Clinical Pharmacology of Antivirals, Antifungals, and Antibiotics Flashcards
Macrolides (Azithromycin)
ADME, Side Effects
Administered orally; food delays absorption
Diffuses into all fluids except CSF. Can cross placenta and enter fetal circulation; also enters breast milk
Excreted by kidney and liver
Large doeses cause epigastric distress. Inhibit CYPs and can have drug-drug interactions
Elevates QT interval and is associated with cardiovascular disease !!
Sulfonamides
Use, ADME, Side Effects
Highly concentrated in urine, good for treating UTI’s
May precipitate in acidic urine
Can cause acute hemolytic anemia in those with G6P Dehydrogenase Deficiency
Commonly cause rashes, ulceration on mucous membranes, and serum sickness
TOXIC EPIDERMAL NECROLYSIS - similar to Scarlet Skin Syndrome (Staph); skin loses glue that holds epidermis together and looks like second degree burn
CAN CAUSE ENCEPHALOPATHY AND BILIRUBIN DEPOSITS IN BRAIN OF FETUSES AND INFANTS - ABSOLUTE CONTRAINDICATION
Clindamycin
ADME, Side Effects
Can be given orally, parentally, or topically
Does not get into CSF, but crosses placenta
Accumulates in Neutrophils, Macrophages, and Pus - good for treating Staph and Strep
Excreted by liver and kidneys
Causes C. diff colitis and skin rash. Can lead to toxic megacolon
Cidofovir
Use, Pharmacokinetics, Side effects, Interactions
Nucleotide analog that does not require phosphorylation - activity against Herpes, Papilloma, Polyoma, Pox, and Adenovirus
IV formulation treats CMV Retinitis and Acyclovir-resistant HSV infections
Does not penetrate CSF
HIGHLY NEPHROTOXIC - Co-Administer with Probenecid and Saline to limit toxicity
Enfuvirtide:
Administration, Side Effects, Interactions
HIV Fusion inhibitor
only HIV drug given parenterally, route of elimination not known
Can cause cysts and reactions at site of injection
No interactions
Which B-Lactam does not cross-react with Penicillin?
Aztreonam (a Monobactam)
Carbapenems: Imipenem
Use, ADME, Side Effects
Broad-Spectrum with activity against Pseudomonas
Imipenem must be co-administered with cilastatin to inhibit its secretion in urine
Excreted by kidneys
Cause Nausea and Vomiting
Can cross-react with penicillins
(Anti-mitotic) Griseofulvin:
Distribution, Side Effects, Drug Interactions
Absorbed through GI
Deposited in keratin precursor cells where it persists and provides prolonged fungal resistance
Is Teratogenic (embryo deformation) and causes Confusion
Is a CYP 450 Inducer that Increases Warfarin metabolism
Side Effects and Interactions of Polyenes
- High Nephrotoxicity - drug accumulates in kidney since it’s excreted in urine
- Restriction of renal blood flow and toxic to distal tubules
- Due to drug attacking cholesterol renal membranes at high concentrations
- Drug-Drug interactions with Cyclosporine and Aminoglycosides (concurrent nephrotoxicity)
Toxicity of Penicillin (other than Hypersensitivity)
- Pain at injection site (dose related)
- large doses given to renal failure patients can cause confusion, twitching, and seizures
- C. diff colitis
Tetracyclines
ADME, Side Effects
Given orally or parenterally
Divalent cations interfere with absorption (milk and antacids)
Wide distribution, including CSF
Minocycline is completely absorbed by stomach and excreted through bile
Causes nausea and vomiting. Hepatic toxicity in large doses. Renal Toxicity and Fanconi Syndrome if taking expired drug
COMMONLY CAUSES PHOTOSENSITIVITY AND GETS DEPOSITED IN BONES AND TEETH - contraindicated in Pregnant and Children
Administration of Polyenes
Amphotericin B comes in:
- Oral suspension
- 4 IV Lipid formulations (Lipid formulations reduce toxicity and side effects)
- Topical - Nystatin
- Opthalmic - Natamycin
Cross-Reactivity of Cephalosporins and Penicillins
6-10%
ADME of Polyenes
- Polyene = Amphotericin B
- Poor oral absorption - must be given IV
- Does not penetrate CSF, eye, or amniotic fluid
- Half life of 15 days
What drug needs to be co-administered with Cilistatin?
