shigella, haemophilus influenzae) IV and PO= cefuroxime (zinacef, ceftin) Added anaerobic coverage (especially B. Fragilis) IV= cefotetan (cefotan)
2nd Generation Cephalosporins- Use
Added gram (-) IV and PO= cefuroxime (zinacef, ceftin) Useful for sinusitis, otitis, CAP Added anaerobic coverage IV- cefotetan (cefotan) Useful for tx of abd and gynecological infections
Summary of 2nd generation cephalosporins
Gram (+): 2nd generation < 1st generation (somewhat)
Gram (-): 2nd generation > 1st generation (Significantly)
3rd Generation Cephalosporins- Spectrum
Expanded gram-negative coverage and penetration of BBB
Cefpodoximine (Vantin), cefdinir (omnicef), cefixime (suprax)=oral
Cefotaxime (claforan)
Ceftriaxone (rocephin) = IV and IM
Ceftazidime (fortaz) distinguishes itself w/ increased anti-pseudomonal
3rd Generation Cephalosporins- clinical use
Used to tx a wide variety of serious infections caused by organism that may be resistant to other antimicrobial agents
Drugs of first choice in tx of meningitis, pneumonia in children and adults, sepsis, peritonitis
Tx of UTI, skin infections, and oesteomyelitis, Neisseria gonorrhea infections
Summary of 3rd generations cephalosporins
Gram (+): 1st generations > 2nd generation or 3rd generation
Gram (-): 3rd generation= 2nd generation > 1st generation
4th Generation Cephalosporins- Spectrum
Cefepime (maxipime) IM/IV
Good activity against both gram(+) and gram (-) bacteria; ALSO ANAEROBIC COVERAGE
4th Generation Cephalosporins- coverage
P. aeruginosa, H. influenzae, N. meningitidis, N. gonorrhoeae
Enterobacteriasceae that are resistant to other cephalosporins
4th Generation Cephalosporins- clinical use
Intra-abdominal infections, respiratory tract infections, skin infections
Summary of 4th generation cephalosporins
Improved gram (+) compared to 2nd and 3rd generations (Closer to 1st generation) Retain gram (-) = or > 2nd and 3rd generations
5th Generation Cephalosporin
Ceftobiprole medocaril
Approved March 2008
Tx of complicated skin and skin structure infections (MRSA)
Inhibits PBPs involved in cell wall synthesis
Well tolerated-nausea and taste disturbances
IV form only
Cephalosporins Pharmacokinetics
Orally administered absorbed rapidly
Presence of food may increase, decrease, or not affect absorption
Extensive distribution (most don’t cross CSF except cefuroxime, cefotaxime, ceftriaxone, cefepime)
Most eliminated via kidneys
Cephalosporins toxicities/ side effects
Hypersensitivity same spectrum as PCN
Structure is structurally different allowing use in PCN allergy pts
5-10% cross sensitivity
Pts w/ anaphylaxis or angioedema with PCN should not recive
Suprainfection- resistant organism and fungi may proliferate.
Cephalosporins toxicities/ side effects (2)
GI upset- N/V/D
1-3% allergic rxn - rash, fever, eosinophilia, urticaria
Cholelithiasis
Blood dyscrasias- eosinophilia, thrombocytopenia, leukopenia
Methylthiotetrazole side chains
Cephalosporin drug interactions
Increased serum levels if co-administered with probencecid
Increased effects of warfarin- cefotetan, cefazollin, cefoxitin, ceftriaxone
Carbapenems (the most broad spectrum)
Resistant to many beta-lactamases, most broad spectrum of beta-lactam class of ABX (gram + and gram - coverage)
Ertapenem (Ivanz), and imipenem-cilastin (primaxin)
Meropenem (merrem)
Carbapenems- Ertapenem (Ivanz), and imipenem-cilastin (primaxin)
Coverage included resistant gram (-) bacilli (P. aeruginosa), gram (+) bacteria (MRSA, enterococcus), and anaerobes (bacteroides)
Tx of UTI, pneumonia, intra-abdominal infections, skin and soft tissue infections
Carbapenems- meropenem (Merrem)
Greater activity against gram-negative
Intra-abdominal infections
Meningitis > 3 mo. of age
Carbapenems- Pharmacokinetics
Given parenterally-> unstable in stomach acid
Cilastin inhibits dehydropeptidase I which inhibits imipenem by breaking beta-lactam ring
Well distributed in the body
Renal excretion
Carbapenems- toxicities
Well tolerated- N/V, phlebitis at infusion site, leukopenia, elevated LFTs
Seizures in pts w/ renal failure
High degree of cross-sensitivity with PCN
Carbapenems- Drug interactions
Ertapenem cant be infused w/ dextrose or other medications
Meropenem reduces valproic acid levels
Meropenem and ertapenem category B- safe
Imipenem/cilatin category C- not removed from option when considering risk vs. benefit
Monobactams
Aztreonam (Azactam) the only monbactam available in the US
Spectrum of activity is purely gram-negative rods (inihibits mucopeptide synthesis in cell wall by binding to PBP, resistant to most beta lactamases)
No cross reactivity with PCN or cephalosporin allergic pts
Monobactams- pharmacokinetics
Tx of gram (-) infections- pneumonia, soft-tissue infections, UTI, intra-abdominal and pelvis infections
Acid Labile
Widely distributed including inflames meningeal tissue
Excreted in urine unchanged
Monobactams- Toxicity
No major toxicity- rash, N/V, elevated LFT, transient eosinophilia
No reported drug interations
Special populations- category B in pregnancy and safe in kids over 9 mo.
