Pharmacology Lecture 7: Pharmaco-Kinetics - PDF

Pharmacology Excretion and elimination LECTURE (7) Pharmaco-kinetics (3) DR. El-Sawy 0  Pharmacology...

Pharmacology Excretion and elimination LECTURE (7) Pharmaco-kinetics (3) DR. El-Sawy 0  Pharmacology Excretion and elimination ‫الاخراج‬ Definition  Volume of plasma cleared from this substance per minute.  Rate of elimination / Plasma concentration Calculation  Vd x kel = Vd x 0.693 / t1/2 1. Give biological fate of the drug (route of excretion) → e.g. Renal clearance of a drug  If eliminated only by glomerular filtration Clearance can not exceed the GFR (127 ml/min). Clinical  If clearance is > 127 ml/min: significance of Drug is eliminated also by tubular secretion (e.g. renal renal clearance of benzyl penicillin = 480 ml/min). clearance 2- Calculate total clearance of a drug from the body * Calculate clearance for each organ then calculate sum of all 3. Calculate t1/2:  Dosage rate = clearance x cpss DR. El-Sawy 1  Pharmacology Excretion and elimination 1. Kidney (the major route).  Passive glomerular Filtration: Pass Small molecules (proteins not filtered)  Active Tubular secretion: 2 systems for acids & bases) INCLUDE 2. Bile and liver. 3. Intestine (Stool) 4. Lungs. 5. Milk. 6. Saliva and sweat. 1. Avoid drugs eliminated by a diseased organ. Clinical importance of 2. Help to adjust the dose to avoid cumulation. knowing route 3. Targeting therapy: e.g. drugs eliminated by the lung could of elimination be used expectorants. DR. El-Sawy 2  Pharmacology Excretion and elimination Definition:  Time taken for elimination of 50 % of the plasma conc of a drug to fall half its original value Calculation:  From clearance equation: 0.693 X Vd Clearance (CL) = Half-life (t1/2)  Experimentally: curve for calculation of t1/2 DR. El-Sawy 3  Pharmacology Excretion and elimination Clinical significance:  Drugs are given every t1/2 to avoid wide fluctuations of Determination of inter-dosage Peak level (highest plasma concentration of drug) interval Trough level (lowest plasma concentration of drug).  If a drug is started as a constant infusion, the Cp will accumulate to approach steady-state after 4-5 t1/2. Time-course of  If a drug is stopped after an infusion, the Cp will decline drug elimination to reach complete elimination after 4-5 t1/2.  Drugs having long t1/2 could be given once daily to improve patient compliance. DR. El-Sawy 4  Pharmacology Excretion and elimination  The steady level of drug in plasma achieved when the rate Definition administration equals the rate of elimination.  this equation suppose no barriers between intake & Calculation elimination → Cpss = dosing rate /clearance  If the desired Cpss is is (x) mg → give the patient 2/3 (x) m.g How to achieve Cpss → rule of every t1/2 for 5 t1/2 or  or if dose is X mg / t1/2 → Cpss is 3/2 the dose or 1.5 the ( ) dose  The Cpss is reached after 4- t1/2 When to reach  If we changed the dose, the new Cpss is reached after 4- t 2 1/ it → rule of  If dosing stops, complete elimination of drug from plasma occurs after 4- t1/2  A drug with t1/2 =1 hr. What is its dose that achieve a desired Cpss = 75 mg? Examples Give the patient (x) m.g = 2/3 x 75 = 50 mg / l hr wait for 5 t1/2 → reach cpss 75 mg (i.e. → the other 1/3 is obtained by cumulative effect DR. El-Sawy 5  Pharmacology Excretion and elimination  If we want to ↑ the Cpss from 75 mg to 150 mg → ↑ the dose as following give (2/3 x 150) = 100 mg / l hr (every t1/2) wait for another 5 t1/2  If we want to ↓ the Cpss from 150 mg to 75 mg →↓ the dose as following give (2/3 x 75) = 50 mg / l hr (every t1/2) wait for another 5 t1/2  If we want to reach Cpss after one t1/2 = Loading dose = doubling calculate 2/3 (x) m.g give double the dose at first = 4/3 (x) mg = loading dose Then back to regular dose = 2/3 (x) m.g e.g. → if need fast cpss 75 mg a. 2/3 dose = 5o mg b. give double