Clinical Pharmacology Practical course 5th year Clinical Pharmacokinetics: Def: It is the study of what the body does to a drug. This part involves the following items: 1- Routes of drug administration. 2- First order kinetics. 3- Zero order kinetics. 4- Dosage regimens. 1- Routes of drug administration: 1- Alimentary routes: a- oral. b- sublingual. c- rectal. 2- Parentral routes: a- intra-venous. b- intra-muscular. c- intra-arterial. d- intra-dermal. e- sub-cutaneous. f- intra-peritoneal. g- intra-thecal. h- intra-cardial. 3- Topical route. 4- Respiratory route. * Alimentary routes: 1- Oral route: Adv.: safe, easy, economic and does not need complete sterilization. Disadv.: not suitable for unconscious and vomiting patients, not suitable for irritant drugs and drugs inactivated by gastric secretions or first pass effect. 2- sublingual route: Adv.: rapid effect, bypass GIT inactivation and first pass effect. Disadv.: not suitable for unconscious patients bitter and irritant drugs. 3- Rectal route: Adv.: rapid effect, suitable for unconscious and vomiting patients. By pass GIT inactivation or first pass effect. Disadv.: not acceptable by the patient, oily base may cause diarrhea. * Parentral routes: 1- Intra-venous route (I.V.): Adv.: rapid effect, high bioavailability, used in emergency, suitable for unconscious patients and irritant drugs. Disadv.: needs complete sterilization, well trained person for injection, used only for aqueous soln., not for suspensions, emulsions or oily formulations. 2- Intra-muscular route (I.M.): Adv.: suitable for oily formulations, gives sustained action. Disadv.: not suitable for irritant drugs, slower than I.V. route, needs sterility. 3- Intra-arterial route (I.A.): Adv.: suitable for cytotoxic drugs. Disadv.: needs highly skilled person. 4- Intra-dermal route: Adv.: used in vaccination and sensitivity test. Disadv.: needs sterility. 5- Subcutaneous route (S.C.): Adv.: used for oily colloidal soln., suitable for drugs degraded by GIT enzymes e.g. insulin, rapid acting than oral. Disadv.: not suitable for irritant drugs, more painful than I.V or I.M. 6- Intra-thecal: Adv.: used for anesthesia. Disadv.: needs highly skilled person. 7- Intra-cardial: Adv.: used in cardiac arrest. Disadv.: needs highly skilled physician. * Topical route: Adv.: gives local action. Disadv.: not suitable for irritant and unstable drugs. * Respiratory route: Adv.: gives local action on bronchi as in bronchial asthma, used in anesthesia as ether. Disadv.: suitable only for volatile drugs. I.V. route Intra-thecal route Intradermal, subcutaneous and intramuscular routes 2- Zero order kinetics: A constant amount of drug is eliminated per unit time. This form of kinetics occurs with several important drugs at high dosage concentrations: phenytoin, salicylates, theophylline, and thiopentone (at very large doses). 3- First order kinetics: A constant fraction of the drug in the body is eliminated per unit time. The rate of elimination is proportional to the amount of drug in the body. The majority of drugs are eliminated in this way. What follows concerns drugs which follow first order kinetics. The Volume of Distribution (Vd): is the amount of drug in the body divided by the concentration in the blood. Drugs that are highly lipid soluble, such as digoxin, have a very high volume of distribution (500 litres). Drugs which are lipid insoluble, such as neuromuscular blockers, remain in the blood, and have a low Vd. The Clearance (Cl): is the volume of plasma from which the drug is completely removed per unit time. The amount eliminated is proportional to the concentration of the drug in the blood. The elimination constant (K): is the fraction of the drug in the body eliminated per unit time. Cl = K x Vd Rate of elimination (R) = clearance (cl) x concentration in the blood (Cp). Elimination half life (t1/2): the time taken for plasma concentration to reduce by 50%. After 4 half lives, elimination is 94% complete. t1/2 = 0.693/K Likewise, Cl = K x Vd, so, Cl = 0.693Vd/t1/2. And t1/2 = 0.693 x Vd / cl 4- Dosage regimen The strategy for treating patients with drugs is to give sufficient amounts that the required therapeutic effect arises, but not a toxic dose. The maintenance dose is equal to the rate of elimination at steady state (i.e. at steady state, rate of elimination = rate of administration): Dosing rate = clearance x desired plasma concentration. Drugs will accumulate within the body if the drug has not been fully eliminated before the next dose. Steady state concentration is thus arrived at after four half lives. This is all very well if you are willing to wait 4 half lives for the drug to be fully effective, but what if you are not? What you may need to do is to "load" the volume of distribution with the drug to achieve target plasma concentrations rapidly: the loading dose. The loading dose = the volume of distribution x the desired concentration (i.e. the concentration at steady state). or Loading dose = usual maintenance dose / usual dosage interval x K (t1/2/0.693). or Loading dose = rate of drug elimination/elimination rate constant. Practice problems 1- Penicillin has Cl of 15 ml/min. Calculate the R for penicillin when Cp is 2 µg/ml. Ans: R = Cl x Cp = 2 µg/ml x 15 ml/min = 30 µg/min. 2- Calculate the Cl for a drug in a 70-Kg male patient. The drug follows the kinetics of a one-compartment model and has an elimination t1/2 of 3 hrs with Vd of 100 ml/kg. Ans: k = 0.693/t1/2 = 0.693/3 = 0.231 hr-1. Cl = 0.231 hr-1 x 100 ml/kg = 23.1 ml/kg.hr. for a 70-kg patient Cl = 23.1 ml/kg.hr x 70 kg = 1617 ml/hr. 3- A new anti-biotic is actively secreted by the kidney and Vd is 35 L in the normal adult. Cl of this drug is 650 ml/min. calculate the usual t1/2 for this drug and calculate the new t1/2 for this drug in adult with partial renal failure whose Cl of the anti-biotic was only 75 ml/min. Ans: t1/2 in normal adult = 0.693 (35000 ml)/650 ml/min = 37.3 min. t1/2 in patient = 0.693 (35000 ml)/75 ml/min = 323 min. 4- A physician wants to administer an anesthetic agent at a rate of 2 mg/hr by IV infusion. The k is 0.1 hr-1 and the Vd (one compartment) is 10 L. What loading dose should be recommended if the doctor wants the drug level to reach 2 µg/ml immediately? Ans: Loading dose = R/k = 2 mg/hr /0.1 hr-1 = 20 mg.