Cycloserine
Inhibition that ultimately disrupts assembly of cell wall synthesis.
HIghly susceptible to resistance
Cycloserine- indications
restricted for use as a secondary anti-tubercular drug
Cycloserine- ADRs- very toxic
CNS toxicity-reversible w/pyridoxine
Renal impairment will accelerate toxicity
Vancomycin Mechanism and Spectrum
Acts on diff binding site than beta-lactamase but has the same effect on cell wall synthesis.
Bactericidal
Vancomycin Mechanism and Spectrum- mechanism of resistance
Acquired (plasmid born)- VanA phenotypes. A component of the peptidoglycan has modified so that vancomycin can not bind.
Innate resistance- most gram negatives-outer membrane resistance penetration
Vancomycin
Active against gram positive organisms only.
Including beta-lactamase producing varieties
Reserved for pts allergic to B-lactams with serious gram (+) infections, infections resulting from MRSA, and used in antibiotic associated enterocolitis.
Vancomycin Pharmacokinetics
Not absorbed when given orally and used orally in tx of C. Diff.
Given IV to maintain levels in a range that enhances outcome and avoids toxicity.
Widely distributed including CNS when meninges are inflamed.
Not metabolized by 90% renally excreted
Vancomycin clinical use
Main indication for parenteral vancomycin is for methicillin resistant staph aureus or staph epu
Used for penicillin resistant pnemococcus pneumonia
Vancomycin-adverse effects
Local and infusion related reactions- red man syndrome (very flushed, hot, and itchy); phlebitis
Ototoxicity- irreversible hearing damage
Nephrotoxicity- reversible damage to the kidneys
Bacitracin-MOA
Polypeptide compound
Interferes w/ recycling steps of the phospholipid carrier of petidoglycan synthesis
Not a very specific target (membrane lipid)
Bacitracin- clinical use
Very nephrotoxic, so limited to topical use
Most gram (+) cocci and bacilli are sensitive
Often combined with neomycin or polymyxin or both
Aminoglycosides- spectrum of activity
Active against aerobic gram-negative bacilli (klebsiella species, enterobacter, psudeomonas aeruginosa)
Little activity against anaerobes due to lack of stability
Tx- UTI, respiratory tract, skin and soft-tissue infections
Aminoglycosides- combination w/ other agents
To broaden coverage in serious illness (bacteremia or sepsis and psuedomonal infections)
For synergism w/ vancomycin or penicillins in the tx of endocarditis
Aminoglycosides- spectrum of activity
Exhibit concentration-dependent killing and have a pronounced post-antibiotic effect
Aminoglycosides- streptomycin
Useful in treating enterococcal infections
Aminoglycosides- gentamicin, tobramycin, amikacin
Most widely used Aminoglycosides.
Cross-resistance b/w these drugs
Aminoglycosides- Neomycin, kanamycin
Limited to oral or topical due to neprhotoxicity
Aminoglycosides-Spectinomycin
Structurally related to Aminoglycosides but lack amino sugars and glycosidic bonds. Used to tx for gonorrhea in PCN allergy patients.
Aminoglycosides- Adverse Effects
otoxicity- may be irreversible (sterptomycin is the most ototocix; not reported w/ genatamicin)
Nephrotoxicity- usually reversible
Aminoglycosides- Adverse Effects Neuromuscular blockage
Aggravate muscle weakness; respiratory paralysis in myasthenia gravis or Parkinson’s disease due to curare-like effect
Aminoglycosides- hypersensitivity
Hypersensitivity rxn not common (rash, fever, urticaria, angioneurotic, edema, eosinophilia)
Aminoglycosides- Rare reactions
Optic nerve dysfunction, peripheral neuritis, encephalopathy, pancytopeniam exfoliative, dermatitis, amblyopia
Aminoglycosides- Adverse Effects tobramycin
Bronchospam and hoarseness with inhalation solution
Aminoglycosides- streptomycin
Contains metabisulfits avoid in sulfite allergies.
Aminoglycosides Phamacokinetics
No oral absportion (parenteral administration)
Widley distributed in ECF
Insoluble in lipid
Poor distribution in bile, aqueous humor, bronchial secretions, sputum, CSF
Clearance is proportional to creatinine clearance.
Gentamicin Dosing Strategies
Once daily dosing- Recommended for most clinical situations. Exclusion of Gram (+) infections, CrCl<30 ml/min, CF, spinal cord infections and burn patients
Multiple daily dosing- smaller amounts more times a day
Aminoglycoside drug interactions
Increased nephrotoxicity w/ loop diuretics
Respiratory depression when given w/ non-depolarizing muscle relaxants
Neomycin effects digoxin levels
Tetracyclines- Semisynthetic
Tetracycline
Doxycycline
Minocycline
Tetracycline- broad spectrum
Gram (+), gram (-), aerobic and anaerobes.
