Rational Antimicrobials 3 Flashcards
Key parameters governing drug disposition (PK)
- Volume of distribution
- Clearance
- Elimination half-life (t1⁄2)
what order process is movement of drug molecules, usually? what does this mean?
Movement of drug molecules is usually a first order process
> ie. constant proportion (%) and not amount
Most important PK parameter
CLEARANCE (mL/min/kg)
what is drug clearance? what is this parameter used for?
- Most important PK parameter; efficiency of plasma drug elimination
- Total systemic clearance; elimination of drug from all organs
- Expressed as complete removal of drug from the plasma per unit time per unit body weight…ie mL/min/kg
- Clearance used clinically to calculate dosing rate and maintenance doses to maintain target drug conc (TC)
Dosing rate =
CL*TC
= clearance * target drug concentration
what is volume of distribution? what does it tell us?
Vd relates the amount of drug in the body to the concentration of drug in the blood
- Vd is a proportionality constant
- Vd does not refer to an identifiable physical volume or anatomical compartment eg. intracellular fluid space
= theoretical volume that would be necessary to contain the total amount of an administered drug at the same concentration that it is observed in the blood plasma.
what would we expect about the Vd of a water solible drug and why?
- Water soluble drugs tend to remain in ECF
- have small to intermediate Vd values
- includes plasma space (~7% of total body water)
- includes interstitial fluid (~20% total body water)
- not entering intracellular fluids (~30-40% total body water)
what type of drugs have high Vd values?
- lipid soluble drugs
- drugs that bind extensively to tissue sites outside the plasma space
what is Vd useful for calculating?
Useful as a PK parameter for calculating loading dose of a drug needed to achieve a specific plasma drug level eg. KBr, digoxin
Loading dose = Vd x TC
what is a drugs elimination half life? what does it depend on?
- Half-life is the time required to change the amount of drug in the body by one half due to elimination
> Half life (t1⁄2) is a hybrid PK constant; dependent on Vd and CL
> Plasma clearance expresses only the ability of the body to eliminate drugs
> t1⁄2 expresses the overall rate of the actual drug elimination process
what is half life useful to calculate?
- Useful as a PK parameter for…….calculation of dosing interval
- Prediction of drug accumulation following dosing
> Short t1⁄2…………….little drug accumulation
> Determining time to steady-state (drug input equals drug elimination
> Generally takes ~3-5 half-lives
how many half-lives are generally needed to reach steady state?
Generally takes ~3-5 half-lives
Concentration-dependent antibacterials examples
aminoglycosides
fluoroquinolones
metronidazole
Time-dependent antibacterials examples
bacteriostatic drugs
beta lactams
concentration-dependent antibacterial require what for effeicacy?
- adequate inhibitory quotient for efficacy
> 8-10 X (Cmax/MIC)
> 125-250 X (AUC0-24/MIC)
post-antibiotic effects
time-dependent antibacterial require what for effeicacy?
- > 50% of dosing interval above MIC for efficacy
- 80-100% of dosing interval to minimize resistance
Why are drugs given in differing dosage forms?
- Ease of administration > compliance
- Controlled rate of drug delivery
- Husbandry constraints
what does dosage form influence?
- Dosage form has greatest influence on the rate and extent of drug absorption
- affects action of drug: onset, duration and intensity
how does formulation of a drug affect PK?
- Following administration, drug is released from it’s dosage form > molecules enter solution
Dissociation into free acid or base is…….
- rapid if drug is formulated as a salt
> potassium, sodium, hydrochloride
- slower if drug formulated as a depot or extended release product
> acetate, trihydrate, liposomes, biodegradable gels
what affects the route of admin chosen?
Formulations available will affect route choice
- not all antibacterials available by all routes
- enteral vs parenteral: advantages/disadvantages
- owner compliance is important !!
what must we be cautios of with generic drugs?
Bioequivalence proven for generic against proprietary drug formulation
issues with transdermal preparations?
- few veterinary approved transdermals available
- Compounded transdermals appear attractive, but are not recommended without supportive PK data
Duration of therapy considerations; lenth of treatment depends on?
Length of treatment depends on location and nature (chronicity) of infection
§ more chronic or more inaccessible—longer duration
§ “treating awaiting healing”; not usually a function of how long to kill bacteria, rather how long to return infection site to normal with restored local immunity
how long do acute infections generally take to treat? considerations?
Acute infections: 7-10 days
§ some exceptions; simple UTI is 3-5 days
§ neutropenic or immunocompromised; 10-14 days
§ 2-3 days past resolution of acute infection
how long should we treat pyrexia for?
§ until afebrile for 4-5 days
how long should we treat chornic and serious infections for?
Chronic and serious infections: 4-6 weeks
§ eg. deep pyoderma, pyelonephritis, pneumonia
§ 7-10 days past resolution of clinical signs of infection
