Pharmacokinetics Lecture One August 24, 2009 Pharmacokinetics is the study of drug Absorption, Distribution, and Elimination or how

the drug moves through the system; Elimination can be broken down into Metabolism and Excretion; some drugs may go through either metabolism or excretion, and some drugs may go through both Clinical pharmacokinetics deals with how these concepts apply to individual drugs Pharmacokinetics is employed in every aspect of pharmacy

Drug Interactions
Drug-drug, drug-food, and drug-disease interactions can either increase or decrease the effect of a particular drug Drug-food interaction: for example, if bisphosphonates are given with food absorption decreases causing a decreased drug response; if iron is given with orange juice absorption increases causing an increased drug response Drug interactions can either be kinetic or dynamic: 1. Kinetic interactions- 80% or more of drug interactions are kinetic in nature; any alteration in kinetics will change the dynamics (or response), but alterations in dynamics do not alter the kinetics; the more drug that gets to the receptor site, the more intense the response [D -> DR -> Intensity]; the kinetics can alter the amount of drug that gets to the receptor site; the interaction of Probenacid and Penicillin is kinetic because Probenacid decreases the renal excretion of Penicillin; Zyvox can cause the levels of Demerol to increase; this interaction would only be a problem if the patient continues to take the Demerol; if the patient takes their last dose of Demerol and then takes Zyvox it would not be a problem because if the patient is not still taking the Demerol it cannot accumulate in the body; Demerol concentrations may increase in the body, but they will not be able to reach a toxic level because there is not any accumulation; kinetic interactions involving absorption can be overcome by spacing the drugs out, but kinetic interactions involving distribution and elimination cannot because the drug is already in the system 2. Dynamic interactions- i.e. Vancomycin and Aminoglycosides Some drugs work synergistically to cause a greater response: - Aminoglycosides and Vancomycin used to treat MRSA; Aminoglycosides do not treat MRSA because they are strictly Gram - and Staph is Gram +, but for some reason when Aminoglycosides are used with Vancomycin the killing activity increases;

Aminoglycosides do not affect any kinetic parameters (absorption, distribution, elimination) of Vancomycin so this is a pharmacodynamic interaction Probenacid decreases the renal excretion of Penicillin, because it blocks the renal tubular secretion of Penicillin; this causes the Penicillin response to increase because less Penicillin is being excreted; this is a kinetic interaction

Drugs can either be bound or unbound to plasma protein: 1. Bound: highly protein bound drugs are inactive because they cannot cross membranes to get to the site of action 2. Unbound: the unbound form of the drug is the active form because it can cross membranes to get to the site of action When we take a blood level it contains a combination of bound and unbound drug; if protein binding is affected, then distribution is affected; if something displaces a drug from its protein binding site there is more unbound drug to interact with the receptor site (increased distribution); when distribution increases, blood concentration decreases Volume of Distribution - When the volume of distribution increases, the blood concentrations decrease because the drug has moved out of the blood and into the tissue - A blood sample will contain bound and unbound drug, but most of it will be bound because the unbound drug has the potential to leave the bloodstream and diffuse into the tissue - If you give something that causes protein displacement the concentration of drug in the blood will decrease because the unbound drug now has the potential to leave the bloodstream and go into the tissue; this will cause an increased drug response because more drug is able to get to the site of action; thus there can be situations where the blood concentration is low, but the response is greater - Example: it doesnt matter if you give Coumadin at 8 am and Aspirin at 8 pm, the Aspirin will still displace whatever Coumadin is left on the protein binding sites causing an increased Coumadin effect The terms blood concentration, serum blood concentration, and plasma concentration do not mean the same thing, but in practice they are often used interchangeably Blood concentration- in practice we usually obtain a blood concentration, not a plasma concentration; the blood concentration measures the total amount of drug in the plasma, as well as the blood elements Plasma concentration- the blood is centrifuged and the RBCs, WBCs, and platelets are removed (the clotting factors are still present); a plasma concentration only measures the amount of drug present in the plasma, but some of the drug will be in the blood elements that are removed

Serum blood concentration- the blood is centrifuged again until just the waste products are present (electrolytes, water, albumin); all blood elements and clotting factors are removed so this concentration does not represent the amount of drug present in those tissues

Things that can alter the pharmacokinetics of a drug include: - Diet: diet usually affects absorption, but not in every situation; an exception to this would be foods high in Vitamin K and Coumadin; if someone is on Coumadin and they are eating a lot of collard greens their Coumadin response will go down because Coumadin works on Vitamin K dependent clotting factors (the more Vitamin K given, the more clotting factors are produced) - Disease: disease states can affect any aspect of kinetics (i.e. liver cirrhosis and elimination, Chrons Disease and absorption) - Other drugs: other drugs can affect any aspect of kinetics (i.e. Questran prevents the absorption of Digoxin in the GI tract, Aspirin increases the distribution of Coumadin by displacing it from protein binding sites, Probenacid prevents the elimination of Penicillin by blocking renal tubular secretion)

Pharmacokinetics Lecture Two August 26, 2009 Factors that can alter pharmacokinetics: - Food - Disease - Other drugs If all you see is a change in response (synergism, antagonism), it is a pharmacodynamic interaction; if there is an alteration in ADME then it is pharmacokinetic

Absorption

Every route of administration has to be absorbed except for IV; intrathecal injections have to be absorbed into systemic circulation as well in order to be excreted; some drugs are broken down before they are absorbed by stomach acid, bacteria, etc; some drugs are excreted through the feces unchanged (it got absorbed, went through the enterohepatic circulation without being metabolized, and went back into the intestines or it was never absorbed to begin with) There are 3 basic rate limiting steps for oral absorption: 1. Disintegration- this is the first thing that has to happen; the faster the drug breaks down, the faster it is absorbed; this is where brand and generic (or two different generics) products might differ; if one drug is bound tighter than the other it will take longer to disintegrate; powders absorb faster because they are already disintegrated (i.e. BC powder) 2. Dissolution- the faster it goes into solution, the faster it is absorbed (gelcaps vs. tablets); gelcaps will work faster because they disintegrate faster and are already in solution 3. Absorption across the cell membrane Water crosses the cell membrane (which is lipid) freely; water moves from a higher concentration to a lower concentration across a concentration gradient (osmosis) Things that cross the membrane freely: unionized particles that are not too big; select small molecules; lipid soluble substances (lipid soluble vitamins A, D, E, & K); Vitamin E is an antioxidant that is able to cross into the CNS; if you eat a meal high in fat not all of the fat will be absorbed, and Vitamin E absorption will decrease because the Vitamin E will get trapped in the fat; this is a kinetic interaction Things that do not cross the membrane freely: highly charged particles (just because a substance is highly charged it doesnt mean that it wont cross, it just wont cross freely; it needs a carrier; if something is said to be 100% ionized there is still a small portion that is unionized; this small percentage of unionized particle will be able to

cross the membrane; thus highly charged substances might absorb slower, but they still absorb; if GI motility increases the drug will be pushed through the GI tract and not have the opportunity to be absorbed); large molecules, such as proteins, cannot cross the membrane freely; these molecules can cross but they need energy or a carrier The rate and extent of absorption depends on the solubility and formulation (liquid, elixir, tablet, ER tablet) of the drug; the rate and extent of absorption also depends on the pka and whether the drug is acidic or basic, and the individuals physiological environment (vascularity, GI motility, stomach pH, fat content, amount of lean muscle mass with IM injections); warm drinks increase absorption and cold drinks decrease absorption, but water is best absorbed when it is cold

Bioavailability

Absorption is a subcategory to bioavailability; anything that affects absorption will affect the bioavailability, but everything that affects bioavailability does not affect the absorption Bioavailability describes how much drug is available in systemic circulation; absorption tells how much drug is absorbed; a drug has to be absorbed in order to go through first pass metabolism; if the drug goes through first pass metabolism there is less available in systemic circulation, thus absorption is not affected but the bioavailability is F tells us the amount of drug that is absorbed (the amount of drug that enters systemic circulation); F does not represent the absolute bioavailability F = (the amount of drug that reaches systemic circulation)/(the amount of drug given) Absolute bioavailability = 1 ER nonhepatic loss Dose x S x F = what is available to work S (the chemical form) does not affect absorption, but it does affect bioavailability because it changes the amount that is available in systemic circulation; for example, lets take Dilantin (Phenytoin sodium); Dilantin is 92% acid and 8% salt so the S factor for Dilantin would be 0.92; if 100 mg of Dilantin were given by mouth and all of it was absorbed the F would be 1.0 because all of the drug is absorbed but only 92% is available to work so the absolute bioavailability would be different

Pharmacokinetics Lecture Three August 31, 2009 F represents bioavailability F = how much drug that reaches systemic circulation/ the total amount of drug given S is the chemical form Dose x S x F = the amount of drug that reaches systemic circulation Things that affect absorption/bioavailability: 1. Solubility 2. Chemical form 3. Physiologic environment of the individual 4. First pass affect: does not affect absorption (because the drug has already been absorbed), but does affect bioavailability; some drugs undergo first pass affect, but it doesnt make that much of a difference (i.e. only 1% of the drug is lost); some drugs do not undergo first pass at all; about 1,500 mLs of blood comes through the liver per minute; some of it comes from the hepatic artery and some comes from the portal vein; about 75-80% of the 1,500 mLs comes from the portal vein which gets its blood from the stomach and small intestines; thus 900-1000 mls of blood comes from the stomach and small intestines into the portal vein; the first stop the portal vein makes is the liver; this is why some drugs go through first pass affect; when the drug goes to the liver some of the drug is extracted out and what is left is the amount that is able to work in systemic circulation; thus, the amount that is given by mouth is not the amount that is available to work; if the drug is given IV it bypasses first pass; Morphine is an example of a drug that undergoes first pass affect Extraction ratio: ER = (Ca (amount that went in) Cv (amount that came out))/Ca ER = (10-2)/10 = 0.8; the ER = 0.8 5. GI motility: fast GI motility causes decreased absorption; slow GI motility causes increased absorption Gastric emptying: the first place the drug goes when it is taken orally is the stomach; the pH of the stomach is about 2 (it can be as low as 1 or as high as 3); when a basic drug is taken it will increase the pH of the stomach; when food comes into the stomach, acid is secreted to maintain a low pH; anytime something causes the pH to drop, gastric emptying is triggered; gastric emptying can take anywhere from 1-3 hours; the duodenum is small part of the small intestine, but it is where most absorption takes place (things can be absorbed anywhere in the intestine, but not as much as they are in the duodenum); the average pH of the duodenum is 6; the pancreas secretes pancreatic juices including bicarbonate directly into the duodenum causing the pH to rise; the pancreas also secretes lipases that help to

emulsify fats; if you want to avoid decreasing absorption of drugs when taking antacids you should take the drug 1 hour before or 2-3 hours after the antacid; it is easier to take the offended drug before the offending drug (i.e. take Digoxin 1 hour before Questran rather than taking it 3-4 hours after Questran) Small intestine transit time: SITT is the time it takes for food to be emptied into the duodenum and expelled through the anus; if something causes gastric emptying to proceed faster it can cause GI motility to increase; just because gastric emptying is increased (emptied faster) it does not mean that SITT has to change (but it can change); SITT is roughly 3-4 hours; average GI motility is 4-8 hours; if SITT proceeds faster or GI motility increases, absorption decreases because there is less time for the drug to be absorbed 6. Vascularity: blood vessels under the tongue absorb drugs rapidly; we used to tell people with hypertensive urgency to chew up a Nifedipine and hold it between their gums; this can lower the BP too fast 7. Ionization state 8. pH: enteric coated ASA will stay intact in the acidic environment of the stomach and will dissolve in the basic environment of the duodenum; pH affects absorption because of the ionization state but also because like dissolves like

AUC = concentration/time True bioavailability takes AUC into account; F only deals with the extent of absorption; true bioavailability not only takes into account how much gets there, but also how long it takes to get there; true bioavailability deals with the concentration and the time (AUC) Bioequivalent: same AUC, same Cmax, and same Tmax; this is usually the case for brand and generics, but not all brand and generics are bioequivalent because they may have the same AUC, but a different Cmax and Tmax; this difference has to do with the amount of pressure used to bind the drug; if a drug is bound tighter it will release disintegrate more slowly; brand vs. generic and generic vs. generic should be bioequivalent; if there is greater than a 5% error in the Cmax and Tmax, the drug is considered to not be bioequivalent Therapeutically equivalent: therapeutically equivalent drugs treat the same thing (Toradol and Vicodin are considered to be therapeutically equivalent); not only does the drug have to treat the same thing, but the dose has to match to get the equivalent therapeutic effect (Zocor 20 mg = Lipitor 10 mg, Zocor 40 mg = Lipitor 20 mg, Zocor 80 mg = Lipitor 40 mg)