Mycoplasma pneumoniae. chlamydia, rickettsia, borrelia burgdorferi, inflammatory acne, sinusitis, inhalation anthrax,
Concern for opportunistic infections
Tetracyclines- 3 groups based on PK traits
Short acting- Oxytertracycline, tertracycline (frequent dosing needed)
Intermediate acting- demeclocycline (Tx of SIADH)
Long acting- doxycycline and minocycline (BID dosing)
MOA of tetracycline
Inhibit protein synthesis by reversibly binding to the 30 S subunit of RNA
Tetracycline resistance
Bacterial efflux pump is the most important mechanism
Mutations that prevent entrance of TCN into the cell cause resistance.
Tetracyclones ROA and ADRs
Oral, parenteral, and ophthalmic
GI- N/V/D most common, Modified GI flora can develop candidiasis C diff
Bony-structures and teeth- binds to newly formed/forming bones and teeth
Photosensitization
Vestibular rxns- dizziness, vertigo
Pseudotumor cerbri
Lupus like rxn
Tertracyclines- pharmacokinetics
Absorption- Incomplete absorption from GI, impaired further by concurrent ingestion (Dairy, aluminum, Ca2+, Mg2+, iron, zinc, bimuth subsalicylates)
Distribution- throughout the body including meninges, accumulation in the liver, spleen, bone marrow, bone, and enamel of unerupted teeth
Elimination- mostly kidneys (except doxycycline through hepatic)
3rd Generation TCN- Tigecycline (tygacil)
Broad spectrum antimicrobial activity including MRSA
Indicated for tx of complicated intra-abdominal infections and complicated skin and skin structure infections in adults
Develped to overcome bacterial resistance mechanisms to TCNs
Chloramphenicol
50S inhibitor
Broad spectrum- gram (+), gram (-)
Due to blood dyscrasias it is reserved for life threatening infections such as typhoid fever, RMSF, and meningitis in pts allergic to PCN
Chloramphenicol- MOA
Both bactericidal and bacteriostatic depending on bacterial species
Reversibly binds 50S inhibiting formation of peptide bonds
Inhibits mitochondrial protein synthesis in mammalian cells
Broad tissue distribution, CNS and CSF.
Chloramphenicol- contraindications
very limited use- never in neonates or pregnant women
Chloramphenicol-ADRs
Myelosuppression
Reversible anemia
Neutropenia and thrombocytopenia
Gray baby syndrome in neonates (pallor, abd distention, vomiting, and collapse)
Macrolides
50S inhibitors
Erythromycin
Semisynthetic derivatives:
Clarithromycin and Azithromycin
Macrolides- MOA
Inihibit protein synthesis by binding to 50 S ribosomal unit, blocking translocation and preventing peptide elongation
Bacteriostatic; at high concentrations or with rapid bacterial growth -> bactericidal
Macrolides- spectrum of activity
Erythromycin is effective against most gram (+) bacteria and spirochetes (Legionella pneumophila, N gonorrhoeae, N meningitidis) poor anaerobic coverage
Clarithromycin- active against gram (+) and anaerobic bacteria (H. influenzae, H. pylori, mycobacterium avium)
Azithromycin- as above with anaerobic coverage.
Macrolides-resistance
H. Influenzae resistant to erythromycin alone, susceptible in combo with sulfonamide
Resistance is usually plasmid mediated.
Erythromycin Pharmacokinetics
Erythromycin base is destroyed by stomach acid and must be administered as enteric coated tablet or capsule.
Widely distributed including prostate and macrophages
Available PO, IV, and ophthalmic
Erythro, azithro excreted unchanged in bile
Clarithromycin excreted unchanged in bile and urine
Erythromycin Adverse Effects
GI- N/V/D and cramps, binds to motilin reveptor and increased peristalsis
Cholestatic jaundice (most common with estolate salt form)
CV- concern w/ macrolide ABX IV
Ventricular arryhtmias (Erythro), palpitations, CP, Dizziness, HA, IV- QT prolongation
Semisynthetic Macrolides- Clarithromycin (Biaxin)
Spectrum of activity = to erythromycin + enhanced coverage of atypical mycobacteria.