Imipenem
Cefazolin (First Gen)
What it’s good for, ADME
Good for susceptible Staph and Strep (surgery prophylaxis)
Given parentally (other 1st gens are given orally)
largely circulates bound to plasma proteins
excreted by kidneys
Adverse effects of Azoles
In general, they are well-tolerated
INHIBIT TESTOSTERONE SYNTHESIS (ketoconazole)
“Associated w/ endocrine dysfunction”
CYP Inducer
Rifampin
HIV Integrase Inhibitors:
Side effects, Interactions
Raltegravir
May cause Rhabdomylosis and Hypercholesterolemia
No interactions
Drugs to avoid during pregnancy and what they cause
“SAFe Children Take Really Good Care”
- Sulfonamides - Kernicterus (bilirubin deposition in brain)
- Aminoglycosides - Ototoxicity
- Fluoroquinolones - Cartilage damage
- Clarithromycin - Embryotoxic
- Tetracyclines - Discolored Teeth, Inhibited Bone Growth
- Ribavirin - Teratogenic
- Griseofulvin - Teratogenic
- Chloramphenicol - Gray Baby Syndrome
Cefoxitin (second generation)
what it’s good for, ADME
Good for RTI’s, intra-abdominal infections, pelvic inflammatory disease, and diabetic foot ulcers
Given Parentally (others in gen given orally)
excreted by kidneys
Ganciclovir:
Pharmacokinetics, Use, Side Effects, Interactions
Monophosphorylated by Phosphotransferase in CMV
Commonly causes Neutropenia, Thrombocytopenia, Leukopenia, and is more toxic to host enzymes than Acyclovir
Do not give during pregnancy
Co-administration with nephrotoxic agents increases nephrotoxicity
NNRTI’s
Side Effects and Interactions
- Non-competitive inhibitors of HIV Reverse Transcriptase*
- Efavirenz, Nevirapine, Delaviridine*
May cause Rash and Hepatotoxicity
May also cause CNS side effects such as depression, hallucination, and mania
Eliminated by CYPs, so may interact with other drugs metabolized by CYPs
Acyclovir and Valacyclovir:
Pharmacokinetics, Activity, Absorption, Distribution, Excretion
Monophosphorylated by Thymidine Kinase in HSV/VZV
Used to treat HSV-1 and HSV-2 to reduce pain and improve recovery times
Can also treat VZV if used within 24 hours of rash onset
No activity in CMV, poor for EBV
Low oral bioavailability, Prodrug rapidly converted to ACV by liver
Widely distributed, including CSF
Excreted via kidney
Aminoglycosides
Use, ADME, Side Effects
Parenteral Administration
Poor penetration - does not get inside cells, CSF, or Eye
No activity against anaerobes
Excreted by kidneys - Nephrotoxic
Accumulates in Perilymph and Endolymph of Inner ear - Causes Dizziness and Ototoxicity
Can cause Neuromuscular Blockade - Contraindicated in Myasthenia Gravis
Which Penicillins are Oral vs IV?
Oral: Penicillin V, Amoxicillin
IV: Penicillin G, Ampicillin, Nafcillin, Piperacillin-Tazobactam
Flucytosine:
Distribution, Side Effects, Interactions
Well absorbed through GI tract - Concentrates in CSF
May cause Bone Marrow Suppression
No drug interactions
What determines what antibiotic to use?
Can the concentration of that antibiotic reach the minimum inhibitory concentration at the site of infection?