Pharmacokinetics Lecture Four September 2, 2009 We have a patient that normally takes Captopril first thing in the morning, before breakfast; they called in their Rx the night before and forgot to pick it up; on this day they do not take it first thing in the morning because they have to pick it up at the pharmacy; on the way to the pharmacy they eat some oatmeal; the pharmacy dispenses a different generic than what the patient usually gets; now the patients blood pressure is not being controlled as it normally is: - This could be due to differences in the two generic medications (different bioavailabilities) - This could be due to eating before taking the medication; the absorption of the drug was decreased due to food - The blood pressure was checked at a different time than it usually is - The patient might have been under more stress than usual When something is absorbed, the first place it goes is the liver; 75% of the blood that goes to the liver comes from the portal vein; not every drug is affected by first pass effect Things that affect GI motility: 1. Cold drinks can slow GI motility because they cause blood vessels to constrict; this decreases blood flow to the stomach and intestines 2. High fat meals slow GI motility 3. Anticholinergic drugs slow GI motility; Cholinergic drugs increase GI motility 4. Prolonged affects of diabetes can slow GI motility (Diabetic Gastroparesis); we can treat this by giving drugs that increase GI motility, such as Cholinergic Drugs, Metoclopramide (Reglan), and Erythromycin 5. Severe diarrhea increases GI motility Distribution - Anytime a drug is absorbed into the body, it circulates the system and is distributed throughout the entire body - We have to use enough drug so that it reaches the site of action (if you have a big toe infection, all of the medication does not go to the big toe, but we have enough drug in the system to treat the problem) - If we know how the drug is distributed to different areas we can have an idea of how much drug will reach the site of action - The amount of drug in the blood is proportional to the amount of drug at the receptor site; as the amount of drug in the blood increases, the amount of drug at the receptor site should increase (there are certain things that can cause this rule to falter)

We need to dose the drug so that the concentration in the blood remains at a level to where there is enough drug to reach the receptor site When a drug transfers from the GI tract to the bloodstream it is absorbed; when a drug transfers from the blood to a tissue it is distributed; if the drug then leaves the tissue and goes back into the bloodstream it is reabsorbed Volume of distribution: a concept that helps us to understand the volume that the drug is contained in; this is not an accurate number, it is an estimate; you only use Vd to calculate the loading dose The loading dose allows us to achieve a certain concentration, provided we know the volume we are putting it in If S and F are not given, use 1 If you put 100 mg in and the concentration came out to be 1 mg/L, then the volume would be 100 L; use Vd = Dose/C (100 mg)/(1 mg/L) = 100 L If the volume is 10 L and we have a concentration of 10 mg/L we would need to give 100 mg; use LD = Vd x C/(S x F) (10 L x 10 mg/L)/(1 x 1) = 100 mg Use the clearance to find the maintenance dose; use the Vd to find the loading dose Loading dose is the same thing as a bolus dose; these give the concentration that we need immediately

Equations:
D=SxF D = Vd x C LD = (Vd x C)/(S x F) Cl = Vd x k D = dose, F=bioavailability, S=chemical form Vd=volume of distribution, C=concentration LD=loading dose Cl=clearance, k=rate constant

C = (D x S x F)/(Vd x k) or C = (D x S x F)/Cl

Pharmacokinetics Lecture September 4, 2009

Volume of distribution is used to determine the loading dose: LD = (Vd x C)/(S x F) Vd = (LD x S x F)/C Example: A 22 year old female needs to receive Tobramycin at a concentration of 10 mg/L; calculate the loading dose if she weighs 110 lbs and the volume of distribution is referenced as 0.25 L/kg (if S and F are not given, assume them to be 1) 1. (110 lbs)/(2.2) = 50 kg 2. Vd = 0.25 L/kg (0.25 L/kg) x 50 kg = 12. 5 L (12.5 L x (10 mg/L 0))/(1 x 1) = 125 mg

3. LD = (Vd x (C desired - C actual ))/(S x F) Answer: LD = 125 mg

Example: Now assume a maintenance dose (MD) was not given; the concentration is later measured to be 4 mg/ml; figure out the LD to get the patient back up to the desired concentration of 10 mg/ml 1. LD 2 = (Vd x (C desired C actual ))/(S x F) (12.5 L x (10 mg/L 4 mg/L)/(1 x 1) = 75 mg Answer: LD 2 = 75 mg

Example: The patient receives the loading dose of 125 mg, but the concentration in the blood is measured to be 6 mg/L (which is not the desired 10 mg/L); calculate the loading dose that would be required to bring the patient to 10 mg/L; take into account the Vd for this patient obviously came out different than the population average of 12.5 L 1. We need to find the patients Vd LD = (Vd x C)/(S x F) Vd = (LD x S x F)/C (125 mg x 1 x 1)/6 mg/L = 20.8333 L 2. Using the correct Vd, recalculate the next LD to bring the patient up to the desired concentration of 10 mg/L LD 2 = (Vd x (C desired C actual ))/(S x F) (20.8333 L x (10 mg/L -6 mg/L))/(1 x 1) = 83.3332 mg Answer: 83.3332 mg The LD 2 will add 4 mg/L of Tobramycin to bring the patient up to 10 mg/L

Dosing is usually based on ideal body weight (IBW); IBW only takes into account those who are 5 feet tall and taller; this can be problematic for children and adults under 5 feet tall since dosages are generally based on weight; people that do not fit into the normal parameters for IBW dosing are dosed upon actual weight; depending upon the drug, this patient is at risk for drug toxicity because the dose may be too high (this is a problem for obese children) IBW for men: 50 kg + (2.3 x every inch over 60 inches) IBW for women: 45.5 kg + (2.3 x every inch over 60 inches) Each inch greater than 60 inches is approximately 5 pounds; if someone is under 60 inches tall, we can adjust the dosage based on this weight conversion For example, if a person is 49 they are 3 inches under 60 inches; if they weigh 160 pounds we might subtract 5 pounds per inch under 60 inches (it is better to under dose than overdose Ex: (5 lbs x 3) = 15 lbs 160 lbs 15 lbs = 145 lbs

We would dose the patient as if they were 145 lbs instead of 160 lbs Round to four decimal places at the very end when working problems! Factors that affect distribution: - Differing characteristics of body tissue The higher the Vd the lower the blood concentration A very lipophilic drug in an obese person will have a larger Vd because it distributes well to the adipose tissue thus they will have a greater affect; a hydrophilic drug will not distribute very well in an obese person, thus they might have a decreased affect A very hydrophilic drug in a patient with fluid accumulation will have a higher blood concentration - Disease states that alter physiology CHF causes edema which alters drug distribution Liver failure decreases albumin production leading to ascites; ascites is accumulation of fluid in the peritoneal cavity; if a drug is hydrophilic, it will distribute to this area, thus increasing Vd - Protein binding Increased protein binding will decrease the Vd causing a decreased effect (protein bound drug does not cross the membrane; as protein binding decreases, more drug stays in the blood stream; this makes the concentration look high, but the effect is decreased) Decreased protein binding will increase the Vd causing an increased effect (more drug crosses the membrane to get to the site of action; the blood concentration is lower, but the effect is increased) We need to know if a drug is significantly protein bound to discern whether this will be an issue

Pharmacokinetics Lecture Six September 9, 2009 Volume of distribution (Vd) Concept that tells us how much volume the drug is contained in; it can appear to be very high or very low; it is not accurate, it is just a concept Concentration and Vd are inversely proportional; if Vd increases, blood concentration of the drug should decrease Concentration and therapeutic response are proportional; a higher drug concentration in the blood should give a higher amount at the receptor site and therefore produce a higher therapeutic response; this relationship can be altered by protein binding Protein Binding Protein binding can alter volume of distribution If we have a drug that is highly protein bound and we cause binding to decrease, then the amount of drug in the blood will decrease; the volume of distribution increases because decreased protein binding allows more free drug to get to the site of action which will lead to an increased response; when the blood concentration decreases, the response is supposed to decrease, however, decreased protein binding can lead to an increase in response because more drug is free to cross the membrane and get to the site of action A measured drug blood level contains the concentration of bound and unbound drug in the body; the unbound drug is the free drug/active form; it has the ability to cross the membrane and work; if it is bound, 9 times out of 10, it will not cross the membrane and work because it has to be free in order to distribute across the membrane and reach the site of action; we technically only need a small amount of free drug to gain a therapeutic response; if 99% of a drug is protein bound, and 100 molecules are put in, all we really need is 1 free molecule to produce the desired response In theory, if protein binding increases, the Vd should decrease and so should the response; if protein binding decreases, then volume of distribution increases Just because protein binding decreases, it doesnt mean there will be toxic effects (it is just that the potential for toxic effects is there); the response should increase but sometimes it will and sometimes it wont Example: o Phenytoin (Dilantin) is a highly protein bound drug; it is 80-90% bound; if protein binding with this drug decreases, the blood concentration will decrease due to an increase in Vd; the therapeutic

range for Dilantin is 10-20; if the patient has a concentration of 8, do we adjust the dose? In practice, if the concentration was 8 and the patient wasnt having signs/symptoms of seizures and was doing fine, then leave it as it is; if we adjust him to 15 and his therapeutic range reaches 20 then he will start to experience toxicities; we should monitor the patient until an adverse event occurs and then re-evaluate the patient Example: o Scenario 1: a patient who is not on ASA comes in and is started on a LD and MD of Phenytoin for his seizures; a blood level is taken and it reads 8; we can then adjust the level to 15 because we would want him to be in therapeutic range since hes just starting treatment o Scenario 2: a patient has been on Phenytoin for a while and his therapeutic range is usually at 15; another physician prescribed him Ibuprofen 600 mg TID everyday; now, all of the sudden he is experiencing toxicities; his blood level is taken and it reads 12; even though it is still within normal range, the problem is a decrease in protein binding because the Ibuprofen has caused the Phenytoin to be displaced and more free drug is available to reach the receptor sites; we could stop the Ibuprofen but the physician wants it to be continued, therefore, we need to decrease the dose of Phenytoin; doing this might cause the concentration to drop to a lower than normal range but even though blood concentration is lower, the amount at the receptor site will be at normal range; we can assume that at 8, this patient will be fine o A decrease in protein binding should mean more drug at the receptor site, but if something also stimulates hepatic microsomal enzymes, then there will be increased excretion/metabolism; would we see an increase in response? probably not; we would most likely need to increase the dose of the drug

Compartment Models Multiple compartments can exist depending on the drug and body composition; generally, we deal with 1 and 2 compartment model Most of the drugs we talk about will follow a one-compartment model One-Compartment Model o A one-compartment model says that the body is considered to be one compartment and that when a drug is added to the system, it distributes throughout the entire body instantaneously o C = C o e-Kt is the one compartment model equation o After a drug is placed into the system, it distributes instantaneously and the body will then try to eliminate it via metabolism or excretion o The equation A=A o e-Kt is essentially equal to the C= C o e-Kt equation; C is equal to concentration, and A is equal to amount, thus A and C represent the same thing depending on what we are talking about Co = A o = C 1 = C max = Peak C = Cp = C 2 = C min = Trough o k, k el , k all represent the elimination rate constant o t represents time o k = slope of the conc vs time line o t = Ln (C 2 /C 1 )/k o K = Ln (C 2 /C 1 )/t o e-kt = factor of decline or % remaining; if this is 100 and this answer comes out to be 0.2, how much did we lose? 80% is lost and 20% is remaining A drug is placed into the system: At t=0, no drug is lost, therefore 100% is still remaining and e-kt = 1 If we allow time to pass, e-kt will change It takes 5-7 half lives before C becomes 0; at 5 half lives, about 90% of drug will have been lost; at 7 half lives, about 97-99% of drug is lost and C is close to 0 because the drug is almost completely eliminated from the system

Example: Given: t 1/2 = 8 hours; 70 kg male; Vd = 0.5 L/kg; Cd = 15 mg/L; calculate a loading dose 1. LD = (Vd x C)/(S x F) [(0.5 L/kg x 70 kg) x 15 mg/L]/(1 x 1) = 525 mg Answer: LD = 525 mg

Example: The physician decides to give another bolus dose 24 hours later; what is the concentration 24 hours later? 1. k = (0.693)/(t) 0.693/8 hrs = 0.0866 hr-1 2. C = C o e-kt C = 15 mg/L x e-(0.0866hr-1*24hrs) = 1.8770 mg/L Answer: C = 1.8770 mg/L

Pharmacokinetics Lecture Seven September 11, 2009 Example from Wednesday: Given: 70 kg male; t 1/2 = 8 hours; Vd = 0.5 L/kg; Cd = 15 mg/L

1. LD= (Vd x Cd)/(S x F) (35L x 15 mg/L)/ (1 x 1) = 525mg

2. Calculate A after 24 hours: k = ln2/t 1/2 A= A o e-kt 0.693/8 hours 0.0866 hr-1

525mg x e-(0.0866hr-1 * 24hrs) = 65.6934 mg after 24 hours

3. Calculate Concentration after 24 hours: C=C o e-kt C= 15 mg/L x e-(0.0866hr-1*24hrs) = 1.8770 mg/L

Example: Using the concentration from the previous example (Wednesday), figure out the loading dose (LD) required to bring the concentration up to 15 mg/L 1. LD = [Vd x (Cd-Ca)]/(S x F) [35 L x (15 mg/L 1.8758 mg/L)]/(1 x 1) = 459.3470 mg Answer: LD = 459.3470 mg

Example: If we gave 525 mg of drug as the LD, but the concentration measured in the blood turned out to be 10 mg/L, calculate the necessary LD to get the concentration up to the desired level 1. Calculate the patients actual volume of distribution; the Vd used in the problem above was based off of population averages, but the patients distribution was greater given that the concentration was lower than what it should have been: Vd = (LD x S x F)/C (525 mg x 1 x 1)/10 mg/L = 52.5 L 2. Now calculate the second loading dose given the patients specific volume of distribution: LD 2 = [Vd x (Cd-Ca)]/(S x F) [52.5 L x (15 mg/L 10 mg/L)]/(1 x 1) = 262.5 mg