Less GI upset and BID dosing
ADRs- N/D, abnormal taste, dyspepsia, HA, tooth discoloration, transient anxiety and behavioral changes
Semisynthetic Macrolides- Azithromycin (Zithromax)
Spectrum of activity- atypical mycobacterial and heamophilus influenza coverage
Great tissue penetration and pronlonged intracellular 1/2 life
Angioedema
Macrolide Drug Interactions
Extensive
Erythro and clarithromycin= CYP3A4 substrates and inhibitors (erythro and clarithromycin are contraindicated w/ current use of cisapride. many interactions that increase/decrease effect- statins, ergots, dixogin, cabamezepine, warfarin)
Azithromycin NOT metabolized by CYP3A4
Ketolides
New gen of macrolide ABX
Semi-synthetic derivative of erythromycin
Higher binding affinity to 50S subunit
DIsplays greater potency against gram (+) organisms
Displays activity against macrolide-resistant strains
Telithromycin (Ketek)
Tx of respiratory tract infects in 2004
Tx of CAP, sinusitis, bronchitis
Feb 2007 dropped chronic bronchitis and sinusitis
2006 black box linked to liver failure and death
Telithromycin (Ketek)
Hepatic metabolism w/ elimination in bile and urine
ADRs- N/D, HA, Dizziness, V, reversible LFT elevation, hepatitis, reversible blurred vision, diplopia, exacerbation of myasthenia gravis, and QT prolongation
Lincosamides: Clindamycin (cleocin)
Inhibits protein synthesis
Spectrum of activity- gram (+)- strep, staph, pneumococci, anaerobes = gram (+) and (-) except C diff
Clindamycin (cleocin)- clinical uses
Tx of anaerobic or mixed (polymicrobial infections)
Perforated viscus, infections of the female GU tract, decubitis, venous stasis, or arterial insufficiencyulcers
Aspiration pneumonia
Mild inflammatory acne- topical
Clindamycin (cleocin)- Adverse effects
Gi-N/V/D
Hepatotoxicity
Neutropenia
Most common ABx to cause Clostridium difficile toxin mediated to diarrhea
Streptogramins: Quinupristin Dalfopristin (Synercid)
Inhibit protein synthesis
Bacteriostatic
Indications- life threatening infections associated with VRE bactermia
Tx of complicated skin/structure infections by Methicillin-suspeptible S aureus or S. pyrogenes
Quinupristin Dalfopristin (Synercid)
P450 3A4 inhibitor (nifedipine, cyclosporin drug interactions)
IV only, limited tissue distribution, metabolized in the liver to active metabolites
Quinupristin Dalfopristin (Synercid) ADRS
Phelbitis, arthralgias, myalgias, hyperbilirubinemia
Ozazolidinones: Linezolid (Zyvox)- indications
Vanco-resistant enterococcus faecium (VRE), nosocomial pneumonia due to S aureus including MRSA or S. pneumoniae; complicated/uncomplicated skin/structure infections; gram (+) CAP
Ozazolidinones: Linezolid (Zyvox)- MOA
Prevents function of initiation complex
Mechanism distinct from other 50S ribosomal inhibitors -> active bacteria that is resistant to other protein synthesis inhibitors.
Linezolid
Bacteriostatic against enterococci and staph; bactericidal against strept
Oral and IV preps available
Metabolized by non-P450 enzymes, excreted in urine
Linezolid- ADRs
GI, HA, thrombocytopenia, linezolid=MAOI-> HTN if used with adrenergic and serotonergic drugs
Sulfandomides
Susceptible microorganisms require extracellular PBA to form dihydrofolic acid required for pruine synthesis.
Structural analogs of PABA and competitively inhibit the`enzyme dihydropteroate synthase.
Bacteriostatic against gram (+) and gram (-) bacertia
Three major groups of Sulfanomides
Oral absorbable, oral nonabsorbable, and topical agents.
Sulfanomides- oral absorbables
Sulfanomides- oral absorbables
Sulfonamides- oral non-absorbable agents
Sulfasalazine- used for UC, enteritis, delayed release of tablets is used to treat RA.
Anti-inflammatory properties
Sulfonamides- topical agents
Sodium sulfacetamide (sulamyd)- use in opthalmic solution or ointment for tx of bacterial conjunctivitis. Also used to tx chlamydia trachoma infections SIlver sulfadiazine (Silvadene)- burn infection prophylaxis
Sulfonamide Pharmacokinetics
Well absorbed
Distributed throughout the body including CNS and fetus
Elimination is primarily renal
Sulfonamides Adverse Effects
NVD, HA, PHOTOSENSITIVITY
Up to 10% will have adverse rxn mixture of allergy and toxicity: rash, fever, blood dyscrasias (hemolytic anemia), many itis’s (nephritis, hepatitis, vasculitis), and crystalluria.
Trimethopim
Competitive inhibitor of dihydrofolic acid reductase (Second step of folic acid synthesis)
Similar spectrum of sulfonamides but more potent
Similar pharmacokinetics with improved penetration into the prostate
Adverse effects- GI, megaloblastic anemai, leukopenia, granulocytopenia
Used for community aquired UTI or prophylaxis of UTI.
Sulfamethoxazole/Trimethoprim (Bactrim or Septra)
Produces sequential blocking in the metabolic sequence leading to marked synergism. Combination is bactericidal
Same spectrum as the individual agents
Only available IV sulfonamide antibiotic.
Sulfamethoxazole/Trimethoprim- Clinical uses
Alternative agent for CAP, UTI and prostatitis, acute otitis media
Tx o pneumocystitis carinii, bacterial diarrhea
Prophylaxis of UTI, PCP and taxoplasma gondii in AIDS pts, and peritonitis prevention in patients with cirrhosis.
Drugs that alter nucleic acid processing
Inhibit DNA processing
Quinolones, rafampin, and nirtrofurantoin
Qoinolones- MOA
Block bacterial DNA synthesis by inhibiting DNA topoisomerase IV and topoisomerase II.