the dose = 100 mg c. then back to regular dose 50 mg → cpss 75 mg after one t1/2 DR. El-Sawy 6  Pharmacology Excretion and elimination Clinical significance of Cpss: 1. Determine dose will be given every t1/2 in order to reach Cpss in 4-5 t1/2 = 2/3 CPSS 2. Calculate loading dose to obtain rapid Cpss in one t1/2 3. Calculate time needed to eliminate certain drug from the body after drug stoppage = 4-5 t1/2 4. Therapeutic drug monitoring in clinical practice  Measure drug plasma conc. to see is it equal to Cpss or not If patient not improve &if it is equal → ↑ drug dose to obtain effective Cpss  Measure drug plasma conc. & compare it to Cpss to determine the cause of this side effect. If plasma conc. > Cpss → side effect is due to drug If there is side effect or toxicity overdose If plasma conc = Cpss → side effect is from disease or unpredictable e.g. allergy 5. Calculate Loading dose = Cpss (mg/L) × volume of distribution (L) 6. Calculate Maintenance dose rate (mg/hr) = Cpss (mg/L) × clearance (L/hr) NB: time needed to observe toxicity case  With toxicity of first order, you can follow up patient for 4-5 t1/2 as elimination time is known.  With toxicity of zero order, you must follow up patient till clinical improvement as elimination time is unknown. DR. El-Sawy 7  Pharmacology Excretion and elimination After drug administration:  The drug passes through α-phase followed by β- phase:  Decline in plasma concentration of the drug due to distribution of the drug which is Rapid after i.v. administration → α- phase is short α- phase Slow after oral administration. → α- phase is long → as take time to be absorbed with gradual ↑ in plasma concentration till reach peak then go into β-phase  decline in plasma concentration of the drug due to elimination β- phase of the drug which is slower than distribution DR. El-Sawy 8  Pharmacology Excretion and elimination Types of kinetic order elimination : A. First-order elimination B. Zero-order elimination = saturation elimination  Few drugs e.g. → warfarin, heparin, Prednisolone, ethanol  Occurs to most drugs Chloroquine, Theophyllin & large doses of aspirin, Phenytoin,  Does not depend on saturable enzyme system.  Depends on saturable enzyme, which become saturated & elimination not exceed this point irrespective to plasma conc.  Rate of elimination is proportional to plasma conc.  Rate of elimination is not proportional to plasma conc  Constant ratio of plasma conc (%) is eliminated  Constant amount (not ratio) is eliminated per unit time (25 per unit time. mg/h)  This result in:  This result in: 1. Linear (i.e. plasma conc expected at any time) 1. Non linear (plasma conc not expected at any time) 2. T1/2 is constant. 2. T1/2 is not constant (t1/2 ↑ with ↑ the dose). 3. Cpss is reached after 5 t1/2 3. Cpss can not be expected. 4. Drug accumulation is not common. 4. Drug accumulation is common as when drug conc ↑ → elimination can not ↑ by same ratio. 5. Drug interactions are not common as when 5. Drug interactions are common as elimination of certain drug conc ↑ → elimination also ↑ by same ratio drug is affected by another drug requiring same enzymes for its elimination DR. El-Sawy 9  Pharmacology Excretion and elimination  if drug conc is 100 mg/dl & elimination rate is 25 m/h & if  if drug conc is 100 mg/dl & t1/2 6h. plasma conc. will decline as following: ↑dose to 150 mg, the t1/2 will change (Non constant t1/2) DR. El-Sawy 10  Pharmacology Excretion and elimination Note Some drugs are eliminated by first-order elimination in low doses and by zero-order elimination in high doses Aspirin. Phenytoin. Ethanol. Clinical significance of zero-order elimination: 1. Modest change in drug dose may produce unexpected toxicity. 2. Liability of drug interactions. 3. Elimination of drugs & attainment of Cpss takes long time. 4. Changes in drug formulation may produce adverse effects. DR. El-Sawy 11