EXCRETION A. THE KIDNEYS: 1. Principle route of drug excretion 2. Involves 3 processes: a. Glomerular filtration rate: rate at which compounds leave the plasma and enter the tubules: i. Dependent on bound/free ratio of drug in plasma b. Active tubular secretion: Once a compound reaches the tubules, it is often bound to compounds that are actively secreted by the tubules: i. Such binding is pH-dependent, hence occurs mostly for IONIZED compounds ii. AND ionized compounds have trouble passively crossing back through the tubules and re-entering the plasma, hence circulation iii. This is why many metabolic processes IONIZE drug metabolites iv. Hence drug elimination is dependent upon pH of the urine, and can be altered by altering urine pH. v. Making urine more alkaline increases ionization of weak acids, hence slowing reabsorption/increasing elimination. The opposite is the case for weak bases. vi. EXAMPLE: Increasing urine pH from 6.4 to 8 increases elimination of salicylic acid 5-fold c. Passive tubular reabsorption: greatest for non- polar, lipophilic compounds, B. THE GI TRACT: Fecal elimination 1. Some compounds are excreted unmetabolized and unabsorbed in feces 2. Some liver metabolites are excreted into the bile, reaching the digestive tract in this fashion C. THE LUNGS: Gases are excreted by this route D. etc - saliva, sweat elimination of non-absorbed drug E. THE BRAIN: CONTAINS MANY METABOLIC ENZYMES! 1. These are often critical for the rapid de-activation of neurotransmitters in the synaptic cleft 2. Hence drugs which enhance or inhibit such enzymes can have potent effects on neurotransmission 3. For example, Monoamine Oxidase - MAO - the enzyme which metabolizes dopamine, serotonin and norepinephrine in the brain PHARMACOKINETICS: The quantitative description of drug effects on tissues: i. Most often conducted by repeatedly drawing and analyzing blood samples over time after drug administration. ii. But same can be done with target tissues in experimental animals iii. Modern HPLC/ GC / Mass Spec techniques allow detection of drug AND metabolites, often in parts per billion. iv. AS does use of radiolabelled compounds, altho these often can't distinguish between drug and metabolite v. To understand, must realize that many drugs are stored in lipids, other tissues, and slowly released back into circulation 3 IMPORTANT CONCEPTS IN PHARMACOKINETICS: A. CLEARANCE (Cl): Rate at which the drug leaves the blood or target tissue, due to metabolism and elimination 1. Extremely important clinically - for most psychoactive compounds, the goal is to maintain constant drug levels for months or years 2. Two major RATES of clearance: a. Zero-order kinetics: clearance (metabolic, elimination) mechanisms are SATURATED, so a constant AMOUNT of compound is cleared per unit time i. Example: Alcohol ii. Produces linear decay rates b. First-Order kinetics: Clearance mechanisms are NOT saturated, so constant PERCENTAGE of compound is cleared per unit time i. Most common form of drug clearance ii. Produces curvilinear decay rates, often shown on semi-log graphs iii. Example, in terms of half-life: Number of half-lives Amount of drug in the body percent eliminated percent remaining 0 0 100 1 50 50 2 75 25 3 87.5 12.5 4 93.8 6.2 5 96.9 3.1 6 98.4 1.6 B. VOLUME OF DISTRIBUTION (V): A theoretical, rather difficult concept! 1. In words, The fluid volume necessary to contain the total amount of drug in the body at actual blood or plasma concentrations 2. Hence volume of distribution does NOT correspond to any volume of any compartment in the body! 3. Mathematically, Volume of Distribution=V=Total amount of drug in body/concentration of drug in plasma or blood. a. Example: if 500 æg of haloperidol were in the body of a 70 kg man, and plasma concentrations were 0.7 ng/ml, then: V=500 æg/0.7ng/ml=ml*(500 æg/0.7ng)= (Converting to ng)=ml*(500*103/0.7)=7.14*105 ml (Converting to liters)=7.14*105/103 liters=714 liters (Which is much greater than the total volume of a human being!) 4. So why is V often > total human volume? Many drugs are sequestered in lipid, or bind to other sites 5. Understanding V: when V÷5 liters, the approximate plasma volume in a human being, almost all drug is in the plasma. As V>>6 liters, drug is increasingly bound to other tissues C. CLEARANCE: Rate at which drug leaves a tissue, usually in units of mg of drug/min-kg, where kg is body weight in kilograms D. HALF-LIFE (t1/2): The time it takes for some measure of drug content or concentration to decline by 50% 1. Especially important for first-order kinetics E. CMAX - The highest concentration achieved in a tissue, usually blood, after drug administration F. AUC - Area Under Curve - an integral, over the entire time course of the drug in a tissue, usually blood WHY ALL THIS IS IMPORTANT: A. Therapeutic windows: See diagram B. LD50, ED50, and the therapeutic index (TI) TI=LD50/ED50, so bigger is better C. Toxicity, therapeutic efficacy and pharmacokinetics D. Drug development, cross-species comparisons and pharmacokinetics E. See TABLE for some psychopharmaceuticals