Quinolones- Spectrum of Activity
Primary target differs according to organism-
Topo II primary, Topo IV secondary- E.coli
Topo IV primary, Topo II secondary- staphylococci and streptococci
Active against Gram (+) and gram (-) bacteria, Activity against topo IV accounts for gram (+) spectrum
Quinolone “classes”
Excellent gram negative coverage with only moderate gram (+) activity (Ciprofloxacin) Excellent gram (-) coverage with improved gram (+) coverage Continues gram (-) and (+) coverage with enhanced anaerobic coverage (Trovafloxacin)
Quinolone Spectrum of Activity 2
Atypical pneumonia organisms (Chlamydia pneumoniae and mycoplasma pneumoniae) Intracellular pathogens (Legionella, mycobacteria tuberculosis, and mycobacteria avium complex)
Quinolone Clinical Uses
UTI, sinusitis, mycobacterial infections, bacterial diarrhea, soft tissue, bone, and joint infections, gonoccocal and chlamydial infections, pneumonia, post exposure prophylaxis for anthrax, tx inhalation antrhax infection
Trovafloxacin FDA restricted to life-or limb threatening infections due to severe hepatic toxicity.
Fluoroquinolone resistance
Due to one or more point mutations in bacterial chromonsomes, high levels usually confers resistance to all quinolones.
SHould not be used for routine URI or LRI or skin/soft tissue infections
Quinolones pharmacokinetics
Well absorbed (oral is decreased by divalent and trivalent cations)
Widley distributed including prostate
Excretion is renal, non renal, bile, and urine depending on the drug
Quinolone Adverse Effects
Mostly- N/V/D
Secondary- HA, dizziness, insomnia
Rarely- seizures, blood dyscrasias, and peripheral neuropathy that is irriversible.
May damage growing cartilage, tendinitis and rupture in elderly, renal failure with glucocorticoid use
Quinolone Drug interactions
Interactions if taken at the same time as antacids, sucralfate, iron, and multivitamins
CYP interactions most common with ciprofloxacin
Quinolone- Moxifloxacin (avelox)
Oral or IV
Broad spectrum single dose daily
Targets DNA gyrase instead of topo IV in gram (+)
Quinolone- Gemifloxacin (factive)
Approved to treat mild-moderate CAP due to multi-drug resistant Streptococcus pneumoniae.
Metronidazole (Flagyl) MOA
Bacteriacidal
Metabolized to an intermediate that inhibits bacterial DNA synthesis and decreases existing DNA
Selectivity due to its toxic metabolite that is not produced in mammalian cells
ROA- oral, IV, topical
Metronidazole (Flagyl)- spectrum of activity and pharmacokinetics
Anaerobic and protozoan infections- amebiasis, trichomoniasis, skin infections, CNS infections, inra-abdominal infections, systematic anaerobic infections, tx C. diff, bacterial vaginosis, H. pylori and acne rosacea
Pharmacokinetics- absorption- 80% food delays and excreted in urine
Metronidazole (flagyl)- contracindications/cautions and drug interactiosn
Hx of blood dyscrasias, alcoholism, hepatic dz, CNS disorders, visual changes, 1st trimester of pregnancy
Drug interactions- warfarin, cimetidine, lithium toxicity, ETOH
Metronidazole (flagyl)- ADRs
Vertigo, HA, confusion, seizures (w/ previous condition) Edema N/V/D, abd cramping, constipation Darkened urine, polyuria, dysuria Transient leukopenia, neutropenia Extreme reaction when combines with ETOH
Nitrofurantoin (Macrodantin, Macrobid)- MOA, spectrum of activity, and ROA
MOA- poorly defined reactive form damages DNA nd interferes with RNA synthesis and DNA replication
Spectrum- Gram (+) and (-)
ROA- oral and reaches highest [] in the urine
TX UTI
Nitrofurantoin (marcodantin, macrobid)- ADRs
Gi- N/V Interstitial pulmnary fibrosis with chronic use Hemolysis in pt with G6PD deficiency Aggranulocytosis, thrombocytopenia Peripheral neuropathies, HA, Dizziness, Significant skin reactions w/ allergies.
Polymyxin B- MOA
Bactericidal
Interact w/ phospholipis on the outer plasma cell membrane of gram (-) bacteria disrupting their structure
Disruption destroys bacteria’s osmotic battier leading to lysis
Resistance is low
Polymyxin B- spectrum and ROA
Gram (-) bacteria (pseudomonas aeruginosa)
ROA- high nephro- and neuro- toxicity limits to topical application
IV, IM, intrathecal admin in hospitalized pts w/ serious infections
Topical= gut sterilization, bladder, irrigation, and ophthalmic.