Answer: LD = 262.5 mg

Example: After 36 hours, the physician returned and wanted to give another loading dose to restore the concentration back to 15 mg/L (our desired level); calculate the LD, not taking LD 2 into account: 1. First we need to know the current blood concentration since it has been 36 hours: Co = 10 mg/L (because we gave 525 mg only) t 1/2 = 8 hours K el = 0.0866hr-1 C = Co x e-kt 10 mg/L x e-(0.0866hr-1*36hrs) = 0.4426 mg/L 2. Now calculate a LDthat would increase the blood concentration from 0.4426 mg/L (what it is after 36 hours/currently) to the desired level of 15 mg/L LD = [Vd x (Cd-Ca)]/(1 x 1) [52.5 L x (15 mg/ml 0.4426 mg/L)/(1 x 1) = 764.2635 mg Answer: LD = 764.2635 mg

C 0 = (LD x S x F)/Vd C = C 0 x e-kt C = [(LD x S x F)/Vd] x e-kt

Two Compartment Models - When a drug is given and does not distribute instantaneously to all tissues, it cannot be considered a one-compartment model; instead, the drug rapidly distributes to the central compartment and then slowly distributes to the peripheral compartments

k Central Compartment k

12

Peripheral Compartment
21

The drug moves slowly from the central compartment to the peripheral compartments until equilibrium between the 2 compartments is reached The central compartment consists of highly perfused areas including the: Lungs Kidneys Liver Blood Heart The peripheral compartments consist of tissues whereby distribution occurs at a slower rate; these include: Adipose tissue Skeletal muscle Cerebrospinal Fluid (CSF) The two compartment model consists of 4 stages: I. Initial injection- everything distributes quickly to the central compartment II. Distribution- small amounts of drug are transferred from the central compartment to the peripheral compartment until equilibrium is reached between the two III. Equilibrium- reached between the central and peripheral compartments IV. Elimination- elimination ONLY occurs from the central compartment; as drug is eliminated from the central compartment, drug will transfer from the peripheral compartment back to the central compartment to re-establish equilibrium; as more drug continues to be eliminated from the central

compartment, more drug will shift from the peripheral compartment until the drug is completely eliminated; the central compartment is considered the eliminating compartment because it contains the kidneys and the liver Two Compartment Model Equation - C = A x e-kt + B x e-kt T = time; it is the same for both k = distribution rate constant o (K 1-2 + K 2-1 = K ) A is a concentration obtained by residual method K = elimination rate constant B is a concentration obtained by extrapolation - A will ALWAYS be larger than B; if upon calculation, A doesnt turn out to be larger than B, then something in the calculation is WRONG - Therefore, distribution (represented by A x e-kt) is ALWAYS faster than elimination (represented by B x e-kt) - Also, k (Distribution rate constant) will ALWAYS be higher than K (Elimination rate constant) - Because k > K , the distribution half-life will be SMALLER than the elimination half-life; this means it will take less time for distribution to occur than it does elimination - Once equilibrium occurs, the system will eliminate exactly like a one compartment model; clinically, we can wait until we know equilibrium has occurred before we take blood concentration levels; therefore, we can calculate blood levels using the one-compartment model equation; this is accomplished by knowing the distribution half-life; after 5-7 half lives, distribution can be considered complete and therefore, equilibrium has occurred and only elimination is going on Proof: Consider the distribution half-life is 2 hours: o 5 half-lives x (2 hours/1 half life) = 10 hours o A x e-kt = A x e-k(10 hours) = A * 0 = 0

Pharmacokinetics Lecture Eight September 14, 2009 Be able to distinguish: - One compartment models from two compartment models just by looking at a graph - First order kinetics from zero order kinetics by knowing the drug

A Semi-log Paper B

I II III

I: Initial injection II: Distribution III: Equilibrium IV: Elimination

Concentration

IV

Time

Methods of residual can be used to find A. k a should always be greater than k B

If we are given one concentration (C) and t 1/2a (or k a ) we can calculate A. A = C/(e-kat) Vancomycin is an example of a drug that undergoes a two compartment model. After infusing it, it takes approximately 2 hours to reach equilibrium, at which point it follows a one compartment model. We infuse Vancomycin over at least one hour. For class purposes, we measure Cb (for the peak) one hour after the start of the infusion.

Example: t 1/2a = 0.5 hours t 1/2B = 24 hours A = 30 mg/L B = 20 mg/L

A) Find the concentration after 1 hour has passed 1. Calculate k a and k B given their respective half-lives k a = 0.693/0.5 hr = 1.386 hr-1 k B = 0.693/24 hr = 0.0289 hr-1 2. Calculate C C = A x e-kat + B x e-kBt [(30 mg/L x e-(1.386 hr-1 x 1 hr)) + (20 mg/L x e-(0.0289 hr-1 x 1 hr)) 7.5022 mg/L + 19. 4303 mg/L = 26.9325 mg/L Answer: C = 26.9325 mg/L

B) If the drug reaches equilibrium at 5-7 half-lives, calculate C after 7 hours C = A x e-kat + B x e-kBt [(30 mg/L x e-(1.386 hr-1 x 7 hr)) + (20 mg/L x e-(0.0289 hr-1 x 7 hr)) 0.0018 mg/L + 16.3370 mg/L = 16.3388 mg/L Answer: C = 16.3388 mg/L

Digoxin also undergoes two-compartment model kinetics. It is recommended that the loading dose be split into 3 doses, but some practitioners split it in half. If given all at once, too much Digoxin will distribute rapidly to the central compartment leading to toxicity. It will take about 4 hours for Digoxin to reach equilibrium because the t 1/2a for Digoxin is 35 minutes (35 minutes x 7 half-lives = 245 minutes or 4.0833 hours). We then wait 12-24 hours after the loading dose to get the blood concentration (Cb). The t 1/2B for Digoxin is 36-48 hours.

Pharmacokinetics Lecture Nine September 16, 2009 In two compartment models there are four stages: - Stage I: this is time zero (but it really isnt at zero time); we are looking at the system as if we got all of the drug in - Stage II: this is the distribution stage (elimination is also occurring); if distribution (or elimination) is altered the entire process is affected - Stage III: in stage III, equilibrium is reached; distribution has taken its course and we are at steady state (if you wait until distribution has occurred, you can treat it as if it were a one compartment model) - Stage IV: this stage represents elimination

A Semi-log Paper B

I II III

I: Initial injection II: Distribution III: Equilibrium IV: Elimination

Concentration

IV

Time

*** There are 3 types of people that will remember change down to the penny (because pennies make dollars): Broke people Stingy people Drug dealers/pimps

How to Calculate the Concentration at Normal Protein Binding

The following equation will correct concentration measurements based on fluctuations in a patients normal albumin levels

Equation:

Cb = Cb actual /[((1 ) x (P actual /P normal )) + a]

** The albumin levels need to be altered in order to use this equation; if albumin levels are not altered, we do not use this equation** Cb = concentration P actual = actual protein (patients actual albumin level) P normal = normal protein (normal albumin levels range from 3.5-5.5 g/dL; in this class we will use 4.5 g/dL) a = amount or % unbound (if there is a range, apply the amount or % that makes it more significant)

Example: A patient had an actual measured plasma concentration of 8 mg/L of Phenytoin and an albumin level of 2.5 g/dL. Find the actual concentration of Phenytoin if it is 90% bound. Cb = Cb actual /[((1 a) x (P actual /P normal )) + a] Cb = (8 mg/L)/[((1 0.1) x (2.5 gdL-1/4.5 gdL-1)) + 0.1] = 13.3333 mg/L Answer: Cb = 13.3333 mg/L

In patients that are less than 5 feet, BSA is the most accurate parameter to use; this is especially true for pediatric patients BSA = kg0.425 x cm0.725 x 71.84 Normal BSA = 1.73 m2 If BSA dosage is less than the IBW dosage, we use the lower dose; we always want to air on the side of caution and therefore underestimate rather than take the chance of overmedicating

Osmosis vs. Diffusion Osmosis deals with the transfer of water from one area to another; it does not deal with concentration because water does not have a concentration Diffusion deals with concentration; it is the transfer of a molecules from an area of higher concentration to an area of lower concentration; diffusion can further be broken down into active diffusion and passive diffusion; anytime a drug is in a system and can cross the membrane, it will constantly move back and forth

Kinetics Dr. Scott 11/13/09 SCENARIO Pt has been taking an over the counter bronchial dilator Primatene tab or mist. Which would be a bigger problem when looking at systemic effects? - The tablet because the it has a greater systemic absorption & thus more adverse effects taking this po formulation versus mist - we prefer someone to use the mist, it is formulated to work more topically in the lungs, there will be some systemic absorption but the person will feel better faster - albuterol also has systemic effects TA 30 yo female 142lbs comes in, & has been taking primatene mist w/ no relief, has had wheezing & SOB for the past 3 hours, she has never been to the doctor for asthma, theyve just been taking otc products. Labs: SCr 1.1., BUN 19, Na 138 K 4.2 Problem #1 The physician wants to give a LD of theophylline (aminophylline) 650 mg to maintain conc 15mg/L. Do you agree or disagree with this dose? Solution: Theophylline LD 650mg, S= 0.8, F = 1, Conc 10-20mg/L, t1/2 = 8hr, Vd = 0.5L/kg, 1) find wt, 142lbs/2.2. = 64.545 2) find Vd, Vd = 0.5kg/L*64.545kg = 32.273L 3) LD = (Vd*Conc)/(S*F); Conc = (LD*S*F)/Vd = (650mg*0.8*1)/(32.273L) = 16.113mg/L, yes we agree with that dose; it is in btwn the range of 10-20mg/L Problem #2 The physician comes back and says, after the LD start a continuous infusion dose that will maintain a conc of 15mg/L? MD = (Cl*Conc*)/(S*F) 1) Cl = 0.04L/kg/hr *wt = 0.04L/kg/hr*64.545kg = 2.582L/hr o we dont calculate CrCl for this drug b/c it is not significantly cleared renally, only 10-15%; using CrCl in this pt wont help o if a drug is metabolized and it has an active metabolic most times the metabolite will be excreted really unchanged, in this situation renal clearance is important; e.g. Prozac has an active metabolite which is probably excreted renal and if it has a longer half life than a primary drug then this is a problem; most drugs once broken down are more hydrophilic and thus renally excreted o there are exceptions to the rule, a drug could be broken down to an active metabolite and may be conjugated

if a drug active and is broken down to an active metabolite and the person is experiencing hepatic cirrhosis; the drug effect will stay the same but stay longer b/c the liver has not completely broken down and active metabolite conc will increase o if parent drug was inactive then there may be a decreased in effect b/c there is a slower turn over from inactive drug to active drug [slower metabolism] but excretion is still at the same rate; in this situation we need to change the drug e.g. enalapril has to be converted to enalaprat, if pt has hepatic failure and liver func is declined the conversion of the drug is less but renal Cl is the same so any drug changed is still excreted at the same rate 2) MD = (Cl*Conc*)/(S*F) = (2.582L/hr*15mg/L*1hr)/(0.8*1) = 48.413mg; 48mg/hr will be given continuous infusion o Problem #3 Physician wants the drug conc 10 hr after start of infusion; LD was given at 7 am and continuous infusion at 8am. The eq we need to use is C = [(LD*S*F)/(Vd)*(e-kt) ]+ [((MD*S*F)/(Cl*)) * (1-e-kt) but we have to find the value of k first: 1) Cl = Vd*k, k = Cl/Vd = 2.582L/hr 32.273L = 0.08hr-1 2) C = [16.113mg/L* (e-0.08*10hr)] + [14.872 * (1-e-0.08 *10hr)] = [16.113mg/L * .499] + [14.872 * (1.499)] = 7.240 + 8.190 = 15.43 = class said 15.49 o (Refers to drawing) if conc was taken 1 hr after infusion our peak conc was 16.113 at 8 am; if continuous infusion is started immediately at the end of LD we can say the t (time values) for both parts of the equation is the same b/c after 1 hr the LD peak conc begins to decline we use the end of the LD to start the time b/c thus is the time before that was continuous infusion Factor of decline (e-kt) o at t = 0, conc = 1 o at ss it = 0 Factor of incline (1-e-kt), o at t = 0, conc = 0 b/c no drug has accumulated o at ss it = 1 o C= [(LD*S*F)/(Vd)*(e-kt)]+ [((MD*S*F)/(Cl*)) * (1-e-kt), the bolded part of the equation was found in problem #1.

