objectives for today problems / questions & review concerning chemical distribution …? a...

Objectives for Today•Problems / Questions & Review concerning

Chemical Distribution …?

•A Physiologic View of Chemical Clearance from the Body

• Develop a definition for Clearance.

ClearanceFrom A Physiologic Perspective

Chemical Clearance from the Body

Clearance

With time, where does the drug go?

Why are drugs lost from the body?How are drugs lost from the body?

Based on random flow?Like the elimination of an

coloured gas or odour from a roomor …?

Blood Flows1

1. Spector, WS. Handbook of Biological Data2. Includes only arterial flow; total equals about 1500 mL/min. (25%)3. Cardiac Output / 70 kg = 5-6 L/min [85 mL/min/kg]

Tissue Weight % Blood % Cardiac or (kg) of Flow Output3

Organ IBW (mL/min)Kidneys 0.16 0.23 1200 23Adrenals 0.011 0.02 65 1.2Thyroid 0.03 0.04 165 3.2Brain 1.35 1.93 729 14Liver 1.5 2.14 3002 5.8Muscle 28 40 850 16Skin 18 26 260 5.0Fat 10 15 105 2.0

ClearanceWith time, where does the drug go?

Organs are strategically arranged (liver – to deal with entry & elimination

of compounds and are well perfused tissues.

If a drug is eliminated by an organ (kidney or liver),

the organ will have access to a greater amount of drug if a larger percentage of drug

is found in the blood / plasma or serum.

Theophylline 9.8%Levo: 3.5% / 4.2%

Cipro: 2.9 %Cyclosporin: 0.15%

ClearanceWith time, where does the drug go?

Organs are strategically arranged (liver – to deal with entry & elimination

of compounds and are well perfused tissues.

The blood emerging from an eliminating organ has a lower concentration

than the blood entering the organ.

This effectively dilutes the drug concentration

in the primary storage area … the rest of the body.

Focus on an Eliminating Organ

PumpClearing Chamber

Blood leaving the organ has a lower drug concentration than drug entering.

Drug is “cleared” by the organ.The efficiency of Removal is

quantified by the Extraction Ratio [ER].


Extraction Ratio can be viewed as the proportion of drug removed during passage through the organ.

CaCv


Extraction Ratio can be viewed as the proportion of drug removed during passage through the organ.

At constant concentration (steady – state)

extraction can be estimated from thedifference between arterial and venous concentrations.

ER = [ (Ca – Cv) / Ca ]

where Ca is the concentration in the artery on entry to the organ and and Cv is the concentration

in the vein on exit from the organ

CaCv


PumpClearing Chamber

Clearance of drug is dependant on 2 factors:Efficiency of Removal [ER]

andThe rate at which drug can be

delivered to the organ [Flow Rate: Q].Clearance = Q x ER (mL/min)


At constant concentration (steady – state) clearance can be estimated from blood flow

and the difference between arterial and venous concentrations.

ClH = Q [ (Ca – Cv) / Ca ] = Q*ERor

Cl = Q x ER

where ER is the Extraction Ratioand Q is organ blood flow.

When we focus on a single organ, Hepatic Clearance would be symbolized by ClH

and Renal Clearance by CLR


When we focus on a single organ, Hepatic Clearance would be symbolized by ClH

and Renal Clearance by CLR …ClTOTAL = ClHEPATIC + ClRENAL + ClLUNG

Clearance as the units of Volume per time(mL/min)

Definition:Clearance:The volume of distribution volume of the sampled fluid from which drug is irreversibly removed per unit time.


How Efficient is a Normal Kidney in removing Creatinine?

Cardiac Output = 85 mL/kg/min 70 kg maleCreatinine Clearance = ~ 120 mL/min (serum)

QRBLOOD = 25% CO




QRBLOOD = 25% CO

= 0.25 (85)= 21.25 mL/min/kg

QRSERUM = QR

BLOOD

Equations

Conc = Dose / V

V = Dose/Conc

Cl = Q x ER

ER = Cl / Q




QRBLOOD = 25% CO

= 0.25 (85)= 21.25 mL/min/kg

QRSERUM = QR

BLOOD (0.55)(70)= 820 mL/min (serum)

ER =

Equations

Conc = Dose / V

V = Dose/Conc

Cl = Q x ER

ER = Cl / Q




QRBLOOD = 25% CO

= 0.25 (85)= 21.25 mL/min/kg

QRSERUM = QR


ER = 120/820 = 0.146 or 14.6%

Equations

Conc = Dose / V

V = Dose/Conc

Cl = Q x ER

ER = Cl / Q


How Efficient is a Normal Kidney in removing Ciprofloxacin?