Daptomycin (Cubicin)
Used for multi-drug resistant gram (+) bacteria
Bactericidal disruption of plasma membrane
Once daily dosing
ADRs- reversible myopathy, GI
Isoniazid (INH)- MOA
Inhibition of cell wall synthesis by inhibiting acid synthesis
Bacteriostatic for stationary phase and bactericidal for rapid dividing phase
Penetrates host cell and drug retained within hose cell longer
Metabolized by N-acetylation and hydrolysis
Isoniazid (INH)- Resistance and Adverse effects
No cross resistance to other TB drugs
AE- peripheral neuritis- pyroxidine deficiency
Inhibits phenytoin metabolism and may produce convulsions in seizure prone patients
Hepatitis/hepatotoxicity- most severe and increased with rifampin and daily ETOH
Isoniazid (INH)- Black box Warning
Sever and sometimes fatal hepatitis associated with isoniazid therapy may occur & may develop even after many months of tx
Rifamycins- Mechanism
Blocks transcription by interacting w. the beta subunit of bacterial DNA-dependent RNA polymerase.
Antimicrobial spectrum- Broader spectrum vs INH
Rifamycins- Spectrum of activity
Bactericidal against gram (+) and (-) organisms: used prophylactically in individuals exposed to meningitis.
Rifabutin, analog of rigampin, active against mycobacterium gyium complex, but less active for TB
Rifamycin- pharmacokinetics
Oral admin, distribution all body fluids and organs
Induces hepatic mixed-function oxidases increasing its own metabolism and other drugs
Eliminated via feces and urine which may have an orange-red color.
Adverse effects- nausea and vomiting.
Pyrazinamide- MOA
Bactericidal
Enters M. tuberculosis by passive diffusion, concerted to pyrazinoic acid by PZase
Inhibits fatty acid synthase I
Accumulates within acidic environment of macrophages monocytes and kills tubercle bacill.
Pyrazinamide- Adverse Effects
Liver injury (15%) with jaundice (2-3%), rarely fatal Get liver function test, do not use if problems
Ethambutol
Bacteriostatic
Inhibits cell wall synthesis by inhibiting synthesis of polysaccharides and transfer of mycolic acids to the cell wall.
Helps prevent emergence of RIF resistant organisms
Ethambutol- Adverse reactions
Optic neuritis
Results in diminished visual acuity and loss of red/green discrimination
Decreases urate excretion= gout if predisposed.
Isoniazid (INH)- MOA
Inhibition of cell wall synthesis by inhibiting acid synthesis
Bacteriostatic for stationary phase and bactericidal for rapid dividing phase
Penetrates host cell and drug retained within hose cell longer
Metabolized by N-acetylation and hydrolysis
Isoniazid (INH)- Resistance and Adverse effects
No cross resistance to other TB drugs
AE- peripheral neuritis- pyroxidine deficiency
Inhibits phenytoin metabolism and may produce convulsions in seizure prone patients
Hepatitis/hepatotoxicity- most severe and increased with rifampin and daily ETOH
Isoniazid (INH)- Black box Warning
Sever and sometimes fatal hepatitis associated with isoniazid therapy may occur & may develop even after many months of tx
Rifamycins- Mechanism
Blocks transcription by interacting w. the beta subunit of bacterial DNA-dependent RNA polymerase.
Antimicrobial spectrum- Broader spectrum vs INH
Rifamycins- Spectrum of activity
Bactericidal against gram (+) and (-) organisms: used prophylactically in individuals exposed to meningitis.
Rifabutin, analog of rigampin, active against mycobacterium gyium complex, but less active for TB
Rifamycin- pharmacokinetics
Oral admin, distribution all body fluids and organs
Induces hepatic mixed-function oxidases increasing its own metabolism and other drugs
Eliminated via feces and urine which may have an orange-red color.
Adverse effects- nausea and vomiting.
Pyrazinamide- MOA
Bactericidal
Enters M. tuberculosis by passive diffusion, concerted to pyrazinoic acid by PZase
Inhibits fatty acid synthase I
Accumulates within acidic environment of macrophages monocytes and kills tubercle bacill.
Pyrazinamide- Adverse Effects
Liver injury (15%) with jaundice (2-3%), rarely fatal Get liver function test, do not use if problems
Ethambutol
Bacteriostatic
Inhibits cell wall synthesis by inhibiting synthesis of polysaccharides and transfer of mycolic acids to the cell wall.
Helps prevent emergence of RIF resistant organisms
Ethambutol- Adverse reactions
Optic neuritis
Results in diminished visual acuity and loss of red/green discrimination
Decreases urate excretion= gout if predisposed.
Inhibitors of viral attachment, uncoating or release
Pleconaril Docosanol Amantadine Rimantadine Osteltamivir Zanamivir
Amantadine and Rimatadine- Inhibitors of Viral Attachment
Bind viral protein M2 and inhibit viral uncoating
Used to tx and prophylaxis of influenza type A, no effect on type B-lack M2
Large volume distribution
Amatadine-90% excreted unchanged in urine (used in parkinson’s disease)
Rimantadine- metabilized by the liver
Neuraminidase Inhibitors- Oseltamivir and Zanamivir
Selective inhibitors of viral neuraminidases which are essential for release of virus from the infected cell.
Tx of influenza A and B, duration 5 days
Prophylaxis before or after exposure to influenza A or B
Oseitamivir- oral
Zanamivir- intranasal or inhalation of dry powder
Inhibit attachment- Pleconaril
Prevents attachment of the virus and viral uncoating within the human cell
Effective against picornavirus- not FDA approved
Non-specific inhibition of RNA and protein synthesis- Interferons
Immunomodulatory and antiviral
Dose limiting toxicities include- neutropenia and anemia, flu like sx, fever, fatigue, and myalgia
Interferons mainly act to prevent translation of viral proteins.