Pharmacokinetics Dr. Scott 9.21.2009 Exam is Friday at 9 am ELIMINATION - deals w/ is drug leaving the body - looks at 2 basic things in elimination: 1) Metabolism 2) Excretion Metabolism - the major site for metabolism is the liver it can also occur in other places; the hepatocyte are designed to metabolism drugs - transforms one substance into another sub, a drug goes to liver biotransformed to another drug - another name for metabolism is biotransformation (when a drug goes in the sys it is transformed inside the body to something else); biotransformation is a form of metabolism b/c there is still something in the syst but it is not the same substance we started w/, the new substance can still be active or inactive, an active metabolite or inactive metabolite, e.g: 1) Active metabolites - Fluoxetine (Prozac) when metabolized it is broken done into a metabolite and it has an active metabolite (active metabolites have a half-life just as long as the parent cmpd) but when looking at the sys if we look for flouxetine it has been transformed to another drug so we take into account the active metabolite 2) Prodrugs - some drugs are prodrugs which are in an inactive form, then metabolized to its active form and then it begins to work e.g. enalipril is metabolized to enalaprat, the active form and the drug begins to work; as time goes on if we looked for enalapril in the sys it wont be there - most times we metabolize a drug so that it will be: 1) inactive 2) more water soluble to be renally excreted - it is important to know 1) if a drug has an active metabolite AND 2) if so how long is the half-life of the active metabolite b/c most times the metabolite is more water soluble and it wont be metabolized but excreted; this means a drug can have good liver function and has poor renal function; if a drug is primarily broken down in the liver but the kidneys are not working well this is ok unless the metabolites are active b/c most metabolites are renally excreted - a drug can be metabolized to an active metabolite and that metabolite can be biotransformed to something else but most times it becomes water soluble for renal excretion - looking at metabolism there are 1) phase 1 rxns 2) phase 2 rxns Phase 1 o primary phase 1 type rxn include: cyp 3A4, 2D9, oxidation, hydrolysis ,reduction ect DYNISHA M. IVY

1) require P450 enzymes 2) requires liver func to be at its best Phase 2 o are conjugative processes that include: glucoronidation, methylation o doesnt require liver function to be at its best o as we get older drugs that undergo phase 2 rxn are handled better by the elderly in Pediatric cases < 5 yo, these pt dont conjugate well so drugs that have to go thru conjugation we want to avoid especially in new born pt e.g. bilirubin has to be conjugated & in some pt when they are young, some pt have a problem conjugating bilirubin and their bilirubin levels become high so they are given some time under a light to get their bilirubin levels to come down and the pt will be fine but we have to avoid drugs like rocephin b/c it can interfere w/ the conjugation process in pediatric pt, newborn pt and pt less than 1 yr old, this is seen more often in these situations but after they get older it can still happen but not as much in pediatric cases pt have 80% of P450 enyzmes running at a high level, remember the heart rate is faster in these pt so distribution is higher, drugs go to the liver faster and the metabolism of these drugs are a lot higher than w/ phase 2 type rxn but phase 1 rxn work well; in phase 2 rxn the conjugative process is not the same in pediatric pt; when child is 2-3 yr old things start normalizing almost to levels we see in adults, b/c kids are bigger a child may have the same Vd as an adult depending on the drug. so at the start of life give drugs that undergoes phase 1 type rxn and at end of life use drugs that undergoes phase 2 type rxn, normally phase 2 drugs will have a shorter half-life e.g.: o an alcoholic is in the hospital & cant drink (some hospitals keep alcohol on stock) after 24-48h they can go thru withdrawal or delirium tremors (DTs), DOC in this situation is (valium) diazepam, or (Librium) chlordiazepoxide can be used; both these drugs have a very long half- life, in a pt drinking alcohol for a long period of time can decreased liver function, so if this person has this or liver cirrhosis we dont want to give valium but in some situations we will give it 1 time only dose of valium just to have some control o a benzodiazepine we would use under previous circumstances would undergo conjugation & include: DOC is (Ativan) lorazepem, (Restoril) temazepam or (Serax) Oxazapem; so even though liver func is declining our focus is on phase 2 rxn b/c liver funt is not required to be at its highest and these tend to have a lower half-life

Elimination - we start talking about order of kinetics 0, order 1st, 2nd ect. - most of the drugs in practice go thru 1st order (from a metabolism pov, point-of-view) there are few drugs that we deal in practice that deals w/ 0 order kinetics - 1st order kinetics: 1) another name is linear b/c when plotted on graph paper it gives a straight line 2) as the amt of drug in the body decrease the amt eliminated decreases 3) the fraction or percent eliminated is constant, k is the fraction or percent eliminated (in 1st order k is constant) over a given period of time 4) while the percent is constant/the same the amt varies e.g. 1000 mg of Drug A w/ half-life of 5 h DRUG TIME (h) Percent lost 1000 mg 0 500 mg 5 50% 250 mg 10 50% DYNISHA M. IVY

but the amt varies in 2nd order and there is no k really In zero order kinetics: 1) is nonlinear when graph on semi log paper it gives a curve 2) the drug amt eliminate over a period of time is constant fraction or percent will vary; this is why there is not a k and therefore no true half-life 3) depending on the drug at low doses it will go thru 1st order kinetics but the higher the dose given it can go thru zero order kinetics 4) is concentration dependent b/c we can saturate its metabolism cycle, we can be at one level and be in a normal range but if we saturate it, drug level will be toxic; in other words in zero order kinetics, the > conc, the longer the drug will be in the sys e.g. giving a drug that under goes zero order kinetics losing 100 mg/hr (constant drug amt) Concentration dependant zero order kinetics e.g. Less DRUG TIME (h) More DRUG Variable percent 1000 0 2000 100% 500 5 1500 75% = (15002000*100) 0 10 1000 66.7% =(10001500*100) 15 500 50% = (5001000*100) 20 0 in 1st order, no matter how much drug is given if the half-life is 5 hours then half of the drug will be gone and in 7 half-lives most of that drug will be gone enzymes can also be saturated c/ing a persons levels to go even higher and have drug stay in the system even longer e.g. phenytoin there is not a true half-life w/ zero order kinetics but we can look at a drug and get an average e.g. phenytoin and dilantin half-life is 24 hours however they are nonlinear so we can c/ sites to be saturated and have drug stay in the sys much longer there are some drugs that will have 0 order kinetics when it comes to absorption but once it gets into the system it undergoes 1st order kinetics e.g: 1) Ca++ - after giving so much Ca++ it wont be absorbed 2) Rafampin no matter how much is given after a while it wont be absorbed anymore and this means absorption sites can be saturated and only a certain amt is absorbed over a certain period of time; this may vary from person to person but we have a set standard for the population then see how each individual person deals with it zero order can also be in distribution, saturation, absorption, elimination there can be zero order kinetics in excretion e.g PNC goes thru active tubular secretion (ATS) which can be saturate but this is not significant, sometimes we use drugs to try to keep PNC from excreted too rapidly o

Excretion - main site is the kidney, the renal system - if drug A is put in the system Drug AB should be excreted, AB is a metabolite, something has changed - if a drug undergoes excretion only then what we started w/ should be what we finish w/, if we see anything differ then it was metabolized first, so then the question becomes: for the sub being excreted, was it metabolized before excretion, was it an active metabolite or an inactive metabolite? DYNISHA M. IVY

most drugs excreted by the kidneys should be unchanged if they are changed than they have been metabolized eg Drug A is in the system and is 100% excreted as drug AB, this is 100% metabolized drug excreted renally is excreted unchanged in the kidney we look at a drug to undergo: 1) glomerular filtration OR 2) tubular secretion (active) and be excreted in the urine or be 3) reabsorption (Refers to drawing) all this takes place at the nephrons the active part of the kidneys, where things are forced in or filtered thru glomerular filtration e.g. some drugs, Na+, waste products; larger substances go thru ATS (actively transported thru the nephron) and once something goes out of the blood, goes in the nephron, circulates and goes back into the blood this is reabsorbed if a drug undergoes 100% of glomerula filtration (GF) then its rate of Clearance is = GF rate, since GF rate is = to CrCl, whatever the CrCl is, then that is the drugs Clearance, e.g. 1) gentamicin gets into the sys and is cleared 100% of the kidneys by glomerular filtration, drug Cl of aminoglycoside is = to CrCl 2) a drug is cleared 100% by the kidney but it is cleared 65% by GF and 35% ATS, then drug Cl is = 0 .65 * CrCl b/c only 65% went thru GF CrCl formulas: 1) Male CrCl = ((140-pt Age)*pt wt in kg)(72*SCr) 2) Female CrCl = [((140-pt Age)* pt wt in kg)(72*SCr)]*0.85 for class purposes calculate pt actual and IBW, use the lower of the 2 when doing any calculations

Key points: - finding Clearance 1) Cl = Vd *K - finding K: 1) Prefer method , K = (ln (C2C1)* -1) t OR K = (ln (C2C1)* -1) (t 1 -t 2) ) nd 2) 2 preferred method, K = ClVd 3) least preferred method, K = 0.693t1/2 - Maintenance Dose eq, MD = (Cl*Conc* ) (S*F), , is the dosing interval how often we give the drug - when looking at the CrCl for a drug excreted 100% by the kidney by GF and using this MD equation make sure that if dosing interval () is hours then convert CL units from minutes to hour Remember units of Cl mL/min - MD replaces what is lost; as successive amt of a drug is given the drug begins to accumulate steady state (ss) is the point where the amt of drug given over a specified time = the amt of drug that is lost or eliminated over that same period of time OR ss is when the first dose no longer affects successive doses e.g. it takes 5-7 half-lives to reach steady state but if 1 dose of drug A is given it takes 5-7 half-lives for the drug to be eliminated from the body - to reach ss we have to have more than one dose; one dose is automatically eliminated but giving more than one dose causes a drug to accumulate - every drug has the potential to reach ss, even intermittent infusion can reach ss - (Refers to drawing) Intermittent infusion e.g if Dr Scott gives you ten dollars, the half-life of that money is 5 hr at which half the money will be taken away but ten dollars will be given; so 5 hours later Dr. Scotts takes half the money 10 dollars and gives you ten more dollars, the max amt of money you can have at that point is 15 dollars; we continue this and the graph up to 20: DYNISHA M. IVY

Time (hr) 0 5 10 15 20 25 (5th half-life) 30 35 (7th half-life)

Result of half of max money being taken away @ half life (5hr) 5 7.5 8.75 9.375 9.6875 9.84375 9.921875 9.9609375 9.98046875

Money given (dollars) 10 10 10 10 10 10 10 10 10 10

Max money at that time 10 15 17.5 18.75 19.375 19.6875 19.84375 19.921875 19.9609375 19.98046875

it keeps going up and down until we reach $20 and Dr. Scott takes half of $20, leaving us $10 (the original amt he gave) but gives us 10 more dollars making the max amt we can reach is $20; then half of $20 is taken away again (which is $10) leaving us w/ $10 again, we are now at ss where the amt of drug (or money in this case, $10) given over a specified time = the amt of drug (or money in this case, $10) lost or eliminated over that same period of time OR we lost 10 dollars over 5 hours and we get 10 dollars back so the most money we can have at one point is ~20 dollars in 5-7 half- lives or close enough the MD only replaces what is lost over a given period of time intermittent infusion eq is a type of MD but it is not the same eq; in intermittent infusion a certain amt is given after so many hours and after a while the drug begins to accumulate so that now what is given over a certain amt of time begins to = what is eliminated over that same period of time

DYNISHA M. IVY

Pharmacokinetics 9.23.09 Dr. Scott STEADY STATE - everything (drug )can reach ss - ss occurs when the amt given over a period of time = amt lost over the same period of time e.g. if Dr. Scott gives 100 mg every 8hr then when it gets to the point over 8hr where we lose 100mg then this is ss - (Refers to Drawing) so looking at elimination t1/2 it says we need 5-7 half-lives to reach steady state; it also takes 5-7 half-lives to be eliminated from the body, so another way to look at steady is that it will be reached when the 1st dose is at zero or eliminated out of the body b/c nothing can accumulate or build off of that dose Loading Dose - ss can never be reached in one dose; LD conc is not ss, it doesnt achieve ss, it achieves the conc that we want when we reach steady state; the LD will not achieve ss unless the LD is the same as the MD and if they are the same then the LD still didnt get us to steady state - LD doesnt accumulate but to reach ss the LD would have to be the same as the MD, meaning the LD had to accumulate to get to steady state (but REMEMBER: LD does not accumulate) - the LD is always larger than MD - to calculate a LD all we need is a Vd and the desired Conc to know exactly how much drug to give to get to X conc; the LD gets you to the conc but cant maintain the conc - giving a LD more than once will c/ the conc to accumulate beyond ss Maintenance Dose - MD doesnt achieve the desired conc we want at first, it must accumulate until we get to ss; once we reach ss the conc will stay the same; MD is designed to keep accumulating until ss is reached and once we reach ss it stays there where the amt given = the amt lost over the same period of time - the eq, MD = (Cl*Conc* ) (S*F) , assumes ss (that Conc represents the conc at ss)has been reached for example if Dr Scott ask us to calculate a MD that will maintain a conc of 15mg/L, he wouldnt ask for a MD before reaching ss - w/o a LD wed have to wait for accumulation Accumulation - Accumulation eq Acc = D*(1/(1-e-k)), is a dosing interval, a type of time that specifies what type of time we are looking at e.g. if = 8h then it means the time btwn doses is 8 hours Problem #1 - Given D = 10 mg, = 5 hr, t1/2 = 5h then how much drug will accumulate? 1) k = 0.6935h = 0.1386h-1 2) Acc = D*(1/(1-e-k)) = 10mg*(1/(1-e-0.1386h1-*5h)) = 10mg *2.0003 = 20.003mg; so 20mg is the most that will accumulate, after dosing every 5h with 10 mg - (1-e-kt) is the accumulation factor or the percent of steady state e.g. if (1-e-kt) = .8 this means we are 80% at steady state

