4. Drug Clearance.pdf

↑ Body or organ tissues #compartment of fluid witha definite volume ( - apparent volume of distribution) in which the drug is dissolved. Expressed in (nits) &ml/min or litres/hour dependent for volum & piride Ma...

↑ Body or organ tissues #compartment of fluid witha definite volume ( - apparent volume of distribution) in which the drug is dissolved. Expressed in (nits) &ml/min or litres/hour dependent for volum & piride Mathematically * clearance : rate of drug elimination divided by plasma drug conc. at that time point. Rate of elimination Cl = plasma drug conc.  Renal Clearance mine (Amout) ↳ Renal excretion of drugs quantitatively described - - - by renal clearance value for the drug. Renal excretion : major route of elimination for - many drugs. on : Drugs eliminated by renal excretion Dependent G ⑳ - = water soluble,- * - have low mol. weight( less than or equal to 300), or - are - * slowly biotransformed by liver  Glomerular Filtration Summary Clearance of inulin will(one * Uni-Direction proceses direction) be equal to the glomerular * filtration rate which Fours - Hydrostatic prusseris 125-130 ml/min. (High to Low Value for glomerular filtration rate correlates fairly * well with Occure For body > Small - surface area. - Less than 500 nw Molecule Glomerular↳ filtration of drugs is directly related to Ionized and non-lonized the free or non-protein-bound drug concs. in the plasma. · so Large protine drug find don't get filliter As the free drug conc. in the plasma increases, the ↳filtration Happen for free/unbond drug glomerular onlytheindrug will increase proportionately. free drug Con in. plasm * glumerular Filtration. Example Inulin #Creatinine (only Filter /Secreation N * Drug Reabsorption - · · * Filtrat rate of Inulin - 125-130 mL/min => Active tubule secreation Active renal secretion => Need Energy (enzyme-carrier) An active process from Low mu - - High) to Carrier mediated system which &requires energy - input,· Drug is transported against a conc. gradient. s The-carrier system is capacity limited and may be - saturated.- m Drugs with similar structures may compete for the - same carrier system.# - Two active renal secretion systems are -1. Systems for weak acids - ↓2. Systems for weak bases. -  · Probencid will compete > ~ with penicillin for the same carrier system (weak acids) - - Active tubular secretion rate is dependent on renal -- plasma flow. - Drugs commonly used to measure active tubular - S secretion : PAH · p-amino-hippuric acid(PAH) and - 3 iodopyracet(Diodrast). I iodopyracet # & These substances are both filtered by the glomeruli - and secreted by the tubular cells. - Active secretion is extremely rapid for these drugs, - and practically all the drugs carried to the kidney are  mi 650 mit 425- -- * eliminated in a single pass. The clearance for these drugs therefore reflects the & effective -a renal plasma flow. ERPF varies from 425-650 ml/min. - - For a drug that is excreted solely by glomerular filtration Elimination half life may change markedly in ↳ accordance with the binding affinity of the drug for - plasma proteins. Protein binding has very little effect on the - - elimination half-life of a drug excreted mostly by - active secretion.  Since drug-protein binding is reversible, the bound drug and free drug are excreted by active secretion during the first pass through the kidney. - · Some of the penicillins are extensively protein bound, but their elimination half lives are short due - to rapid elimination by active secretion.  