Drugs that block DNA synthesis from Viral DNA
Active against herpes family of viruses
Guanosine analogs- acyclovir, valacyclovir, penciclovir, famiciclovir, ganciclovir
Adenosine analog- vidarabine
Cytosine analog- cidfovir
Acyclovir and Valacyclovir (oral prodrug of acyclovir)
Tx and prophylaxix prevention of herpes simplex (type I and II), and zoster
Varicella zoster- treatment
Drugs that block DNA synthesis from viral DNA- penciclovir and Famciclovir (oral prodrug of penciclovir)
Used to tx herpes zoster, herpes simplex Type II, topical tx of oral/labial herpes simplex virus
Drugs that block DNA synthesis from viral DNA- acyclovir and penciclovir
Pregnancy category B
Drugs that block DNA synthesis from viral DNA- Ganciclovir and Valganciclovir (oral prodrug)
Active against all herpes virus
Tx of CMV in immunocompromised patients
Neutropenia, thrombocytopenia, teratogenic- catergory C
Vitasert- an intraocular sustained release implant for CMV retinitis.
Drugs that block DNA synthesis from viral DNA- vidarabine
Broad spectrum antiviral activity- herpes, pox viruses, rhabdoviruses, hepadenaviruses, some RNA tumor viruses
Primary use- keratitis, keratoconjunctivitis, life threatening herpes simplex virus, varicella zoster infections
Drugs that block DNA synthesis from viral DNA- cidofovir
Broad spectrum antiviral activity- herpes and pox viruses, adenoviruses, papilloma viruses, and hepadenavirus
Primary use for tx of cytomegalovirus in AIDS pts who are intolerant, relapsed, or nonresponsive to ganciclovir or foscarnet
Neutropenia and nephrotoxicty
Drugs that block DNA synthesis from viral DNA- Foscarnet
Does not require phosphorylation- broad spectrum
Active against all herpes viruses, influenza, and HIV
Primary uses- CMV (cytomegalvirus) infections, acyclovir, resistant herpes simplex or varicella zoster
Nephrotoxicty
Drugs that block DNA synthesis from viral DNA- Ribarvirin
Purine nucledoside analog
Ribavirin aerosol treatment of RSV
Ribavirin plus pegiterferon- Hep C
Non-specific inhibition of RNA and protein synthesis- Interferons
Immunomodulatory and antiviral
Dose limiting toxicities include- neutropenia and anemia, flu like sx, fever, fatigue, and myalgia
Interferons mainly act to prevent translation of viral proteins.
Antifungal Drugs
Polyene antibiotics Imidazole antifungals Triazole antifungals Other antifungal agents Tx can last weeks to months and is more effective on the skin than the nails.
Amphortericin B
Polyene ABX
Naturally occuring polyene macrolide antibiotic produced by streptomyces nodosus
MOA- Bind to ergosterol in the fungal cell membrane and form pore-> leak “-cidal”
Selective toxicity
Resistance- infrequent due to decreased ergosterols in membrane
Nystatin
Polyene ABX
MOA- Bind to ergosterol in the fungal cell membrane and form pore-> leak “-cidal”
Selective toxicity
Active transport mechanism
Amphortericin- pharmacokinetics
ROA- IV
Liposomal preps less renal and infusion toxicity
Amphortericin indications and ADRS
Broad specturm anti-fungal used in potentially fatal systemic infections
-Candida albicans, histoplamsa capsulatum, cyrptococcus neoformans, coccidoices immites, blastomyces dermatitides, aspergillis
ADRs- HYPOTENSiON, anemia, nephrotoxocity, thrombophlebitis, fever/chills, allergic reactions
Nystatin-pharmacokinetics
Topically as a cream
Vaginal troches
Suspension deliver drugs to oral mucosa
Nystatin- indications and ADRS
Used to supress candidiasis on the sin and mucous membranes (oral&vaginal)
ADRs- N/V/D
Flucytosine (Ancobon)
Polyene ABX
MOA- inhibits synthesis of fungal pyrimidines
ROA- PO
Indications- in combination w/ amphoB to treat systemic candiasis and cryptococcuss meningitis
ADRs- N/V/D, rare hepatotoxicity and seen more often is thrombocytopenia, neutropenia, bone marrow suppression
Griseofulvin (Fulvicin)
Polyene ABX
MOA- binds to fungal microtubules disrupting mitotic spindles “-static”
Indications- DOC in kinds for wide spread dermatophyte or intractable dermatophyte infection where topical agents have failed. No longer for dermatophyte infection of nails
ADRs- fever, HA, mental confusion, rashes, GI disturbances.
Griseofulvin (Fulvicin)- drug interactions
P450 inducer- barbiturates, OCP, warfarin
High fat meals increase absorption
Potentiates intoxicating effects of ETOH
Ketoconazole (nizoral)- MOA
Azoles Imidazoles
MOA- broad spectrum: histoplasma, blastomyces, candida, coccidioides, NO ASPERGILLUS
Predominately fungistatic but can be -cidal depending on dose
Inhbits C-14-alpha-demethylase (P450 enzyme) disruptong the membrane
Also inhibits human steroid synthesis leading to decreased testosterone and cortisol production.