Cardiac Output (Renal)= 820 mL/min (serum)Cipro Clearance = 35 L/hour (serum)

=

Equations

Conc = Dose / V

V = Dose/Conc

Cl = Q x ER

ER = Cl / Q




= 583 mL/min

QRSERUM = QR

BLOOD

Equations

Conc = Dose / V

V = Dose/Conc

Cl = Q x ER

ER = Cl / Q




= 583 mL/min

QRSERUM = QR


ER =

Equations

Conc = Dose / V

V = Dose/Conc

Cl = Q x ER

ER = Cl / Q




= 583 mL/min

QRSERUM = QR


ER = 583/820 = 0.71or 71%

Very efficient

Equations

Conc = Dose / V

V = Dose/Conc

Cl = Q x ER

ER = Cl / Q

Physiologic Approach to Cipro Pharmacokinetics

Male with PneumoniaGiven the clearance of ciprofloxacin, how much drug is required each day to maintain an average concentration of 2 mg/L? (peaks of 3-4; troughs ~0.5)Age: 45 yrWeight: 80 kgDrug: CiprofloxacinSerum ciprofloxacin concentrations average 2 g/mL (mg/L)Cipro Volume: 1.5 L/kgCipro Am’t in body:

Cipro Clearance:

Male Acute Community Acquired Pneumonia

Equations

Conc = Dose / V

V = Dose/Conc

Cl = Q x ER

ER = Cl / Q


Male with PneumoniaGiven the clearance of ciprofloxacin, how much drug is required each day to maintain an average concentration of 2 mg/L? (peaks of 3-4; troughs ~0.5)Age: 45 yrWeight: 80 kgDrug: CiprofloxacinSerum ciprofloxacin concentrations average 2 g/mL (mg/L)Cipro Volume: 1.5 L/kgCipro Am’t in body: = 80 x 1.5 x 2

= 240 mgCipro Clearance: = 35 L/hr

= 840 L/day


Equations

Conc = Dose / V

V = Dose/Conc

Cl = Q x ER

ER = Cl / Q


Male with PneumoniaGiven the clearance of ciprofloxacin, how much drug is required each day to maintain an average concentration of 2 mg/L? (peaks of 3-4; troughs ~0.5) Age: 45 yrWeight: 80 kg

Cipro Clearance: = 840 L/dayAverage concentration over a day

2 mg/LDose required to maintain [ ]

= 2 (840) mg= 1680 mg/day


Equations

Conc = Dose / V

V = Dose/Conc

Cl = Q x ER

ER = Cl / Q


How Efficient is a Normal Liver in removing Theophylline?

Cardiac Output = 6.0 L/minProportion of CO to the Liver = 25%

Liver Blood Flow = 1.5 L/minProportion of Blood as Serum = 55% Liver Serum (plasma) Flow = 1.5 L/min

= 0.82 L/minOR = 820 mL/min

Cardiac Output = 85 mL/kg/min 70 kg maleProportion of Blood as Serum = 55%Liver Serum (plasma) Flow

= 85 * 70 * 0.55 * 0.25= 818.12 mL/min

Equations

Conc = Dose / V

V = Dose/Conc

Cl = Q x ER

ER = Cl / Q


How Efficient is a Normal Liver in removing Theophylline?Cardiac Output = 6.0 L/min (Blood)Liver Plasma Flow = 820 mL/min/70 kg male

Theophylline: 85% metabolized15% excreted unchanged

Total clearance ~ 0.7 mL/min/kg= 50 mL/min (serum)

Hepatic Clearance ClH =

Equations

Conc = Dose / V

V = Dose/Conc

Cl = Q x ER

ER = Cl / Q





Hepatic Clearance ClH = 50(0.85)= 42.5 mL/min

QHBLOOD = 820 mL/min (serum)

ER =

Equations

Conc = Dose / V

V = Dose/Conc

Cl = Q x ER

ER = Cl / Q





Hepatic Clearance ClH = 50(0.85)= 42.5 mL/min

QHBLOOD = 820 mL/min (serum)

ER = 42.5/820 = 0.052or 5.2%

Equations

Conc = Dose / V

V = Dose/Conc

Cl = Q x ER

ER = Cl / Q

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