Tubular reabsorption - - Occurs after the - drug is filtered through the - glomerulus - - ~ Can be active or passive. - If a drug is completely reabsorbed (e.g. glucose) & - then the value for the clearance of the drug is - - approx. zero. For drugs which are partially reabsorbed, clearance - values will be- less than the GFR of 125-130 ml/min. otumar Fate - - The pka of the drug is constant, - & Normal urinary pH may vary from 4.5 to 8.0 - depending on the diet, pathophysiology and drug - intake. & Vegetable - diets or diets rich in carbohydrates will result N in - higher urinary pH & pH. - - Diets rich in protein will result in lower urinary Drugs such as ascorbic acid and antacids such as - = sodium carbonate may alter urinary pH when -  Most imp. changes in urinary pH are caused by fluids administered intravenously. Intravenous fluids such as solutions of bicarbonate - or ammonium chloride are used in- acid-base -therapy. Excretion of these solutions may drastically change urinary pH and alter drug reabsorption.  ionized Fekseid > -- PH = pKa + Log ionized - - The # percentage of ionized weak acid drug corresponding ↓ to a given pH can be obtained from the Henderson-Hesselbalch eqn.: - [ionized] & pH = pKa + log --------------- ↓ [ unionized] (5) ↳ wiRearrangement [ionized] of this equation gives Tweak Acid --------------- = 10 pH - pKa (6) PKa(2 [unionized] ↓ ionized in Urine pH  # Application of equation 58 important The percentage of weak acid drug ionized in any pH - environment can be calculated by eqn 7. % [ 15 o ① The extent of dissociation is more greatly affected by changes in urinary pH with a# pka of 5 than with a⑤ > - - pka of 3. i - Weak acids with pka values of less than 2 are highly ionized = at all urinary pH values and are only slightly affected by pH variations. For a Oweak base drug, the Henderson-Hesselbalch eqn.: 5 [ unionized ] - Tweak Acid pH = pKa + log ------------------- (8) PKa(2 [ ionized ] ↓ ionized in Urine pH  * weak acid 22 ↳ pka gs). a ionized in c) &↓ weak base # * 7 5-10 5. Percent of drug ionized ↳ pla. 10 pKa – pH O -------------------- x 100 1+ 10 pKa – pH o Greatest effect of urinary pH on reabsorption occurs with weak bases with pka of 7.5-10.5 From the Henderson-Hesselbalch relationship, a conc. ratio for the distribution of a weak acid or basic drug between urine and plasma may be derived 10 5. per effecti for compination #Metable - r  Alkaline I weakt ↓ ⑳ Y * reabsorbed 2- unionized Urine pH made alkaline Lipid Soluble S - drug bat the weak base reabsorbed : unionized > - in it's unabsorbed state so - - more lipid soluble unionized species formed. Acidification of the urine : weak base become more ionized ( form a wea - - se salt). -Acidification - reabsorbed Salt form [W Form ·ionized wate more water soluble - Eless likely to be reabsorbed = - excreted into the urine more quickly. - -  Weak Base ↳ Acidification : Excretion Lionized) ↳ Alkalinization : reabsorbed Lunionized) Weak acids acidification of urine : greater reabsorption = - alkalinization of urine : more rapid excretion Conized - mine Besides pH of the urine: Rate of urine flow : influence amount of filtered drug which is reabsorbed. ⑧ Normal flow of urine : approx.6 - 1-2 ml/min.  Non-polar and unionized drugs 3 normally reabsorbed in renal tubules sensitive to changes in rate of urine flow. - Drugs which increase urine flow (Excreationnee Decrease time for drug reabsorption - promote their excretion. & time Forced diuresis : diuretics useful adjunct for removing excessive ↑ drug in an intoxicated patient. increase renal drug excretion. & Renal clearance [ Rate of elimination by kidney ClR = ------------------------------------------ (12) C &Filtration rate + secretion rate- reabsorption rate ↳ ClR = ------------------------------------------------- (13) C (plasma drug conc) reabsortation - Filtration Rate Secreation rate LR = 8 Con (Plasma diy. )  Maintenance Dose Maintenance dose which will produce desired average plasma conc. at steady state. * (Cl)(Cssave)(τ) Maintenance Dose = ---------------------- (16) (S)(F) (T) Issave) 57 -  si · Factors that=> alter Clearance(Cl) ga Body O weight 50 Body surface area Cardiac output 80 Drug-drug interactions o Extraction ratio Genetics Live Hepatic function 20 Binding Plasma protein binding less plassma protine more clearence Renal function Kidnig Factors that alter Clearance(Cl) 1. Body Surface Area (BSA) various charts. S Equation & Patient’s wt. in kg - 0.7 BSA in m2 = ( --------------------------) 1.73m2 (17) - 70 kg =>  Clt : estimated in presence of renal or hepatic failure or both. Metabolic function difficult to quantitate, Clt most commonly adjusted when there is decreased renal function. E Cl adjusted = ( Cl m) + [( Cl r) (Fraction of normal renal function remaining)] ( 24 ) Clm (0) (1 0)x(0 8) o Dadjusted = = +.. 