1. Lecture 2

2.  Clearance Ability to eliminate the drug  Volume of distribution (Vd) The measure of the apparent space in the body available to contain the drug Relates the amount of drug in the body to the concentration of the drug in blood or plasma  It is the volume apparently necessary to contain the amount of drug homogeneously at the concentration found in the blood or plasma or water  High Vd = higher concentration in extravascular tissue than in blood  not homogeneously distributed.

3.  Clearance Additive character of clearance  Elimination may occur in the kidneys, liver, lungs, etc.  Major sites are kidneys and liver First order elimination  Rate of drug elimination is directly proportional to concentration  Rate of elimination may be saturable, if drug is given high enough (V max = maximum elimination capacity) Zero order elimination  Rate of drug elimination is constant or independent of concentration

4.  Clearance Zero order elimination will follow first order elimination at low concentrations 3 common drugs that follow zero order elimination  Ethanol  Phenytoin  Aspirin

5.  Clearance and half life Half-life (t ½ ) = the time required to change the amount of drug in the body by one half during elimination (or during constant infusion)  Indicates the time required to attain 50% of steady state or to decay 50% from steady state conditions Steady state = maximum drug level where there is an equilibrium between administration and elimination  Will be achieved after 4 half lives have elapsed Useful in determining drug dosage regimens

7.  Clearance and half life Drug accumulation = if dosing interval is shorter than four half lives

8.  Bioavailability The fraction of unchanged drug reaching the systemic circulation, following administration by any route After administration, drugs need to be absorbed and pass through several compartments (depending on the route of administration)  Absorption (ex. intestines, blood, body compartments, etc)  Elimination (orally administered drugs will pass thru the liver first)

9.  Bioavailability Extent of absorption  Depends on drug characteristics (lipophylic, hydrophilic, pH, etc)  If too hydrophilic = difficult time to pass thru the cell membrane  If too lipophilic = difficult to enter the blood plasma  Some drugs are actively pumped back into the gut lumen (ex. P-glycoprotein transporter)  Drinking grapefruit juice will inhibit the P-glycoprotein transporter, thus increasing drug absorption

10.  Bioavailability Extent of absorption  Absorption rate also follows zero-order and first- order absorption  Zero order: rate of absorption is independent of drug concentration  First order: rate of absorption is proportional to drug concentration in the gut (which is saturable)

11. RouteBioavailability (%)Characteristics IV100 (by definition)Most rapid onset IM75-100Large volumes often feasible; may be painful SC75-100Smaller volumes than IM; may be painful Oral5 to <100Most convenient; first pass effect may be significant Rectal30 to <100Less first pass effect than oral Inhalation5 to <100Often very rapid onset Transdermal80-100Usually very slow absorption; used for lack of 1 st pass effect; prolonged duration of action

12.  Bioavailability Extent of elimination  biotransformation = may reduce or increase bioavailability  First pass elimination  Drugs absorbed in the gut will first travel to the liver (portal system)  Drugs can be metabolized by the gut wall, by the blood, but mostly in the liver  Phase I and Phase II reactions  Second pass elimination  After the drug has circulated in the body, it is ready for excretion  May need to be modified again by the liver or kidney for excretion

14.  Phase I reactions Usually convert the parent drug to a more polar metabolite  More polar = more water soluble = more easily excreted in the kidneys  Phase II reactions Conjugation type of reaction  Make drug even more polar or non-polar to prevent rapid excretion from the body

15.  Usually occur in the liver Liver enzymes (cytochrome p450) = will metabolize or transform the drug Enzyme inducers and enzyme inhibitors  Certain drugs can induce or inhibit cytochrome p450  Drug metabolites may be potentially toxic Ex. paracetamol (acetaminophen) = liver = produce liver damaging metabolites if given at high doses

16. Drugs metabolized in the liver Enzyme inducersEnzyme inhibitors Paracetamol Warfarin Propofol Celecoxib Phenytoin Benzodiazepines (diazepam) Dapsone Erythromycine Macrolides Azoles (fluconazole) ETC. Rifampin Phenobarbital Carbamazepine Phenytoin Cyclophosphamide Isoniazid Carbamazepine Charcoal broiled foods Cruciferous vegetables Allopurinol Cimetidine Clopidogrel Quinidine Azoles (fluconazole, itraconazole) Macrolides (erythromycin) Grapefruit juice

17.  Bioavailability Extent of elimination  Some drugs, after the 1 st pass or 2 nd pass effect, will produce metabolites that are toxic  These will determine how a drug is administered.  Ex. Lidocaine is never administered orally, because its metabolites are toxic to the brain. = always given IV AUC = area under the curve (blood concentration time curve)  Blood concentration of drug is directly proportional to bioavailability of the drug

19.  Time course of drug effect Immediate, delayed, prolonged, etc. Directly related to drug concentration and rate of elimination  How fast a drug reaches the organ or tissue  How fast it is eliminated Depends on drug’s mechanism of action Effect may accumulate over time if dosage exceeds elimination

20.  Reach a target concetration (TC) Concentration of drug that will produce the desired effect Ideally the lowest concentration in this range  Maintenance Dose Reach a steady state concentration Just enough drug is given in each dose to replace the drug eliminated since the preceding dose At steady state: rate in = rate out

21.  Loading Dose A higher drug dose that will attain the target concentration, even with just 1 dose Especially frog drugs that have long drug dose intervals Consequences  Reach a therapeutic level quickly = faster respone  May produce more toxic by products

23.  Patient factors Compliance Genetic or metabolic differences, which may increase or decrease drug bioavailability Health conditions (ex. liver or kidney problems, s/p intestinal resection, etc.) that can affect absorption and clearance Weight, sex, nutritional status, pregnancy = can affect volume of distribution