PK Flashcards
Absorption
How drugs (and to what extent) enter the body
Usually used to refer to the uptake of orally administered drugs into the bloodstream
Bioavailability- percent of non-IV drug that enters the bloodstream relative to the IV form
Several antibiotics have very good bioavailability but oral doses are substantially lower than IV doses (usually because high oral doses lead to excess GI toxicity)
Three factors can affect absorption
Food
Gastric acidity
Cheating agents
Small group of drugs highly dependent on gastric acidity for adequate absorption; avoid concomitant drugs that raise gastric pH
Tetracyclines and FQ can bind to coadministered minerals in the gut (calcium, iron, aluminum, zinc)
Drugs with High Bioavailability and Similar IV-PO doses (95-100%) Metronidazole Levofloxacin Linezolid Fluconazole Doxycycline Ciprofloxacin (~80%)
Drugs with High Bioavailability but Different IV-PO doses (~90%)
Aminopenicillins
1G Cephalosporins
Drugs with Low Bioavailability and Different IV-PO doses
Cefuroxime (~40%)
Acyclovir (~25%)
Absorption Improved with Food
Posaconazole suspension Itraconazole capsules Atazanavir Darunavir Rilpivirine
Absorption Impaired with Food
Voriconazole Itraconazole solution Rifampin Isoniazid Pyrazinamide
Absorption Impaired Drugs that Raise Gastric pH
Itraconazole
Posaconazole suspension
Atazanavir
Rilpivirine
Distribution
Where drugs go once they are inside the body; moves into various tissues
Can be greater, lower, or equal concentration to that of in the blood
Macrolides concentrate in pulmonary macrophages
Data on drug distribution often extrapolated from animal models
Extent of distribution into different tissues largely determined by physicochemical properties of the drug (lipophilicity, charge, molecular size)
A key determinant is degree to which an antibiotic binds to proteins in the bloodstream, most importantly albumin (fraction bound/unbound)
Drug bound to proteins not able to diffuse across membranes into different tissues (highly protein bound drug may fail to reach CNS)
Concentration-time curves in many tissues are different than in the bloodstream
Must be adequate blood flow to a tissue for distribution
Conditions that reduce blood flow to tissues locally (PVD) or systemically (septic shock) can reduce concentrations at the site of infection
Patients with severe infections can develop abscesses/dead and devitalized tissue- surgical management along with antibiotics sometimes necessary
Obesity-extent to which drugs distribute into adipose tissue
Underdose- if drug distributes extensively into adipose tissue but standard weight dose is used
Overdose- higher dose used but drug does not distribute well into excess adipose tissue
Dosing recommendations:
Total/actual body weight
Ideal body weight (estimate of patient’s body weight without their excess adipose tissue)
Adjusted body weight- value in between
Susceptibility testing usually does not account for distribution and based on bloodstream concentrations
Metabolism/Excretion
How drugs get out of the body
Many antibiotics excreted in the same form as administered
Drug that is excreted unchanged can reach very high concentrations where it is excreted
Need to reduce the dose of most beta lactams in kidney dysfunction to avoid accumulation of toxic levels of the drug; need to increase dose in improving renal function
Other drugs undergo extensive metabolism and are substrates of drug metabolizing enzymes- may be subject to drug interactions
Induction- increase in metabolism of other drugs
Inhibition- decrease in metabolism of other drugs
Most common classes involved in drug interactions: macrolides, azoles, anti-TB, antiretrovirals
Substrates
Erythromycin Clarithromycin Telithromycin Atazanavir Darunavir Efavirenz Elvitegravir Maraviroc Rilpivirine
Inhibitors
T/S Metronidazole Fluconazole Voriconazole Itraconazole Posaconazole Erythromycin Clarithromycin Telithromycin Ritonavir Cobicistat Etravirine
Inducers
Rifampin Rifabutin Efavirenz Nevirapine Etravirine
