Rational Antimicrobials 3

Question 1

Key parameters governing drug disposition (PK)

Answer 1

• Volume of distribution
• Clearance
• Elimination half-life (t1⁄2)

Question 2

what order process is movement of drug molecules, usually? what does this mean?

Answer 2

Movement of drug molecules is usually a first order process
> ie. constant proportion (%) and not amount

Question 3

Most important PK parameter

Answer 3

CLEARANCE (mL/min/kg)

Question 4

what is drug clearance? what is this parameter used for?

Answer 4

• 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)

Question 5

Dosing rate =

Answer 5

CL*TC
= clearance * target drug concentration

Question 6

what is volume of distribution? what does it tell us?

Answer 6

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.

Question 7

what would we expect about the Vd of a water solible drug and why?

Answer 7

• 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)

Question 8

what type of drugs have high Vd values?

Answer 8

• lipid soluble drugs
• drugs that bind extensively to tissue sites outside the plasma space

Question 9

what is Vd useful for calculating?

Answer 9

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

Question 10

what is a drugs elimination half life? what does it depend on?

Answer 10

• 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

Question 11

what is half life useful to calculate?

Answer 11

• 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

Question 12

how many half-lives are generally needed to reach steady state?

Answer 12

Generally takes ~3-5 half-lives

Question 13

Concentration-dependent antibacterials examples

Answer 13

aminoglycosides
fluoroquinolones
metronidazole

Question 14

Time-dependent antibacterials examples

Answer 14

bacteriostatic drugs
beta lactams

Question 15

concentration-dependent antibacterial require what for effeicacy?

Answer 15

• adequate inhibitory quotient for efficacy
  > 8-10 X (Cmax/MIC)
  > 125-250 X (AUC0-24/MIC)

post-antibiotic effects

Question 16

time-dependent antibacterial require what for effeicacy?

Answer 16

• > 50% of dosing interval above MIC for efficacy
• 80-100% of dosing interval to minimize resistance

Question 17

Why are drugs given in differing dosage forms?

Answer 17

• Ease of administration > compliance
• Controlled rate of drug delivery
• Husbandry constraints

Question 18

what does dosage form influence?

Answer 18

• Dosage form has greatest influence on the rate and extent of drug absorption
• affects action of drug: onset, duration and intensity

Question 19

how does formulation of a drug affect PK?

Answer 19

• 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

Question 20

what affects the route of admin chosen?

Answer 20

Formulations available will affect route choice
- not all antibacterials available by all routes
- enteral vs parenteral: advantages/disadvantages
- owner compliance is important !!

Question 21

what must we be cautios of with generic drugs?

Answer 21

Bioequivalence proven for generic against proprietary drug formulation

Question 22

issues with transdermal preparations?

Answer 22

• few veterinary approved transdermals available
• Compounded transdermals appear attractive, but are not recommended without supportive PK data

Question 23

Duration of therapy considerations; lenth of treatment depends on?

Answer 23

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

Question 24

how long do acute infections generally take to treat? considerations?

Answer 24

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

Question 25

how long should we treat pyrexia for?

Answer 25

§ until afebrile for 4-5 days

Question 26

how long should we treat chornic and serious infections for?

Answer 26

Chronic and serious infections: 4-6 weeks
§ eg. deep pyoderma, pyelonephritis, pneumonia
§ 7-10 days past resolution of clinical signs of infection