DYNISHA M. IVY

Continuous Infusion - to solve for conc change MD eq: C = MD*S*F/Cl*, this eq also assumes ss has been reached - is used when we want a particular time before ss, Continuous infusion eq: C = ((MD*S*F)(Cl* ))*(1-e-kt); we use this b/c (1-e-kt) is the accumulation factor & it tells the percent of ss, therefore when (1-e-kt) = 1 then ss has been achieved - if given a continuous infusion and asked the conc after X hours of starting the dose and it hasnt reached ss yet then we use this eq it assumes we havent reached ss yet - b/c (1-e-kt) = 1 once it reaches ss, and 1 times any number is that number (e.g. 1*3=3), then at ss all we have left of the Continuous Infusion eq is C = ((MD*S*F)(Cl*)) *1 which is the same as MD =( Cl*Conc* ) (S*F) and this is why we say this eq assumes ss - e-kt at time 0 is = 1, so 1-1 = 0, and 0 times any number is 0, so at time = 0 the conc is also zero, when we start accumulating e-kt = 0 at ss, so 1-0 = 1 which says we are 100%??? Problem #2 Continuous infusion, for purpose of this class = 1h for a continuous infusion - Given D = 60mg, = 1 hr, t1/2 = 8h VD = 05.L/kg, pt wt = 70 kg, what would the Conc be at 10h? 1) Vd = (0.5L/kg)*70kg = 35kg 2) k = 0.693t1/2 = 0.693 8 hr = 0.08662 h-1 3) Cl = Vd*k = 35kg*0.8662h-1 = 3.0317L/h 4) Continuous infusion eq, C = ((MD*S*F)(Cl* ))*(1-e-kt) = ((60mg*1*1)(3.0317L/h*1h))*(1-e-0.08662h-1*10h) = Solving the eq in sections, C = (19.7909 mg )* (0.5794) = 11.4668 mg/L at 10h, this is not ss so the drug is still accumulating and will do so until we reach ss - (0.5794) tells us that it is 57.94% ss Problem #3 - Given same inform from Problem #2 , what would be the Conc be at 48h? 1) C = ((MD*S*F)(Cl* ))*(1-e-kt) = ((60mg*1*1)(3.0317L/h*1h))*(1-e-0.8662h-1*48h) = 19.4809mg/L - LD declines and continuous infusion increases and the 2 balance out to maintain the desired conc CLEARANCE - Clearance is a form of elimination, clearance (that we plugged into the eq above) doesnt tell if it is renal or nonrenal , it tells clearance total (Cl T ); Cl total = renal + nonrenal , this says a drug can be put in the body and be eliminated thru metabolism or excretion; just understand that the clearance we use doesnt distinguish btwn the renal or nonrenal - Digoxin is a drug that is metabolized and renal cleared - e.g. a drug is 75% excreted renally and 25%hepatic metabolism . if there is s problem w/ the kidneys the hepatic metabolism will increase but not increase enough to make up for the 75% then well start to see alterations; but if the elimination is 50: 50 or 60: 40 and there is a slight decrease in the renal function then hepatic func can increase to make up for the extra 5-10% but now the problem is that it is not supposed to do that which means the liver is working harder so over time we see problems w/ the liver b/c it is working hard to do something it doesnt normally END EXAM # 1 MATERIAL

DYNISHA M. IVY

Pharmacokinetics Lecture Twelve September 28, 2009 Intermittent Infusions Example of an intermittent infusion: Say we put 120 mg of Gentamicin in 100 ml of NSS and we infuse the medication over an hour every 8 hours (120 mg infused over an hour every 8 hours); after the end of the infusion we wait 8 hours and then start the process again; intermittent infusions do reach steady state; once the drug reaches steady state, the Cmax and Cmin will not change unless the dose, dosing interval, or pharmacokinetics (elimination, distribution) are affected

8 am

4 pm

Intermittent infusions are a type of maintenance dose because it is replacing what is eliminated Equations: Cmax: Cmax = (DSF x 1 e-ktinf)/(Cl x t inf x 1 e-kT)

Dose:

D = (Cmax x Cl x t inf x 1 e-kT)/(S x F x 1 e-ktinf)

Cmin:

Cmin = Cmax x e-k(t2-t1)

t 1 = conc. at Cmax, t 2 = conc. at Cmin

C (same as Cmin) = Co (same as Cmax) x e-kt

Aminoglycosides
-

The three main aminoglycosides that we will look at are Gentamicin, Tobramycin, and Amikacin; the volume of distribution and clearance for these drugs are pretty much the same These drugs are used for Gram infections; are not used for anaerobic microorganisms; they are not used for Gram + infections These drugs affect protein synthesis at the 30s ribosome; aminoglycosides are actively transported into the bacteria; they need oxygen in order to function (this is why they will not work against anaerobic microorganisms) A lot of toxicity with aminoglycosides is seen with a high trough, not necessarily a high peak Aminoglycosides are not absorbed orally; the only aminoglycoside that we give by mouth is Neomycin (used for hepatic encephalopathy; Lactulose is also used to decrease ammonia levels in hepatic encephalopathy); if given this way, Neomycin will work locally; if something is not absorbed, it will not work systemically; Neomycin can be given IM, but absorption is sporadic and consistent peak and trough levels cannot be obtained; IM absorption is affected by muscle mass, adipose tissue, blood supply, muscle movement (because muscle movement affects blood supply); if the vein is lost and the therapy is almost complete we can just give the dose IM We do not give aminoglycosides as a continuous infusion; they are given as intermittent infusions; Aminoglycosides are infused over 30 minutes to 1 hour; for class purposes use 1 hour (i.e. t inf = 1 hour) We take the peak 1 hour after the start of the infusion, even if it was infused over 30 minutes (i.e. if the infusion starts at 8 am, take the peak at 9 am); if we infuse the drug over an hour just take the peak right after the end of the infusion We take the trough 30 minutes to right before the next dose; say the dose is given at 4 pm, the earliest we could take it is 3:30 and the latest we could take it is 3:59 Gentamicin Gentamicin does not work well against Haemophilus or Mycobacteria You wont really see Gentamicin used in Pseudomonas infections because some strains of Pseudomonas are resistant to Gentamicin Peak = 5-10 mg/L Trough < 2 mg/L (for the trough, the closer to 0, the better; if it is 2, it is a no go; if it is 1.99, it is ok) Tobramycin Does not work well against Mycobacteria Peak = 5-10 mg/L Trough < 2 mg/L Amikacin Peak = 20-30 mg/L Trough < 10 mg/L

Pharmacokinetics Lecture Thirteen September 30, 2009 Aminoglycosides are hydrophilic, thus they do not distribute to adipose tissue; aminoglycosides are distributed to pericardial fluid, synovial fluid, pleural fluid, ascites fluid (fluid in the abdomen that is caused by decreased albumin levels in people with liver failure; albumin is responsible for protein binding and oncotic pressure (pressure that stops water from spilling over)) Distribution vs. Volume of Distribution - Vd is a component of distribution; Vd just tells the volume that the drug is contained in; this gives an idea of how well the drug is distributed, but does not tell exactly how a drug distributes from one tissue to another - If you put 1 gram of a drug in certain volume, and the concentration comes out to be 1 mg/L, the volume would be 1,000 L; this does not take into account how the drug distributes from one tissue to the next (tissue A, B, C, etc)

A 10%

B 10%

C 30%

D 15%

E 20%

F 15%

Distribution tells us how well the drug penetrates the tissue; volume of distribution does not Protein binding affects distribution and volume of distribution; protein binding can alter how much drug stays in the blood to make the Vd look like it goes up or down; protein binding can also affect how much drug can cross the membrane to get to the site of action; when protein binding decreases, more drug is able to cross the membrane causing the Vd to increase; decreased protein binding will cause more drug to reach the receptor site to cause a response, thus it also affects distribution; ascites increases the volume, but it does not increase the therapeutic affect; for people with ascites, more drug will have to be given because they have more volume

Aminoglycosides are not highly protein bound, but they are hydrophilic; aminoglycosides distribute well to areas of volume (ascites, edema); if the Vd increases we might have to increase the dose to make sure that we are getting a therapeutic concentration; when the volume of distribution increases, the concentration decreases and the net effect decreases; highly protein bound drugs are an exception to this rule; when protein binding decreases the volume of distribution increases and the net effect can increase because more drug is available to reach the receptor; this is not an issue if the drug is not highly protein bound Aminoglycosides are not metabolized Aminoglycosides do not distribute well to adipose tissue; if we give a dose of an aminoglycoside, say 5 mg/kg to every patient based on weight this can be problematic for obese patients because they are at risk for toxicity; the dose of aminoglycosides should be lowered for obese patients because the dose is being based on a weight that the drug will not distribute to (aminoglycosides do not distribute to adipose tissue); if the dose is not lowered, obese patients may experience symptoms of toxicity Small amounts of every dose of an aminoglycoside have the ability to distribute and bind tightly to parts of the kidney and inner ear; aminoglycosides cause nephrotoxicity and ototoxicity; the higher the dose, the more can accumulate in the kidney and ear causing toxicity The Vd we use for aminoglycosides (which is the population parameter) is 0.25 L/kg; in infants the volume of distribution is higher and as the person gets older the volume of distribution declines; when the patient reaches about 2-5 years of age the Vd is about the same as an adult Because aminoglycosides are hydrophilic and do not distribute to adipose tissue, we are definitely going to use lean body mass to calculate the dose; in calculating the dose for an aminoglycoside, we use the lower of the actual or IBW (it does not make sense to use the IBW if the actual body weight is lower); we stick with this weight when calculating other parameters (CrCl) to keep consistency We usually determine someone to be obese if their BMI is > 30 or if the person is 20-30% above their IBW To calculate the Vd for an obese person: Vd = 0.25 L/kg x IBW + CF(ABW IBW) The CF, correction factor, tells us what percentage of the extra weight is volume; the normal CF factor is from 10-40% (0.1-0.4); for class purposes use 10% (0.1)

Elimination - Aminoglycosides are cleared 100% by the kidneys through glomerular filtration - Aminoglycoside clearance is equal to CrCl (which is in milliliters per minute); we convert this to L/h; to do this, multiply the ml/min by 0.06

Creatinine clearance: CrCl = (((140 age) x kg)/(72 x SCr)) x 0.85 (if female) Multiply this answer by 0.06 and you will have the CrCl in L/h The elimination half-life for aminoglycosides is 2-4 hours (average of 3 hours); it takes 5-7 half lives to reach steady state; in about 15 hours, aminoglycoside concentration will be close to steady state; this is not a large amount of time so we do not need to give a loading dose; within 15 hours the first dose is pretty much gone; to reach steady state, more than one dose has to be given; if only dose is given, the drug will not accumulate; by the 3rd dose (if it is given every 8 hours) we are at steady state

Pharmacokinetics Lecture Fourteen October 2, 2009 Aminoglycosides are cleared 100% by the kidney via glomerular filtration; renal function is critical when aminoglycosides are used; if renal function is decreased, Houston We Have a Problem; liver function does not affect the excretion of aminoglycosides Drugs can be excreted from the kidneys in two ways: 1. Glomerular filtration - When the kidneys fail, glomerular filtration is the first thing to go; decreased kidney function will affect glomerular filtration before it will affect tubular secretion; glomerular filtration relies heavily on the ability of the kidneys to work properly; because aminoglycosides are excreted 100% through glomerular filtration, they are very dependent on the kidneys functioning properly 2. Active tubular secretion - Active tubular secretion puts the drug into the urine - Tubular reabsorption puts the drug back into the blood Types of Pneumonia - Klebsiella: seen in alcoholism, diabetes, chronic debilitating diseases, and sickle cell anemia (Pseudomonas can also occur in people with sickle cell) - Haemophilus: seen in smokers, COPD, and asthma; the person probably has a problem with the lungs Alcoholism: causes ascites and liver failure; ascites affects the distribution of aminoglycosides; liver failure will not affect aminoglycoside therapy because aminoglycosides are not eliminated by the liver; **liver function does not affect the clearance of aminoglycosides; it is only when you see complications of liver failure, such as ascites and edema, that aminoglycoside clearance is affected Factors that Affect Pharmacokinetics/Disposition of Aminoglycosides: a. Renal function: - If renal function decreases, clearance of the drug decreases - If the clearance of the drug decreases, the concentration will increase - The half life of the drug will increase if the clearance decreases b. Age: - Pediatric patients have a larger volume of distribution; renal clearance increases in pediatric patients; pediatric patients have a faster heart rate and a lower blood pressure; for these reasons, pediatric patients usually clear drugs faster; when the child reaches about 5 years of age these parameters mimic that of an adult

The renal clearance decreases in the elderly; when someone reaches the age of 65 there is a good chance that renal function will decrease by 40%; cardiac output decreases in the elderly; if the cardiac output decreases, renal blood flow decreases; if renal blood flow decreases, glomerular filtration decreases causing decreased clearance of the aminoglycoside; clearance can decrease in the elderly, but this does not mean that it will - We do not want to base our decisions on age; we should base our decisions on how the patient is doing c. Hypermetabolic states: - Fever: if a person has a fever, their heart rate increases; this will cause renal blood flow to increase; people that have a fever usually go to the bathroom a lot; patients with a fever should drink a lot of fluid because they can become dehydrated if they do not; when a patient is on an antibiotic, within a day or two, the fever will go away thus fever is a transient factor; if we use a higher dose in a patient with fever we have to be careful because the fever can go away and the dose may be too high - Burns: patients with severe burns will have increased cardiac output; renal blood flow will increase, and drugs will be cleared faster; burns might increase volume of distribution due to blistering; aminoglycosides can accumulate in the fluid of the blisters; because blisters ooze, some people look at this as clearance; either way the concentration goes down - Cystic fibrosis: usually affects Caucasians, but not always; if a person with cystic fibrosis develops pneumonia, Pseudomonas is the usually the causative organism; cystic fibrosis is a hypermetabolic state and physicians will usually put patients with cystic fibrosis on a higher dose of medication d. Factors that alter the volume of distribution: - Dehydration: if a person of dehydrated, the volume decreases and the concentration increases; if a person is dehydrated due to a fever, the dehydration is the more important factor to look at in terms of the aminoglycoside dose - Edema - Ascites - CHF: in severe CHF, there is a two-fold problem: edema and decreased renal blood flow; edema will cause fluid build-up which will increase the volume and decrease the concentration; decreased renal blood flow will decrease the clearance; distribution is altered because the heart is not pumping strong enough to distribute the drug throughout the body; thus edema can increase volume and heart failure can decrease volume; to determine whether the volume has increased or decreased we look at a blood level - Obesity: in obesity, volume of distribution goes down because aminoglycosides do not distribute to adipose tissue

