Lecture 9: Very important supplements TDM Effect of hepatic disease on drugs monitoring: Generally, hepatic clearance is determined by three main factors: - Liver blood flow (LBF). - Intrinsic capacity of liver (Cl int ). - Unbound concentration of the designated drug (f B ). These three factors can be employed in the following equation: The role of these three factors is mainly determined by hepatic extraction ratio as the following: - For drugs with low extraction ratio (less than 0.3): the drug is minimally eliminated by liver due to low hepatic intrinsic capacity and low free fraction of the drug and the above equation becomes as following: - For drugs with high extraction ratio (more than 0.7): the drug is mainly eliminated by liver due to high hepatic intrinsic capacity and high free fraction of the drug and the hepatic clearance equation becomes: The influence of these three factors on various physiologic, pharmacodynamic and pharmacokinetic parameters can be examined in the following examples. 1
Example 1: A Patient with cirrhosis and receiving drug with low extraction ratio. For drugs with low extraction ratio, the hepatic clearance is mainly influenced by changes in drug s free fraction and Cl int. - Here liver blood flow is not important physiological parameter. - Due to destruction of liver both Cl int and Cl are reduced. Cl H = f B. Cl int - Both the free fraction of drug f B and volume of distribution are not influenced. - The half-life will increase as Cl is reduced. - Total steady-state concentration, free steady-state concentration and effect of drug will increase. Maintenance dose K 0 = Css. Cl Then Css = K 0 / Cl (inverse relation between total Css and Cl) Css u = f B. Css (unbound Css is a function of total Css, in other words directly related) 2
Example 2: Patient with hypoalbuminemia or hyperbilirubinemia and receiving a drug with low extraction ratio. The reduction in plasma protein binding will increase the free fraction of drug and also allow drug to leave blood vessels (increase V). - As drug has low extraction ratio, liver blood flow has no influence. - Cl int remains constant as liver is intact (no hepatocyte destruction). - The free fraction of drug will increase and both Cl and V will increase also. Reduction in plasma protein binding will make more drug available for elimination sites. - Half-life can increase, decrease or even remain constant. - Total steady-state concentration will be reduced as clearance is increased. There is always an inverse relation between total steady-state concentration and clearance. - Both unbound steady-state concentration and effect will remain constant as the free steady-state concentration can always be replaced by the reservoir (total steady-state concentration). 3
Example 3: A patient receiving a drug with low extraction ratio and has low liver blood supply. From equation specified above, LBF has negligible effect on drug s various parameters. Example 4: A patient suffering from cirrhosis and receiving a drug with high extraction ratio. For drugs with high extraction ratio, the main determinant of hepatic clearance is liver blood flow as seen in the following equation: - The damage in hepatocytes should lower the intrinsic capacity of liver for elimination. But since the drug has high extraction ratio, the elimination is mainly influenced by LBF. 4
Example 5: A patient receiving drug with high extraction ratio and suffering from hypoalbuminemia or hyperbilirubinemia. - As mentioned before, the reduction in plasma protein binding will increase the free fraction of drug, volume of distribution and t 1/2. - As Cl is constant, then total steady-state concentration will be constant also (Css is a function of Cl). - The response will increase as the unbound Css is elevated due to reduction of plasma protein binding. 5
Example 6: A patient receiving drug with high extraction ratio and suffering from reduced blood supply to the liver. As mention before, hepatic clearance is a function of LBF only for drugs with extraction ratio more than 0.7. - Reduction in blood flow will reduce hepatic clearance. - Reduction in clearance will elevate half-life. - The inverse relationship between clearance and total Css will lead to increase in Css. - As total Css is increased then unbound Css will be increased also and response will be elevated. 6
Example 7: A patient receiving hepatic enzyme inducer like carbamazepine and another drug with low extraction ratio. As we know, carbamazepine increase synthesis of liver enzymes and increase Cl int. - Increase in Cl int will increase hepatic clearance (Cl H = f B. Cl int ). - The increase in hepatic clearance will reduce drug s half-life (t 1/2 = (0.693*V)/Cl). - The increase in hepatic clearance will reduce total Css (Css = K 0 / Cl) - The reduction in total Css will reduce unbound Css (Css u =f B. Css). - The reduction of unbound Css will reduce pharmacological response. 7
Example 8: A patient is receiving carbamazepine together with another drug that has high extraction ratio. In this case, the hepatic clearance is mainly dependent on liver blood flow and not intrinsic capacity of liver enzymes. Here, none of the parameters are changed in response to liver enzymes induction. 8
Problem: A patient is receiving phenytoin (a low hepatic extraction ratio drug) for the treatment of tonic-clonic seizures. Because of continued seizure activity, valproic acid is added to the patient s drug regimen. Valproic acid inhibits the clearance of phenytoin and displaces phenytoin from plasma protein binding sites. Assuming that these changes occur instantaneously with the institution of valproic acid therapy, diagram how the following parameters will change for phenytoin: liver blood flow, intrinsic clearance, free fraction of drug in the blood, clearance, volume of distribution, half-life, total steady-state concentration, unbound steady-state concentration, and drug effect. Answer: - Phenytoin has low extraction ratio, Cl H = f B. Cl int. - Valproic acid displaces phenytoin from plasma proteins and increase free fraction of phenytoin. - Valproic acid competes with phenytoin for metabolism by liver enzymes and decrease Cl int. - Hepatic clearance should remain constant. - Both V and t 1/2 will increase (t 1/2 = (0.693*V)/Cl). 9
- Total Css will remain constant as hepatic clearance is not changed. - The unbound Css will increase due to the increase in free fraction and hence the effect will increase also. 10