Ketoconazole (nizarol)- Pharmacokinetics and ADR
PO-requires gastric acid for dissolution
Penetration into tissues limites, effective in tx of histoplasmosis in lung, bone, skin, soft tissue
Doesn’t enter CNS
ADRs- N/V, anorexia, endocrine effects such as gynecomastia, impotence, irreg menses, teratogenic due to endocrine effects
Ketoconazole (nizarol)- Drug interactions and resistance
P450 INHIBITOR
Resistance- mutation of p450 enzyme leasts to decreased azole binding
Ability to pump azole out of the cell.
Azoles Imidazoles
Clotrimazole (Lortimin, mycelex)
Miconazole (Monostat, desenex)
Terconazole (terazol)
Butoconazole (Femstat3)
Topical only; severe toxicity when used IV
MOA and spectrum same as ketoconazole
Topical use w/ contact dermititis, vulvar irritation, edema
TOPICAL MICONAZOLE IS A POTENT INHIBITOR OF WARFARIN METABOLISM
Fluconazole (diflucan)- MOA
Azoles Triazoles
Inhibits synthesis of fungal membrane ergosterol
Lacks endocrine side effects
Penetrates CSF of normal and inflammed meninges
Fluconozole (diflucan)- uses, ROA and ADRs
DOC- cryptococcuss neoformans, candidemia and coccidioidomycosis, effective against all forms of mucocutaneous candidiasis; used prophylactically in immunocompromised pts
ROA- Oral or IV
ADRs- N/V and rash
Fluconazole (diflucan)- drug interactions
Moderate inhibitor of CYP3A4 (cyclosporin, lovastatin) and strong inhibitor of CYP2C9
Tetratogenic
Itraconazole (Sporanox)
Azoles triazoles
MOA- inhibits synthesis of fungal membrane ergosterol lacks endocrine side effects; -static
DOC- blastomycosis, aspergillis, sporotrichosis, paracoccidiodomycosis, histoplasmosis
Itraconazole (sporanoz)- pharmacokinetics and ADRs
PO- requires acid for dissolution
Extensively protein bound and distributes throughout most tissues including bone and adipose, but not CSF
Biologically an active metabolite
P450 INHIBITOR
Avoid in pregnancy
ADRs- N/V, rash, hypokalemia, HTN, edema, HA
Itraconazole (sporanox)- contraindications
Strong inhibitor and substrate of CYP34A, contraindicated w/ lovastatin, simvastatin, midazolam, triazolam. May decrease OCP effectiveness, and increased digoxin levels
Voriconazole (vfend)
Azole triazoles
PO or IV
Invasive aspergillosis and serious infections caused by scedosproium apiospermum and fusarium species
Penetrates tissues and CSF
ADRs- similar to other azoles; transient visual disturbance occurring shortly after dose
Voriconazole (vfend)- Contraindictations
Inhibitor of CYP2C18, 2C9, 3A4. Contraindicated in patients taking rifampin, phenobarital, carbamasepine. Dose adjustments may be required w/ statins, benzodiazepines, and warfarin
Posaconazole
Azole triazoles (new antigungal)
Only available as oral suspension and must be taken with high fat meal for adequate absorption
Spectrum similar to itraconazole, w/ additional effect on Zygomycetes such as mucor
More effective than other azoles in treating fungal infections in immunosuppressed patients (myelogenous leukemia, stem cell transplantation, refractory esophageal candidiasis)
Inhibits CYP3A4
Terbinafine (Lamisil)
Allylamines
MOA- prevents ergosterol synthesis by inhibiting the enzyme squalene oxidase; -cidal
PK- lipophillic- penetrates superficial tissues including the nails
Administered orally- fingernail and toenail regimens differ, 40% bioavailability due to 1st pass metabolism, therapy is 3 months.
Terbinafine (lamisil)- indications and ADRS
Active against dermatophytes and candida albicans
ADR- mild- HA, N/Dm rash, taste and visual disturbance
Rare but serious effects- cholestatic jaundice, blood dyscrasias, steven-johnson syndrome
Baseline LFTs and CBC (repeat q 4-6wks)
Onychomycosis (nail infection) treatments
Terbinafine- 1st line agent (not candida)
Itraconazole- alternative 1st line therapy (preferred for candida infections)
These drugs have REPLACED grseofulvin and ketoconazole for this type of infection
Caspofungin (Cancidas)
Echinocandins
2nd line therapy for those who failed amphoB or itraconazole (expensive)
Interferes w/ synthesis of fungal wall
Limited to aspergillus and candida species
ADRs- fever, rash, nausea, phlebitis, and flushing rxn.
Micafungin (Mycamine)
Echinocandins
Esophageal candidas
Prophylaxis of invasive candida infections in pts undergoing hematopietic stem cell transplantation
ADRs- fever, rash, nausea, phlebitis, and flushing rxn.