Dialysis: dialysis removes the drug from the system causing the concentration to drop; we can still put patients receiving dialysis on an aminoglycoside depending on the patient and situation; the drug should be given after dialysis so it does not get removed in the dialysis process; we do not start dialysis until the patient is in end-stage renal failure (CrCl < 10-15 ml/min); renal failure (some sources call this renal insufficiency) is when the CrCl < 30 ml/min Inappropriate sample time: if the trough is taken too early the trough will look high (if the trough is high we would adjust the dose or the dosing interval; if we adjust the dosing interval we usually have to adjust the dose, but if we adjust the dose it does not mean that we have to change the dosing interval); if the peak is taken too late the peak will look low (or if the peak looks like it is in normal range it could actually be in the toxic range); the peak should be taken an hour after the start of the infusion; the trough should be taken 30 minutes to just before the next dose

Pharmacokinetics Lecture Fifteen October 5, 2009 The aminoglycoside peak should be taken 1 hour after the start of the infusion; because aminoglycosides have a short half life, steady state is reached quickly; steady state concentrations can be taken around the 3rd dose

K = [(ln(C2/C1) x -1)/t]

(this tells us that we must know 2 points on the line)

Toxic/adverse effects of aminoglycosides: - Ototoxicity: the concentration does not have to be high for this to happen because the drug accumulates over time; we need to monitor for signs and symptoms of ototoxicity; we look for 4 main things: tinnitus (ringing in the ears; tinnitus can also occur due to long term NSAID use), sensation of fullness in the ears, vertigo (the 8th cranial nerve is being affected; in vertigo there is something going on with the nervous system; vertigo and dizziness are different; in dizziness, it feels like the room is spinning; in vertigo, it feels like you are spinning), and nausea/vomiting; in the early stages, ototoxicity is reversible; if the damage continues to progress, ototoxicity (hearing loss) will become permanent - Nephrotoxicity: the concentration does not have to be high for this to happen because the drug accumulates over time; nephrotoxicity can begin within 5 days of therapy; we want to get a baseline CrCl, BUN, and SCr prior to initiation of treatment; the patient probably will not complain of any symptoms of nephrotoxicity thus labs are very important; an increase in SCr greater than 0.5 is considered to be significant; normal SCr is 0.6-1.2; SCr levels can fluctuate daily because it is a waste product from the breakdown of muscle; we also want to look for an increase in BUN and urinary casts; urinary casts are dead cells found in the urine - Aminoglycosides interact with muscle relaxants

Peak and trough levels can cost anywhere from $70-$80 per level Chemo patients can be on long-term aminoglycoside therapy

Factors that will increase aminoglycoside toxicity: 1. Peak and trough concentrations: toxicity is more so associated with high trough levels, but it can also occur with high peak levels 2. Duration of therapy: when the therapy exceeds 10 days there is an increased risk of toxicity (it is not uncommon for therapy to exceed 10 days) 3. Dose: the higher the dose the greater the risk because a small amount of each dose can accumulate in the inner ear and kidney 4. Decreased renal function: aminoglycosides are cleared 100% by glomerular filtration so if renal function is impaired the aminoglycoside will not be eliminated from the body leading to increased toxicity 5. Other drugs: Vancomycin: Vancomycin can also cause ototoxicity and nephrotoxicity; we can still use Vancomycin with an aminoglycoside, we just have to monitor the patient more closely NSAIDs: NSAIDs can cause tinnitus and ototoxicity; we can still use an NSAID with an aminoglycoside, we just have to monitor the patient more closely; NSAIDs can cause renal failure (analgesic nephropathy) if used over a long period of time; we also need to monitor renal function more closely when an NSAID is used with an aminoglycoside Aminoglycoside Dosing: - In practice, many clinicians dose by weight instead of CrCl; a normal adult would be dosed at 3-5 mg/kg/day with the dose divided into three doses - But as pharmacists we use pharmacokinetic principles to calculate the dose - Since aminoglycosides are given by intermittent infusion, we are going to use the Cmax and Cmin equations to determine the dose - Once-a-day dosing: in practice, aminoglycosides can be dosed q 8, 12, 18, 24, 36, 48 hours; for class purposes we will use q 8, 12, 24, 36, 48 hours (DO NOT USE 18 HOURS); if we are doing once-a-day dosing we want the peak to be 15-24; some people do not take a peak and trough for once-a-day dosing, they just take a random level; the trough needs to be less than 2 mg/L within 24 hours - For Tobramycin and Gentamicin, peak should be > 10 mg/L; we prefer the peak to be between 15-24 mg/L; some sources say 15 mg/L is too low; > 24 mg/L does not produce a greater effect, it just causes more side effects A drug could be concentration dependent or time dependent: - Concentration dependent: the higher the dose the more killing effect; examples include aminoglycosides and quinolones; the higher the dose the better they kill; the closer the trough is to zero, the better; if it is below 2 mg/L we are ok - Time dependent: the longer the drug is given the more killing effect; an example is Vancomycin; the trough of Vancomycin is 5-10 mg/L; if the concentration drops less

than 5 mg/L the killing effect is diminished; Penicillins and Cephalosporins are also time dependent Critical thinking to use when dosing an aminoglycoside: - We need to determine when to use population parameters or individualized parameters; base the decision on the answers to the following questions: Is the patient receiving the medication at this time? o No = population information At this point we need to decide on a Cmax and Cmin we want to achieve, a dose, and a dosage interval and we have to use population parameters, including Vd, CrCl, and k o Yes = Ask, do we have peak and trough levels? No = population information Yes = Ask, are they appropriate? Yes = use population parameters No = individualize the therapy

If using population parameters, find: 1. 2. 3. 4. 5. 6. Weight Vd CrCl k T D IBW or ABW, whichever is lower 0.25L/kg x weight in kg [((140-age) x weight)/(72 x SCr))] x 0.06 x 0.85 (if female) Cl/Vd [(ln(C2/C1) x -1)/k] +1 C2= min (2 mg/L), C1= max -kT D = (Cmax x Cl x 1 e )/(tinf x 1 e-ktinf)

***Population information includes: Vd, CrCl In referring to #5, if we use a min of 2 mg/L and the T comes out to 7.9 we can use a T of 8 hours because it takes 7.9 hours to get to 2 mg/L so in 8 hours it will be less than 2 mg/L; if it was 8.9 mg/L we would need to go to a T of 12 because after 8 hours the concentration would be higher than 2 mg/L In once a day dosing, T is always 24 hours

Pharmacokinetics Lecture Sixteen October 7, 2009 Critical thinking to use when dosing an aminoglycoside: - We need to determine when to use population parameters or individualized parameters; base the decision on the answers to the following questions: Is the patient receiving the medication at this time? o No = population information At this point we need to decide on a Cmax and Cmin we want to achieve, a dose, and a dosage interval and we have to use population parameters, including Vd, CrCl, and k o Yes = Ask, do we have peak and trough levels? No = population information Yes = Ask, are they appropriate? Yes = no issue with current dosing No = individualize the therapy

If using population parameters, find: 1. 2. 3. 4. 5. 6. 7. Weight Vd CrCl k T D/Cmax Cmin IBW or ABW, whichever is lower 0.25L/kg x weight in kg [((140-age) x weight)/(72 x SCr))] x 0.06 x 0.85 (if female) Cl/Vd [(ln(C2/C1) x -1)/k] +1 C2= min (2 mg/L), C1= max -kT D = (Cmax x Cl x 1 e )/(tinf x 1 e-ktinf)

If a dose is given, then a T will be given; in this case, skip step 5 and do 6 and 7 ***Population information includes: Vd, CrCl In referring to #5, if we use a min of 2 mg/L and the T comes out to 7.9 we can use a T of 8 hours because it takes 7.9 hours to get to 2 mg/L so in 8 hours it will be less than 2 mg/L; if it was 8.9 mg/L we would need to go to a T of 12 because after 8 hours the concentration would be higher than 2 mg/L In once a day dosing, T is always 24 hours

If a physician gives an order for a dose, they must provide a dosing interval (T) If an MD gives a dose and T: - Check to insure the concentrations are accurate If an MD gives a desired concentration: - Calculate a dose and T If a physician gives dose, we have to figure out if the concentration will be appropriate If we are given a wanted concentration, we have to figure out the dose

Critical thinking to use when dosing an aminoglycoside: - We need to determine when to use population parameters or individualized parameters; base the decision on the answers to the following questions: Is the patient receiving the medication at this time? o No = population information At this point we need to decide on a Cmax and Cmin we want to achieve, a dose, and a dosage interval and we have to use population parameters, including Vd, CrCl, and k o Yes = Ask, do we have peak and trough levels? No = population information Yes = Ask, are they appropriate? Yes = no issue with current dosing No = individualize the therapy

Individualized aminoglycoside dosing: 1) If concentrations are taken appropriately, k = [(ln(C2/C1) x -1)/(t)] so, t = t2 t1 = T tinf t2 = T, t1 = tinf

****If concentrations are not taken appropriately and the peak was not taken at the right time, find Cmax using: C = Cmax * e-kt 2) Find Cl: Rearrange: Cmax = [(D x 1 ektinf)/(Cl x tinf x 1 e-kT)] Cl = [(D x 1 ektinf)/(Cmax x tinf x 1 e-kT)]

3) Find T: T = [(ln(C2/C1) x -1)/k]

4) Find D: Rearrange: Cmax = [(D x 1 ektinf)/(Cl x tinf x 1 e-kT)] D = (Cmax x Cl x tinf x 1 e-kT)/(1 e-ktinf)

Kinetics 10.12.2009 Dr. Scott Practice Problem #1 35 yo female 56 wt 140lbs Admitted to hospital for tx pneumonia PMH: cystic fibrosis Labs: Scr 1.2, Bun 19, Na+ 138 K 3.9 WBC 13,000 - Normal WBC 5000-10000 - Segments are mature; band are immature, shift to left means there is an increase in bands Calculate a dose to achieve a peak of 8 and a trough < 2. Ask the questions, is the pt on the medication? Y or N No, so use pop parameters Find: 1) wt, 140lb 2.2 = 63.64 kg OR IBW = 45.5 + (2.3*6inches) = 59.3 kg 2) Vd. Vd = 0.25L/kg*59.3kg = 14.825L 3) Cl,(((140-35)*59.3) (72*1.2))0.85*0.06 = 3.675L/h 4) k, k = Cl/Vd = 3.675L/h 14.825L= 0.2479h-1 5) , = (ln(C2/C1)*-1 k) +1 = (ln (2/8)*-10.2479) +1 = 6.59 8h dosing interval o we never dose aminoglycosides every 6h, package inserts say we can w/ vancomycin IV but if we do this for a normally adult pt 80-90% of the time the pt will be toxic; if we dose vancomycin po q6h then there is no toxicity; vancomycin is gene q12-24h 6) Dose = (Cmax *Cl*tinf* (1-e^-k)) (1-e^-ktinf) = (8mg/L*3.675L*1*(1-e^-(.2479*8))) 1-e^.2479*1)= 115.45 115mg q8h or 115.5mg q8h - it will take 3 doses to ss at 115 q8h - if starting the infusion at 8am, 4pm and 12am; 1st trough will be at 7:30-7:59 8am; peak at 9:02 9am Practice Problem #2 For some reason the tobramycin peak = 4.7 & trough was 0.002 - this peak it too low, we want 5-10 mg/L Why is it so low? - Clearance is increased b/c this pt has Cystic fibrosis (a hypermetabolic state), so we must increase the dose to achieve an appropriate peak - clearance is a big deal b/c intermittent infusion is a type of MD and we are worried about what is being eliminated Ask the question, Is pt on the medication? Y or N Yes Do we have peak & trough? Y or N Yes Are peak and trough conc appropriate? Y or N yes, since we have levels we can individualized the tx 1

Find: 1) k, k= (ln(C2/C1)*-1)(t2-t1) = ln (0.002/4.7)*-1 (8-1)= 1.1088 2) Cl = (D*1-e^-ktinf) (Cmax* 1-e^-k) = 115 * (1-e^-1.1088*1) (4.7*1-e^-1.1088*8) = 16.3972L/h (class asn 16.3216) o Cl should be higher than population b/c the conc was lower in the pt; when Cl , conc 3) tau = ((ln(C2/C1)*-1 ) k)+1 = ((ln (2/8)*-1) 1.1088) + 1 = 2.25h per dosing interval 8h b/c we dont aminoglycosides at 2.25h so dosing interval is automatically bumped to 8h o have to calculate a new tau that will give use the peak & trough conc we desire o this formula w/o adding the +1 means that is take some many hours to go from C1 to C2 4) Dose = (Cmax* Cl*1-e^-k) (1-e^-ktinf) = (8mg/L* 16.3216* 1-e^-1.1088*8h)(1-e^-1.1088*1) = 195.66 mg 195.66 mg q8h o we dont need to check our trough at this dose b/c we already know that the trough should be 2 and at 2.25h & we went 8h so it will be less than 2; in other words if we calculated the dose we dont need to check the trough o if physician gives us a dose then check the peak & trough