Echinocandins:
Administration, Side Effects, Interactions
IV formulations only
May cause GI upset and flushing due to histamine
Cyclosporine increases levels of caspofungin by 35%
Type II Penicilin Allergy
Penicillin acts as a Hapten and binds to Erythrocytes
This makes them antigenic, and it can result in lysis via complement or phagocytosis of RBC’s
Metronidazole:
Side Effects
DO NOT MIX WITH ALCOHOL
Causes nausea, vomiting, skin flushing, tachycardia, and dyspnea
Can also cause metallic taste (dysgeusia) and black urine
Rifamycin
Side effects
Colors urine, saliva, and tears orange-red
Flu-like illness
CYP Inducer; decreases half life of HIV drugs, contraceptives, and corticosteroids
Allylamines: Side Effects and Interactions
(terbinafine)
Can lead to taste disturbances and hepatotoxicity
Metabolized by Liver
Rifampin decreases plasma concentrations (CYP inducer)
Cimetidine increases plasma concentratoins (increases stomach pH)
Cefepime (4th gen)
Use, ADME
More resistant to Beta-Lactamases than Third Generation
Exellent CSF penetration
Given parentally
Cleared by kidneys
Ethambutol
Side Effects
Dose dependent visual problems
Red-Green Color Blindness
Pyrazinamide
Side Effects
Can cause hepatotoxicity, hyperuricemia, and gout
Vancomycin:
Use, ADME, Side Effects
Use for MRSA, C. Diff, or for G+’s in Penicillin-allergic
Given IV over an hour
Secreted by kidneys
If infused too rapidly it can cause Red Man Syndrome - facial and neck flushing due to histamine release
Isonazid
Side effects
Penetrates into granulomas
Causes Rash and fever
Imidazoles vs Triazoles
Imidazoles are an older class of Azole
Triazoles are metabolized more slowly and have less effect on human sterol synthesis
Ceftriaxone
What it’s good for, ADME
Broad-Spectrum; good for serious infections like Bacterial Meningitis, Lyme Disease, and G- Sepsis
Not active against Listeria and Strep Pneumo
Given Parentally
Good penetration in body tissues and fluids
Excreted through bile
Acyclovir Resistance
How it happens, What to use instead
Lack of Thymidine Kinase (usually)
In this case, give drug that doesn’t require phosphorylation such as Cidofovir
Fluoroquinolones (Ciprofloxacin)
ADME and Side Effects
Orally administered - divalent cations interfere with absorption (milk and antacids)
Gets inside cells
Cleared by kidneys and is excreted in breast milk
Causes nausea, vomiting, and abdominal discomfort
Can cause C. diff colitis
Causes headache and dizziness
Tendonopathy in adults and arthropy in children
aDME of Penicillins
Widely distributed in tissues and secreations, EXCEPT: CNS, prostatic fluid, and eye
Does not kill intracellular pathogens
Rapid elimination through kidney (other compounds added to slow secretion)
secreted in breast milk
Maraviroc:
Side Effects, Drug Interactions
HIV Entry Inhibitor by preventing gp120 from binding CCR5
Can cause allergic reactions and hepatotoxicity
INHIBITOR OF CYP 450
NRTI’s
Pharmacokinetics, Side Effects, Interactions
The active triphosphates have 4x the half-lives of the parent compound - may accumulate in tissues to toxic levels
Cause skeletal muscle myopathy due to depletion of mitochondrial DNA
Also cause Bone Marrow Suppression, Hypersensitivity, Peripheral Neuropathy, Lactic Acidosis
Interacts with Stavudine and Zidovudine
CYP Inhibitors
Erythromycin, Clarithromycin, and Ketoconazole
Empiric Therapy vs Specific Therapy
Emperic Therapy - use of broad-spectrum drug
Specific Therapy - use of narrower drug to target organism
Acyclovir and Valacyclovir:
Side Effects and Interactions
Dose-limiting renal toxicity
Interacts with Zidovudine (antiretroviral) and Cyclosporine (nephrotoxic)
Foscarnet
Use, Mechanism, Side Effects, Interactions
Inhibits Viral DNA Polymerase but is not a nucleoside analog
Used to treat CMV Retinitis and Acyclovir resistant HSV
Causes Nephrotoxicity and Hypocalcemia
IV Pentamidine (anti-protozoal) increases hypocalcemia
Aztreonam:
Use
Only works against G-, incuding Pseudomonas
Useful in patients with Penicillin allergy because it has no cross-reactivity
Drug interactions of Azoles
INHIBITORS OF CYP 450 ENZYMES
Absorb better at low pH - don’t take with antacids
Can ketalate to metal cations in vitamins and slow absorption
Drugs that induce CYPs will significantly reduce serum concentratoins of Azoles
Penciclovir
Mechanism of Action and Use
Phosphorylated by TK in HSV and VZV, similar to Acyclovir
The major difference is that Penciclovir is less potent but the half life is 4x greater
Used to treat Shingles (HZV)
HIV Protease Inhibitors:
Side Effects and Interactions
Commonly cause nausea, diarrhea, and vomiting. Can cause fatal hepatotoxicity.
Can cause crystalluria from poor drug solubility, along with nephropathy and hematuria
Metabolized by CYP3A4 and may interact with other drugs metabolized by CYPs
Toxic Epidermal Necrolysis
Rare side effect of Sulfa drugs
Looks like Scarlet Skin Syndrome caused by Staph
Layers of Epidermis become “unglued” and injury appears like a second degree burn
