Clearance From A Physiologic Perspective Chemical Clearance from

Clearance With time, where does the drug go? Why are drugs lost from the

Blood Flows 1 Tissue or Organ Weight (kg) % of IBW Kidneys Adrenals Thyroid

Clearance With time, where does the drug go? Organs are strategically arranged (liver –

Focus on an Eliminating Organ Pump Clearing Chamber Blood leaving the organ has a

Focus on an Eliminating Organ Ca Cv Extraction Ratio can be viewed as the

Focus on an Eliminating Organ Pump Clearing Chamber Clearance of drug is dependant on

Focus on an Eliminating Organ At constant concentration (steady – state) clearance can be

Focus on an Eliminating Organ When we focus on a single organ, Hepatic Clearance

Focus on an Eliminating Organ How Efficient is a Normal Kidney in removing Creatinine?

Focus on an Eliminating Organ How Efficient is a Normal Kidney in removing Ciprofloxacin?

Male Acute Community Acquired Pneumonia Equations Conc = Dose / V V = Dose/Conc

Focus on an Eliminating Organ How Efficient is a Normal Liver in removing Theophylline?

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Clearance From A Physiologic Perspective Chemical Clearance from the Body Objectives for Today • Problems / Questions & Review concerning Chemical Distribution …? • A Physiologic View of Chemical Clearance from the Body • Develop a definition for Clearance.

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 room or …?

Blood Flows 1 Tissue or Organ Weight (kg) % of IBW Kidneys Adrenals Thyroid Brain Liver Muscle Skin Fat 0. 16 0. 011 0. 03 1. 35 1. 5 28 18 10 0. 23 0. 02 0. 04 1. 93 2. 14 40 26 15 Blood % Cardiac Flow Output 3 (m. L/min) 1200 65 165 729 3002 850 260 105 23 1. 2 3. 2 14 5. 8 16 5. 0 2. 0 1. Spector, WS. Handbook of Biological Data 2. Includes only arterial flow; total equals about 1500 m. L/min. (25%) 3. Cardiac Output / 70 kg = 5 -6 L/min [85 m. L/min/kg]

Clearance With 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%

Clearance With 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 Pump Clearing 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].

Focus on an Eliminating Organ Ca Cv Extraction Ratio can be viewed as the proportion of drug removed during passage through the organ.

Focus on an Eliminating Organ Ca Cv 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 the difference between arterial and venous concentrations. ER = [ (Ca – Cv) / Ca ] where Ca is the concentration in the artery on entry to the organ and Cv is the concentration in the vein on exit from the organ

Focus on an Eliminating Organ Pump Clearing Chamber Clearance of drug is dependant on 2 factors: Efficiency of Removal [ER] and The rate at which drug can be delivered to the organ [Flow Rate: Q]. Clearance = Q x ER (m. L/min)

Focus on an Eliminating Organ At constant concentration (steady – state) clearance can be estimated from blood flow and the difference between arterial and venous concentrations. Cl. H = Q [ (Ca – Cv) / Ca ] = Q*ER or Cl = Q x ER where ER is the Extraction Ratio and Q is organ blood flow. When we focus on a single organ, Hepatic Clearance would be symbolized by Cl. H and Renal Clearance by CLR

Focus on an Eliminating Organ When we focus on a single organ, Hepatic Clearance would be symbolized by Cl. H and Renal Clearance by CLR … Cl. TOTAL = Cl. HEPATIC + Cl. RENAL + Cl. LUNG Clearance as the units of Volume per time (m. L/min) Definition: Clearance: The volume of distribution volume of the sampled fluid from which drug is irreversibly removed per unit time.