Kinetics 10.19.2009 Dr. Scott Begins Exam #3 Material VANCOMYCIN has gram (+) activity only it is an alternative to PNC & Cephalosporins when: 1) a microorganism is resistant or 2) the pt has an allergy o depending on the infection & an allergy to PNC, vancomycin may not be used; it is considered to be a big gun, so it is not used for an mild infections b/c if we develop resistance there arent too many drugs we can go to but there are other drugs we can go to e.g.: a. if MRSA is found in the urine (UTI), Bactrim or Cipro can be used b. vancomycin is not used in toe infection depending on the hospital they wont have methicillin, so looking at C & S, if bacteria is resistant to nafacillin or oxacillin it is considered to be resistant to be Methicillin MSRA vancomycin could be used for: 1) MRSA very serious infections 2) Pneumonia 3) Sepsis 4) A bone infection o in (#2-4) these very severe situations wed use vancomycin along w/ other drugs to kill the organism 5) Enterococci a very serious organism; not used in less severe infections, we want to save b/c if a pt gets Vancomycin resistant enterococci [VRE] this is a problem b/c there only a few drugs that strong enough to deal w/ this particular organism and wed have to give high doses Vancomycin MOA: 1) it inhibits bacteria cell wall formation 2) it also inhibits RNA synthesis o thru these mechanisms cell wall permeability is altered allowing more volume to get into the bacteria cell, the cell swells, cell lyses & killing the bact Resistance: 1) in certain situations resistance can be overcome using volume or giving higher doses to get higher conc 2) but other forms of resistance cant be over come 3) other forms of resistant can be transient e.g. a certain organism can become resistant to an aminoglycoside over a short period of time this is why once a day dosing is thought to be effective b/c of the post antibiotic effect the drug conc gets really high and then there is a moment the drug is not in the system so that resistance does not occur to the same degree, resistance occurs when

the organisms in contact or more w/ the antibiotics; if the person is not on the drug for a minute then the drug is still effective (Refers to Drawing/Reiteration of above point) post antibiotic effect says that for certain drugs if we get the drug conc high enough even if the conc falls below the MIC range it still has a killing effect and resistant goes away this is why hospitals like to use once a day dosing b/c it decreases resistance that can occur to some drugs; REMEMBER normally resistance occurs when there is a significant drug conc in the sys but it is not enough to kill the organism and the bacteria begins to adapt or make changes MRSA treatment includes pairing Vacomycin w/: 1) Gentamicin or tombramycin - but aminoglycosides dont have any affect against MRSA (alone) but w/ vancomycin there is synergistic effect, the killing power is enhanced 2) Rafampin 3) Bactrim Vancomycin Peaks Trough Normal 20-40???mg/L 5-10mg/L In renal failure/insuff 20-30mg/L 5-10mg/L Conc times 1hr after start of infusion Just before the dose is given Therapeutic levels Peak, 30-40-mg/L this is where it is generally wanted but when we have pt who are renally compromised or have decreased renal funct, it becomes hard to maintain the trough conc so the peak conc is decreased to will be 20mg/L- 40 mg/L & trough conc is 5-10mg/L; this change in peak conc can be done b/c: 1) Vancomycin it time dependent, it makes a differ how long it stays in range 2) toxicity w/ this drug is associated w/ a high peak in some books the trough level will be 10 5mg/L which means to him a peak can be as high as 15mg/L and a trough as low as 5mg/L; there are studies were Vancomycin use is similar to continuous infusion and the conc trying to be maintained is 15mg/L w/o a peak or trough, but it has to be maintained w/in the range for a longer period of time some hospitals try to do this and take random conc to make sure they it stays in the range a lot of hospitals take random levels to avoid cost; hospitals will try to maintain it at 15mg/L b/c: 1) it is going to give a greater level of killing activity b/c it stays at this conc for a longer period of time 2) we dont have to worry about spiking to a high peak or as much toxicity but remember the more vancomycin is given over a period of time the more drug can accumulate for class purposes trough is 5-10mg/L & peak will be 20-40mg/L???; if renal function is declining we have to drop the peak to 20-30mg/L dont let trough drop below 5mg/L b/c the drug will be in the system but not working, vancomycin doesnt have a post antibiotic effect post antibiotic effect is more so associated conc dependent drugs drugs that are time dependent are more likely not to have the post antibiotic effect and will have to be given for a longer period of time

KINETICS Absorption - less than 5% is absorbed , so vancomycin F < 0.05 - despite not being used to tx systemically, systemic toxic effects can be seen b/c some drug is still absorbed; over time if a pt has a decrease renal func the drug conc will increase and taking the drug over time this is a problem - 90% of pt on PO adm that have renal problems dont experience toxicity but the potential is there - Clostridium difficile treatment includes: 1) vancomycin - given po only (works locally) dose = 125-500mg qid, normally the smaller dose is reserved for pediatric pt; adults 250-500mg, but an adult can get 125mg dose o kids stop seeing a pediatric physician at 18-19 year of age then switch to a regular doctor e.g. 15 yo 510 175 lbs, this is a pediatric case but they should rcv an adult dose 2) Metronidazole (Flagyl ) - this is cheaper than vancomycin 3) Clindamycin (Cleocin) can also be used but for class purposes we only use Vancomycin - vancomycin is given by slow IVintermittent infusion , we dont give Vancomycin IM; it is very irritating, c/ing: 1) phlebitis 2) extravation [vein ruptures and there is leakage into the tissues] if given IV make sure it is diluted well - we do not infuse in less than 1 hr; for class purposes we infuse for 1hr some hospitals have polices for infusing longer than 1 hour - Vancomycin can c/ serious side effects if: 1) infused too fast or 2) if it is not put in enough volume - Vancomycin Side effects: 1) redman/redneck syndrome sx: a. pt looks like they are having an allergic rxn b. flushing c. rash on face, chest, neck ,upper extremities o the rash or redness is mostly seen in the neck area 2) hypotension 3) wheezing & SOB 4) uticaria (hives) and 5) pruitis [itching] - Problem w/ vancomycin is that it is hard to differentiate btwn redneck syndrome and a vancomycin allergy; the only way to tell is to give another dose, dilute it appropriately and slow infusion eg instead going for 1hr try 1.5 hr; so slow the infusion down if redman syndrome occurs and if it doesnt resolve completely then the pt may be allergic Diluting vancomycin - if conc in the bag is 500 mg we put in 100 ml vancomycin - if > 500 mg then put in a 250 ml eg if 502mg, give pt 500mg - if 550mg = use 250 ml

if 510mg = 250ml or make it 500 and use 100ml; for class purposes leave use the 500 mg greater than or equal to above Distribution - vancomycin is hydrophilic, it has better distribution into adipose tissue than aminoglycosides, however, distribution is not significant to adipose tissue - it can distribute to the: 1) pericardial fluid 2) pleural fluid 3) synovial fluid 4) ascetic fluid 5) a low conc can be in CSF fluid when meninges are inflamed, vancomycin is irritating so this is not a good thing - vancomycin under goes 2 comp model but drug is not completely distribute in 1-2 hr - the issue most time peak conc is taken 1 hour after infusion and trough right before the next dose but it can take up to 2 hours to be distributed, this is one of the reasons why conc can be faulty - 90% of the time aminoglycoside conc are right on the money, but vancomycin about 75-85% of the time conc will be off but the dose will be in the range, a lot of time it will be in normal range but it wont be the predicted conc; eg you calculate a dose to get a conc of 35mg/L, but most times the dose calculate might come out as 32. - vancomycin is given IV intermittent infusion for 1 hr (practice can be 1h, 11/2h or 2h depending on hospital policy) - vancomycin Vd is 0.7L/kg( this is the ave ) in pedatric pt it is a little higher

Kinetics 10.21.2009 Dr. Scott VANCOMYCIN peak is 20-30mg/L & Trough is 5-10mg/L; some sources will say the trough can be as high as 15mg/L b/c toxicity is more associated w/ high peak; however the longer the drug stays in the body at a higher conc the greater the risk of toxicity overtime e.g. AMINOGLYCOSIDES: a physician wanted to give a high dose of gentamicin at once a day dosing but the peak came out high and trough was also high so he extended the tau to 48hthis is no longer once a day dosing - refers to drawingin the example above despite the trough conc being close to zero at the end the dosing interval (48h), it was well above 2mg/L for over 24 hours; REMEMBER for aminoglycosides trough conc should be less than 2mg/L; what we are concerned about is how long the conc stayed above 2mg/L, dont be misled by the fact that after 48 hr the trough was close to zero; in this situation the person can develop toxicity b/c the toxicity is more associated w/ high trough - in practice to save money they take random conc level to see were the drug is and if it is at a certain point btwn they use nomograms that tell say if level is this & CrCl is this then it is good or not good - there are certain situations that outweigh the risk were the conc may be too high eg a pt w/ renal failure & pneumonia can be put on aminoglycosides b/c they already have renal failure, (the pneumonia will kill faster) we need to get pneumonia under control, so we can dose it & at the end of 2 days the trough conc will be less than 2mg/L; or when going thru dialysis this should pull the excess drug out of the system; but we wont try to get a high peak, stay in the 510mg/L (it probably give ~7mg/L) just high enough to kill and have time in the system Back to Vancomycin - understand thatTrough is 5-10mg/L, or some sources will say 10mg/L 5 (b/c toxicity is more associated w/ high peak) but the longer vancomycin is maintained at 15mg/L the more drug can accumulate overtime - w/ vancomycin (a time dependent drug ) it doesnt matter how high we get the conc but how long we maintain; there is better killing activity if maintained at 15mg/L for a long period of time but even if maintained at a lower conc we still get killing activity ELIMINATION - Elimination t1/2 = ~7h - Clearance is 100% by the kidneys; clearance of Vancomycin use eq Cl T = Cl r + Cl nr = 1 + Clnr - Cl T = clearance total - Cl r = clearance renal = 100% or 1 - Cl nr = nonrenal = 0, b/c it is not cleared any other way besides the kidney (unchanged or not metabolized b/c 100% cleared by the kidney) - understand that renal function is important

the kidney functions in diff ways: 1) glomerula filtration (GF) 2) active tubular secretion (ATS ) 3) reabsorption (puts the drug back into the sys) when drug is eliminated by the kidney, it can be filtered or undergo ATS or a combo of both; Vancomycin goes thru a comb of GF = ~65% & ATS = ~35% PROBLEM we can determine GF better than clearance by ATS; it is easy to determine GF b/c of CrCl but there arent really any equations for ATS; therefore when finding the clearance of Vancomycin = CrCl *0.65 = ml/min *0.06 = L/hr the 65% GF is an average, it could be higher or lower; dose calculations for vancomycin are not right on (it should be close) b/c there are things going on that we don take into account e.g. ATS

FACTORS THAT AFFECT PHARMACOKINETICS & DISPOSITION - the same things that affect aminoglycosides will affect vancomycin 1. Renal Function 2. Age 3. Hypermetabolic State 4. Body Composition 5. Inappropriate sample time 6. Factors that affect disposition refer to aminoglycoside lecture o Some studies show that dialysis doesnt affect Vancomycin levels, drug is not readily pulled out of the blood during dialysis o PROBLEM if the persons vancomycin level if high before dialysis it will be high after dialysis so we have to be careful; it can be used in pt w/ renal failure [if benefit outweighs the risk] but if we can use something diff that is effective and doesnt the same amt of toxicity this is also an option Adverse Effects of Vancomycin 1. Extravasation 2. Phlebitis 3. Redman/redneck syndrome Vancomycin Dosing - can be dosed po qid - the average starting dose is ~2g/day (this doesnt mean you should do it this way but most physicians will) - package insert says: 1) vancomycin can be dosed IV q6h 2) or q12h - is the most common dosing; most physicians will give 1g q12h & then adjust 3) 2g q24h; q 12h is the most common dosing; most [physician will give 1 g q12h & then adjust]; 4) IV 500mg q 6h = 2 g/d - most persons become toxic, therefore we really dont use

for class purpose we dose: 1) q 12 2) q18h is used if we try to go to q24h but the trough has dropped less than 5mg/L, so we have to back the trough down to 18h 3) q24h??? Kid dosing 1) neonates < 8 days old 10mg/kg q 12h o sometimes infuser pumps are used, some pumps are syringes pump [60 cc syringe];if the dose is small enough the syringe pump will be used in some cases (especially in pediatrics) & Vancomycin wont be put in 100ml but in 60ml, this is seen a lot in home health care 2) infants 8 days-1month old 10mg/kg q8 3) kids older than 1 month 40mg/kg/day in divided doses e.g. q8h or q12h Adults normal Vancomycin dosing intervals include (these are based on pop parameters & nomograms): 1) q12h 2) q24h or (if needed) 3) q36h 4) q16h (in crazy cases )