2)v = 80 % 30 8. = 0. 8 Fru = 100 % - 1 0.  As the major elimination pathway becomes increasingly compromised, - the “minor” pathway becomes more significant Y ge means the function become dec Why? -. · It assumes a greater proportion of the total clearance. se Drug : usually 67% eliminated by the renal route and 33% by the metabolic route - Will be ↳ s 100% metabolized in the event of complete renal failure: Crea l not work all Total at fulyer) renal = ① Total clearance : one-third of the normal value. -ie  Using this technique the eqn below can be derived: - Dosing rate adjustment factor = I Used to adjust maintenance dose for a - patient with altered renal function. - - ( Fraction Eliminated metabolically)+ [ ( Fraction eliminated renally)( Fraction of normal renal function remaining)]  ↓ Rather dosing rate adjustment factor would be 0.5. Dosing rate adjustment factor = - ( Fraction eliminated metabolically)+ [( Fraction eliminated renally)( Fraction of normal renal function remaining)] = ( 0.25)+ [( 0.75) (0.33)] = ( 0.25) + [( 0.25)] = 0.5 - - 3 so , now i give 0. 5 mg (half at regulal) for patient  Depending on situation and therapeutic intent Either method (or a combination of dose and dosing interval adjustment) might be appropriate. Most pharmacokinetic adjustments for drug elimination are based on renal function we Why ? ↓ - Hepatic function more difficult to quantitate. ~g) - 3 # 0 Serum albumin may be low Due to decreased protein intake or Increased renal or GI loss, as well as Decreased hepatic function. Liver function tests donot provide quantitative data, Pharmacokinetic adjustments must still take into consideration liver function Why? This route of elimination is imp. for a significant number of drugs.  Cardiac output: ↳ Affects drug metabolism.* re s e a r Hepatic or metabolic clearance for some - drugs decreased by 25% to 50% in patients - with congestive- - heart failure. & Metabolic clearances of ↳ theophylline and digoxin - ↓ 1/2 Reduced by approx. one – half in patients with congestive - - heart failure. 30  Metabolic clearance for both these drugs is - much lower than the hepatic blood or plasma flow(low extraction ratio), The decreased cardiac ouput and resultant hepatic congestion must, in some way, decrease the intrinsic metabolic capacity of the liver.  Protein Bound Drugs Not eliminated by glomerular filtration. Only the free drug is excreted by a linear process. Bound drugs usually excreted by active secretion, following capacity limited determind the kinetics. Determination of clearance which separates two components would result in a hybrid - e drug have When the clearance.=> Icomponent way that have different thisnot of elimination , have No simple way to overcome this problem. 2 example : one have => fitration and other secretion => have · Plasma protein binding Very little effect on renal clearance of drugs like penicillin which are actively - - secreted. For these drugs Free drug fraction is filtered at the glomerular; Protein bound drug appears to be stripped from the binding sites and actively secreted into the renal tubules.  Clearance Ratio Probable mechanism of renal excretion & Cl drug j --------- < 1 Drug is partially --reabsorbed Cl inulin - Cl drug ↳ & --------- = 1 Drug is filtered only Cl inulin -  Cl drug · --------- > 1 Drug is actively secreted > Cl inulin