Focus on an Eliminating Organ How Efficient is a Normal Kidney in removing Creatinine? Cardiac Output = 85 m. L/kg/min 70 kg male Creatinine Clearance = ~ 120 m. L/min (serum) Q R BLOOD = 25% CO

Focus on an Eliminating Organ How Efficient is a Normal Kidney in removing Creatinine? Cardiac Output = 85 m. L/kg/min 70 kg male Creatinine Clearance = ~ 120 m. L/min (serum) Q R BLOOD Equations Conc = Dose / V V = Dose/Conc Cl = Q x ER ER = Cl / Q Q R SERUM = 25% CO = 0. 25 (85) = 21. 25 m. L/min/kg = Q R BLOOD

Focus on an Eliminating Organ How Efficient is a Normal Kidney in removing Creatinine? Cardiac Output = 85 m. L/kg/min 70 kg male Creatinine Clearance = ~ 120 m. L/min (serum) Q R BLOOD Equations Conc = Dose / V Q R SERUM V = Dose/Conc Cl = Q x ER ER = Cl / Q ER = 25% CO = 0. 25 (85) = 21. 25 m. L/min/kg Q BLOOD (0. 55)(70) = R = 820 m. L/min (serum) =

Focus on an Eliminating Organ How Efficient is a Normal Kidney in removing Creatinine? Cardiac Output = 85 m. L/kg/min 70 kg male Creatinine Clearance = ~ 120 m. L/min (serum) Q R BLOOD Equations Conc = Dose / V Q R SERUM V = Dose/Conc Cl = Q x ER ER = Cl / Q ER = 25% CO = 0. 25 (85) = 21. 25 m. L/min/kg Q BLOOD (0. 55)(70) = R = 820 m. L/min (serum) = 120/820 = 0. 146 or 14. 6%

Focus on an Eliminating Organ How Efficient is a Normal Kidney in removing Ciprofloxacin? Cardiac Output (Renal)= 820 m. L/min (serum) Cipro Clearance = 35 L/hour (serum) = Equations Conc = Dose / V V = Dose/Conc Cl = Q x ER ER = Cl / Q

Focus on an Eliminating Organ How Efficient is a Normal Kidney in removing Ciprofloxacin? Cardiac Output (Renal)= 820 m. L/min (serum) Cipro Clearance = 35 L/hour (serum) = 583 m. L/min Equations Conc = Dose / V V = Dose/Conc Cl = Q x ER ER = Cl / Q Q R SERUM = Q R BLOOD

Male Acute Community Acquired Pneumonia Equations Conc = Dose / V V = Dose/Conc Cl = Q x ER ER = Cl / Q Physiologic Approach to Cipro Pharmacokinetics Male with Pneumonia Given 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 yr Weight: 80 kg Drug: Ciprofloxacin Serum ciprofloxacin concentrations average 2 g/m. L (mg/L) Cipro Volume: 1. 5 L/kg Cipro 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 Physiologic Approach to Cipro Pharmacokinetics Male with Pneumonia Given 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 yr Weight: 80 kg Cipro Clearance: = 840 L/day Average concentration over a day 2 mg/L Dose required to maintain [ ] = 2 (840) mg = 1680 mg/day

Focus on an Eliminating Organ How Efficient is a Normal Liver in removing Theophylline? Cardiac Output Proportion of CO to the Liver Blood Flow Proportion of Blood as Serum Liver Serum (plasma) Flow = 6. 0 L/min = 25% = 1. 5 L/min = 55% = 1. 5 L/min Equations = 0. 82 L/min OR = 820 m. L/min Conc = Dose / V V = Dose/Conc Cardiac Output = 85 m. L/kg/min 70 kg male Proportion of Blood as Serum = 55% Cl = Q x ER Liver Serum (plasma) Flow = 85 * 70 * 0. 55 * 0. 25 ER = Cl / Q = 818. 12 m. L/min

Focus on an Eliminating Organ How Efficient is a Normal Liver in removing Theophylline? Cardiac Output = 6. 0 L/min (Blood) Liver Plasma Flow = 820 m. L/min/70 kg male Theophylline: Equations Total clearance Conc = Dose / V Hepatic Clearance V = Dose/Conc Cl = Q x ER ER = Cl / Q 85% metabolized 15% excreted unchanged ~ 0. 7 m. L/min/kg = 50 m. L/min (serum) Cl H=