PK: Absorption, Distribution, Metabolism, Excretion, T½, Calculating the LD for a Drug, Clearance, Half-life, Calculating Maintenance Dose, and TDM

Question 1

Where does most of the circulation in the body happen (that is exposed to drugs)

Answer 1

circulation, heart, liver

Question 2

A 20 yo 70 kg male college student (c 1970) undergoes an emergency appendectomy, expected to last 60 minutes under general anesthesia. An IV catheter is inserted, and the patient receives thiopental (a very short acting intravenous barbiturate) 3-5 mg/kg as slow IV push (300 mg)
How long until patient is “out”?
How long until patient wakes up?
How long will the case take?
How would you manage anesthesia? Other drugs needed?
Can you explain the action of this drug, using a concentration-over-time curve?
Can we “model” the various processes going on here, using a fluid model?
Why not use this drug for the entire case?

Answer 2

1) Induction (KNOCK PT OUT): Thiopental / propofol == very lipophilic, fast-acting –> into the brain (w/in 3sec)
- rapid redistribution into muscle and brain (w/in 10 min)

2) Maintenance (KEEP PT OUT): halothane (sevofluorone) == volatile gas anaesthetic

Question 3

A 20 yo 70 kg male college student (c 1970) undergoes an emergency appendectomy, expected to last 60 minutes under general anesthesia. An IV catheter is inserted, and the patient receives thiopental (a very short acting intravenous barbiturate) 3-5 mg/kg as slow IV push (300 mg)

• Cp-over-time curve for this scenario
• What is the LD?
• What is observed Cmax?
• What is the Vc?
• What is the approximate t ½ alpha?
• What is the approximate t ½ beta?
• What is initial Cp after redistribution?
• What is the likely Vp?

Answer 3

• What is the LD? 300mg
• What is observed Cmax? 40mg/L
• What is the Vc? 300mg/40mg/L = 7.5L
• What is the approximate t ½ alpha? 4min
• What is the approximate t ½ beta? 9hr
• What is initial Cp after redistribution?
• What is the likely Vp?

Question 4

In pharmacology, what does “F” stand for?

Answer 4

F = fraction oral bioavailability / IV bioavailability 
== oral bioavailability / 100%

Question 5

A 65 yo man has a lot of chronic pain from his metastatic prostatic CA, with bone mets. His pain is managed reasonably well with MS Contin 60 mg po tablets scheduled q12h, supplemented with MS IR tablets 15 mg po q4h prn breakthrough pain. (total averages about 180 mg per 24 h)
He is now admitted to the hospital with severe pancreatitis, possibly related to his HCTZ. His surgeon wants him to remain NPO.
How would you address his pain?

Answer 5

Can give morphine IV (F=100%), IM , PO (F=33%)

When he was taking the drug PO, he was getting 180mg/24h == 180*1/3==60mg/24h into circulation

so can give up to 60mg/24h (likely start with 45mg, and then increase as needed)

Question 6

If a patient is getting IV morphine 100mg/24h when in the hospital, how much oral morphine should he be sent home on?

Answer 6

100mg/24h / (1/3) == 100 * 3 = 300mg/24h PO

Question 7

A 70 yo man undergoes AVR for acute CHF due to a damaged aortic valve. He weighs 80 kg. During surgery, a lesion is found that looks like a bacterial vegetation.
Pt is begun “empirically” on vanco and ceftriaxone.

What is he getting these antibiotics for?

Answer 7

Vancomycin

• Staph aureus
• Streptococcus (pyogenes)
• Enterococcus

Ceftriaxone
- occasional GNR

Question 8

A 70 yo man undergoes AVR for acute CHF due to a damaged aortic valve. He weighs 80 kg. During surgery, a lesion is found that looks like a bacterial vegetation.
Pt is begun “empirically” on vanco and ceftriaxone.
Culture is eventually positive for enterococcus, resistant to vanco, but sensitive to ampicillin and gentamicin. Further studies demonstrate “synergy” between these drugs. Renal function is normal (creatinine 1.0 mg/dL, eGFR ~ 70 ml/min).
ID consultant suggests “high dose” ampicillin, potentiated by “lower dose” gentamicin, Cpeak ~4 mg/L, Ctrough ~0.5

How would you order the ampicillin (loading, maintenance)?
How would you order the gentamicin (loading, maintenance)? We want to achieve a peak Cp of 4 mg/L (why?)
Vd from the literature is 0.31 L/kg * wt in kg (Goodman and Gilman)

How often do you give the drugs

Answer 8

How would you order the ampicillin (loading, maintenance)?
==> 12gram/day IV, divided q4h

How would you order the gentamicin (loading, maintenance)?
==> 1mg/kg q8h IV

x4-6weeks

==> we would keep ordering troughs
We want to achieve a peak Cp of 4 mg/L (why?)
==> Vd = 0.31L/kg * wt
==> Therapeutic peak of 4 (Cp=4) – too much is nephrotoxic
==> LD = Vd * Cp
==> LD = (0.31L/kg * 80kg) * 4mg/L
==> LD = 99.2mg == 100mg (1-2% error ok)

This LD, diluted into 100 ml D5W and infused over 15-30 min IV, should get us immediately to a therapeutic Cp of just about 4 mg/L (as recommended by ID)

Minimum Cp needed for gentamicin (by the time it gets to the) == 0.5
LD = 100mg (calculated)
MD = 87.5mg (based on LD of 100mg, and need go range Cp from 0.5–>4 to ALLOW for decay - this was 7/8 of the Cp, so choose 7/8 * 100mg)

==> don’t keep Gentamicin (specifically) at 4 d/t oto- & nephro-toxicity - so need to get to 4 –> allow to decay to 0.5 –> maintenance dose to 4 (repeat)
- need to follow Gent fx: hearing, vestibular function

TIMING
– need to wait for Cp to drop from 4mg/L –> 2mg/L –> 1mg/L –> 0.5mg/L == 3 half lives before giving the next dose

Question 9

how to get to a steady antibiotic level in plasma to keep Cp of 4mg/L

Assume
Vd = 0.31L/kg
70yo pt; 80kg, with Cr 1.2

Answer 9

LD = Vd * Cp
LD = (0.31l/kg * 80kg) * 4mg/l == 100mg

MD = rate in = Cl x Cpss/F

Rate in = rate out
F x MD = (4 mg/L) x (Cl)
(1) x MD = (4 mg/L) x (0.8 x Clcr)
MD = (4 mg/L) x (0.8 x 58 ml/min)
MD = (4 mg/L) x (46 ml/min) x (60 min/h)
MD = (4 mg/L) x (2.8 L/h)
MD = 11.2 mg/h = 269 mg/day as a continuous infusion

Question 10

When should we check the drug concentration in plasma (“level”)?
Examples?

why not: metoprolol, furosemide, diazepam, lisinopril

Answer 10

Drug has narrow therapeutic window
Significant interpatient variation in kinetics
Assay is practical, quick, accurate, inexpensive
No simpler clinical parameters to follow
Levels being subtherapeutic causes serious consequences
Levels being supratherapeutic (toxic) causes serious consequences

Examples: gentamicin, vancomycin, phenytoin, digoxin, cyclosporine, methotrexate –> b/c severity of toxicity

these others are relatively safe, or you can follow other vitals (HR/BP)

Question 11

how do the kinetics of alcohol work?

Answer 11

0 order kinetics

==> over 1 hour, will get rid of 50% of the drink (not 50% of alcohol)

Question 12

blood flow per minute for:
heart
liver
kidneys
plasma

Answer 12

heart = 5L/min
liver = 1.5L/min
kidneys = 800mL/min
plasma = 720mL/min