Pharmacokinetics: A Guide to Drug Movement in the Body

The volume of the body that the drug can reach Volume of Distribution What factors affect volume of distribution? Water solubility, size of the drug, affinity for blood proteins, lipid solubility, and affinity for extravascular tissues Relates rate of elimination of drug to its concentration Clearance What happens to clearance if there is damage to one of the elimination organs? Clearance (which has an additive effect, goes down) This slows down as the concentration decreases because of clearance. Because it's proportionate, clearance is consatant Rate of Elimination Ethanol Aspirin Phenytoin Which 3 drugs follow zero-order rather than first-order kinetics? 1/5 these require an endogenous cofactor that is limited in supply Time to change the amount of a drug in the body by 50% Half life what is the effect of Vd on half life? If Vd is increased, you have a longer half life What is the effect of clearance on half life If clearance is lower than normal you'll have a higher than normal half life variable K Fraction of drug cleared per unit time (0.7 / t1/2) How many half lives need to pass to reach steady state? 4 half lives are required to eliminate 94% of the drug Accumulation factor 1/ fraction lost in one dosing interval (k) = 1/ 1-fraction remaining to give you Bioavailability Fraction of drug dose that reaches the site of action or biological fluid from which drug has access to its site of action Bioavailability = fraction made available x (1-Elimination Rate) What route of administration is most ef- IV. It is direct BUT needs a professional fective? to perform What route of administration is least ef- Oral. It has very low bioavailability but is fective? easy to use and has best compliance First pass elimination When you take an oral drug it passes through the liver via portal blood. the liver will metabolize a portion of the drug and will eliminate a portion of it (this is first-pass elimination). ER = Liver clearance/ hepatic blood flow which form of a drug does absorption favor? Non ionized (more lipophilic) 2/5 Is a weak acid or a weak base better absorbed in the stomach? Weak acid Where is a weak base more readily absorbed, the stomach or the intestines? The intestine Why is intestinal absorption higher in the The intestines have a MUCH greater abintestine than the stomach regardless of sorptive surface? pH? Bioequivalence Present if drug products do not significantly differ in rates and extent of bioavailability of active compound; primary differences are in solubility and rate of absorption due to formulations Albumin binds acidic drugs. If albumin is How do albumin levels affect efficacy of low due to a disease state, more of the acidic drugs? acidic drug needs to be administered alpha acidic glycoprotein binds basic drugs. In inflammatory disorders among How do alpha acidic glycoprotein levels other diseases this is high, you need to affect efficacy of basic drugs? give a smaller dose of basic drugs in this case Increased protein (like albumin) binding decreases the amount of the drug that is acting on the target tissue and decreases clearance (because it attaches strongly to plasma proteins). VD AND CLEARANCE ARE SMALLER HERE. You have What is the role of protein binding in drug to give A HIGHER DOSAGE of these availability? drugs If a drug doesn't bind to plasma proteins, you have a much higher clearance and Vd and you have more available to act on target tissue. This means you need less of this drug to get the desired affect Does a drug that is sequestered in fat or High. More of it is likely to leave the blood bone have a high or low Vd? and distribute throughout the body 3/5 Does a drug that binds tightly to plasma Low. Less of it is leaving the blood so the proteins have a high or low Vd? Vd is limited to the vascular system. Target concentration The concentration of a drug that will give maximal efficacy with minimal risk of toxicity Dosing attempting to maintain steady state drug concentration (Dosing rate/oral bioavailability) x dosing interval Maintenance dose the longer the interval the higher the amount of the drug you want to give you want to give the drug in as long of intervals as possible while maintaining efficacy and decreasing the risk of toxicity Dosing rate Clearance x Target concentration. This determines how often you need to dose to keep target concentration Loading Dose Vd x TC -log(PKa of the drug-PH of the environment) This is the ratio of ionized to unionized drug there is in this environment. The higher the ratio the more readily absorbed or the more easily it can cross a How do you determine how likely a drug lipid membrane. is to cross a membrane or be absorbed? For instance a drug with a pka of 4.4 (a weak acid) in the stomach with a pH of 1.4 will yield a ratio of (4.4-1.4 = 3, antilog of 3 is 1000 = 1000:1) which means that it is majority non ionized (can cross). Once it crosses into the plasma (pH = 7.4) the 4/5 drug is not (4.4-7.4 = -3, antilog(-3) = 0.001 = 1:1000) mostly ionized and cannot cross the membrane back into the stomach What do you administrate to trap methamphetamine (weak base) in the urine after overdose? Add ammonium chloride to acidify the urine. More acidic urine will trap more of the base and increase excretion Add bicard to make the urine less acidic. What do you administrate to trap aspirin Less acidic urine will trap more of the (weak acid) in the urine after overdose? acid and increase excretion 5/5