Vancomycin Calculation - Equations & concepts for calculating dose or figuring out if dose or conc are appropriate are the same the equations and format used with aminoglycosides - is pt on med Y or N; if N use pop parameter, find: 1) wt , IBW or AW lower of the two 2) Vd, Vd = 0.7kg/L 3) Cl, CrCl * .65ml/min*0.06 = L/h 4) k = Cl/Vd 5) Tau [if finding the dose] 6) Dose - is pt on med Y or N; if N use pop parameter, find: 1) wt, IBW or AW lower of the two 2) Vd, Vd = 0.7kg/L 3) Cl, CrCl * .65ml/min*0.06 = L/h 4) k = Cl/Vd 5) Cmax 6) Cmin o do steps 5 & 6 if not finding the dose b/c dose is already given, so check its appropriateness; to check this we must find the peak & trough conc for vancomycin o w/ vancomycin dosing we worry about trough conc being too high or too low o w/ aminoglycosides we only worry about the trough being too high

Kinetics 10.26.2009 Dr. Scott

VANCOMYCIN Vancomycin distributes better to adipose tissue than aminoglycosides so in regards to Vd & making changes for an obese pt we dont use the same formula used for aminoglycosides; b/c it has some distribution to adipose tissue for vancomycin use this VD eq is Vd = 0.7 L/kg * wt kg; lowest of IBW or Actual body weight for aminoglycosides corrective dose wt (for an obese person) aka Adjusted dosing wt, ADW = IBW + CF (ABW IBW), this is eq adding 10-40% of your fat wt to your ideal body weight; this will be the dosing wg used in calculations, the ADW multiplied by the a nomogram and the product would be the dose that we would use; e.g. nomogram dose is 5mg/kg 10mg/kg ect e.g. Male 511, wt 265 lbs playing football, all his weight is not adipose tissue, we could dose a little higher ; if we have the same person & he didnt play foot ball or exercise, we wouldnt take this weight into account, we can tell he has a lot of adipose tissue when dosing the pt with Vancomycin use the same questions used for aminoglycosides: Is the pt on the medication? Y or N, if N use pop parameters, Find: 1) wt IBW or ABW 2) Vd 3) CrCl *.65; then either calculate a dose or see if the dose the physician is using is appropriate 4) k Is the pt on the medication? Y or N o if Y, the pt is already on the medication then we dont calculate a dose, we already have dose & interval o if Y, then ask Do we have a conc? Y or N o If Y, 1st thing we do is calculate to see if the dose & interval are appropriate o If N, using the Cmax eq, calculate a new dose and doing interval; or if a physician wants to use a diff dose calculate if it is appropriate or not. Dont continue to dose if it is inappropriate 1) k find this 1st if pt is on the medication; and we dont have Vd; if the timing was inappropriate then we have to adjust the timing to find out what the actual peak was (step 3) 2) Cl find using Cmax eq 3) if peak timing is inappropriate find appropriate Cmax using the eq Cmax = Cmin/e-kt, to take us back ward; t = the time between the conc we have and the time we wanted 4) if Cmin is at inappropriate time - use the eq Cmax = Cmin/e-kt plug in the appropriate Cmax and t = the change in time it should have been; Cmax corresponding time should be one hour less than tau, so if tau is 8h then the change in time = 7h

DIGOXIN - in practice many levels arent taken, pt can go months w/o having a digoxin level - pt will generally start on an ave dose of 0.125 or .25 mg/day, a normal starting dose; .125 mg tid for 1 day then start on .125 mg qd or .25 mg qd; this is not necessarily appropriate so know how to monitor drug based on side effects and toxic effects; know if pt is experiencing blurred vision or N/V or not normal so you can make appropriate adjustments e.g: o if a pt is experiencing N/V, often what you will see is a prescription for reglan (metoclopramide) or for phenergan (promethazine) to tx N/V so: 1. See if there is something going on with the pt 2. Get a digoxin level [if we dont have one] 3. Look for other signs and sx 4. Look for other things that would c/ N/V eg 1st dose of IV morphine or narcotic DIgoxin Indications 1. primarily used for mgmt of CHF 2. Atrial fib 3. Atrial flutter - it is no longer DOC in CHF, DOC is now ACE inh; some studies say ARBs are comparable to ACE inh for the mx of CHF; but not every ACE inh or ARB is FDA approved, but we can leave the pt on it; ACE or ARB are used for renal problems b/c they have a renal protective effect - for board purposes know which ace inh are FDA for CHF mx; in practice it doesnt make a diff; in early stages of CHF and pt can be on a ACE inh & have HTN eg a pt is on Lotensin (benazepril) for HTN then, BP is maintained but not as low as it could be, then the pt develops signs and sx of CHF (Class I); for tx we can: 1. increase the dose of ACE inh 2. add a diuretic 3. used combo drug - when pt is taking a drug long term if possible get comb drug Atrial Fibrillation & Flutter Treatments 1. Can use direct cardio version to shock heart back into normal rhythm 2. digoxin is still a top drug used in CHF mx, also a major drug used in mx atrial fibrillation and flutter - IMPORTANT: before putting a pt on Quinidine the pt needs to be digitalized first (loading them up on digoxin) o quinidine (at first) has a negative effect, blocking the vagus nerve c/ing an increase AV conduction c/ing more impulses to get thru o digoxin stimulates the vagus slowing AV conduction, so loading the pt on digoxin blocks the negative effect of quinidine if we get the digoxin levels high enough - Digoxin MOA 1 : it inh the Na+/K+ pump increasing the efficiency of the Na+ & Ca2+ exchange - (Refers to drawing) the Na/K pump pumps Na+ out and K+ in, when the pump is blocked can Na+ build up inside the cell (and H2O will follow Na+ c/ing the cell to swell & lyse) so the Na+/Ca2+ exchange pumps Na+ out and more Ca2+ will be pumped inside the cell; having the more Ca+ inside the cell will lead to a greater the force of the contraction - Digoxin MOA 2 : increases the sensitivity of the Purkinje Fibers (have automaticity of their own, located in the ventricle) they rcv impulses that goes from the SA node to the AV node, digoxin makes them more

ready to fire when rcving a stimulus and fire faster and harder increasing contractility; The PROBLEM we can have the occurrence of ventricular arrhythmias - Tx for digoxin induced arrhythmias: 1. xylocaine - is the DOC for digoxin induced pt w/ ventricle arrhythmias 2. phenytoin can also be used o other things can be used but these 2 are the most common o in pt tx w/ digoxin as the levels go higher the chance for ventricular arrhythmias increases Adverse Effects of Digoxin: 1. Ventricular arrhythmias 2. AV block - when multiple foci are present as in atrial fib digoxin stimulates the vagus, slowing AV conduction so all impulses dont get thru thus slowing the HR c/ing AV block, here no impulse can get thru - drugs that counteract the effect of AV blocking include: 1. Anticholinergics o atropine inh the vagus, increasing the HR; this is why antipsychotic drugs, antihistamines and TCA or drugs w/ anticholinergic increase HR o other adverse effects of anticholinergics: dry mouth & eyes, tachycardia arrhythmias - therapeutic conc for digoxin: 1-2mcg/L - Atrial fib & flutter requires a higher level of digoxin, b/c the body is at a greater demand o Clearance of the drug is high in these pt so we need a higher conc o in HF we dont need a higher conc; sometimes in practice labs will say .5-2 mcg/L for CHF, if they are fine dont make any adjustments; if at .7 or .8 and has atrial fib then bump up the dose o target conc is 1.5mcg/L for either condition but if it is > 2mcg/L this is toxicity - make sure you tx the pt and not the level; lower chance of seeing adverse effects and improving conditions at lower levels of digoxin PHARMACOKINETICS Absorption - after po it is absorbed in the upper part of the small intestines so anything that increase GI motility will decrease digoxin absorption - delayed gastric empting time & food may slow rate of absorption but not the extent of absorption; the only time there is a problem w/ this is when fiber is eaten; fiber is not absorbed, soluble fiber dissolves in water and the other form does not; high fiber content will decrease absorption e.g. 1. Oatmeal 2. Cheerios - bioavailability will vary depending of the dosage form: 1. tab F = 0.7 2. elixir (contains OH) lanoxin = 0.8 3. gel cap lanoxi caps = 1, it can be as low as 0.9 but well absorbed 4. injection - is faster 1 - salt (chemical form) is 1 - when things are absorbed faster it is less broken down

o it is thought that some of the bacteria in the GI tract can break down lanoxin, so as it is going thru the intestines some may actually be metabolized by the time it gets to circulation o the tab takes longer to be absorb so more is lost o the elixir is absorbed faster but it takes a little longer than the gel cap o gel caps easily cross the membrane and cross faster & absorption is faster so there isnt as much lost and more drug absorbed w/ gel cap than elixir, and more elixir than w/ tab b/c rate of absorption is faster Drugs That Decrease Bioavailability/Absorption 1) Antacids - affect in diff ways b/c of substances that make up the antacids; antacids can block some absorption, slow gastric emptying time and once dumped into the small intestine inh the drug absorption which means it is moving fast thru the system and not being absorbed o Maalox o Mylanta 2) Adsorbent drugs normally used for diarrhea: o Kaopectate o Pepto-Bismol o Amphogel 3) Anything that increases GI motility o Reglan o Erythromycin 4) Questran 5) Colestid Drugs the Increase Absorption 1) Tetracycline - b/c it kills the bacteria that break down the digoxin 2) Erythromycin - cause drugs to pass thru the sys faster b/it also destroys the bacteria however it increases motility, increasing GI motility - to avoid interactions give digoxin 1-2h before or give 2-4 h after ; e.g a. if giving after questran (which really decreases the absorption) then wait 3-4 hours; it is easier give the drug that is affected first then wait 1 hr to administer b. a 2h wait is enough for antacids (Maalox)

KINETICS DR. SCOTT 10.28.2009 DIGOXIN DISTRIBUTION - Digoxin has very good distributes to areas were the Na+/K+ pump is abundant and active eg: 1. skeletal muscle 2. heart tissue 3. liver 4. kidneys 5. stomach 6. intestines o stomach, intestines and skeletal muscles are important when it comes to vomiting an adverse effect seen w/ digoxin; the vomiting is projectile b/c the Na+/K+ pump is inhibited, so more Ca2+ builds up in the cell and now stomach muscles contract w/ a greater force making the vomit projectile - digoxin distributes readily across the placenta; it is preg category C - digoxin undergoes 2 comp model, distribution half, t1/2 = 35 min; Given: 1. IV wait 4 hours to do serum conc 2. PO wait 6 hours to do serum conc 3. however it is suggested that serum conc be taken 12-24h after the dose (either IV or PO) Digoxin Dosing - in practice population parameter Vd = 7.3L/Kg in pt w/ normal renal function; in renal failure Vd = 45L/kg - for class purposes Vd = (3.8L/kg * wt kg + (3.1*CrCl)), leave CrCl in ml/min, but the final answer will be in liters; plug in the lowest of actual Body wt or IBW - once Vd is found and we need LD, LD = (Vd *C)/(S *F) = mcg/L o S is always = 1 o F changes depending on the formulation - for LD dont give at one time b/c digoxin has narrow therapeutic index & it is very easy to become toxic: 1. Give half of the total dose over 4h 2. Then give a of the total dose, wait (4h IV or 6h PO) 3. Then give the remaining of the total dose, eg: LD = 1000mcg, give 500mcg wait 4-6h, then give 250mcg wait 4-6h, then give remaining 250mcg; in practice you may see this given 500mcg qd x 1D, then 250 mcg bid x1D Protein Binding - is insignificant in digoxin at only 20-25% is protein bound, displacement wont make a big difference - flagged drug interactions: 1. K+ & digoxin: they compete for ATPase pump

when K+ is high it can displace digoxin c/ing digoxin levels to increase in the blood digoxin toxicity; the K+ level has to already be really high for this to occur o digoxin can displace K+ c/ing K+ levels to increase hyperkalemia o in practice these interactions dont happen a lot but they can occur; for digoxin to displace K+ and c/ problems digoxin has to get really high and K+ levels have to be borderline, if K+ is not borderline then it is not a big deal; in practice, dig and K are used together all the time 2. Diuretics & digoxin: diuretics can decrease K+, having the potential for more digoxin to get to the SOA c/ing an increase in activity o 9 times out of 10 if a person is in HF and on a loop diuretic then they will also be on a K+ supplement, so monitor the pt b/c digoxin and HYPOkalemia can c/ AV block (an arrhythmia) o if AV block occurs dont assume it is either one e.g.: 1) check levels of K+ & digoxin, if K+ is 4.95 meq/L it is not the problem 2) if pt develops 1st degree AV block & K+ is 5.1 meq/L & Digoxin is 1.9mcg/L, hold back on K+ supplement, if K is 5 meq/L, at this level if the pt developed digoxin toxicity we couldnt give potassium chloride (KCl) holding the K+ lets the level drop & we can see if the effect still occurs then go back & look at digoxin K+ or digoxin can c/ some increase or decrease in each other levels however, the level of either K+ or digoxin has to be significantly high enough but this normally NOT before K+ levels get high enough to c/es problems w/ digoxin we see problems w/ K+ first so we go ahead and adjust to K+; before digoxin levels get high enough to c/ significant changes in K+ were start seeing problems w/ digoxin so we make adjustment ELIMINATION - a small amt of digoxin is broken down in the GI tract (or portion is metabolized in the sys), this is the reason that bioavailability of po drugs, tab and elixir are lower - however the major route of elimination is renal clearance, over 75%, if something is wrong w/ liver func this doesnt make a diff; if liver func declines, the kidneys just do more; when renal func drops drug clearance changes - looking at clearance based on whether pt has CHF: 1. Doesnt have CHF Cl = [(0.8ml/kg/min *wt kg) + (1.02 *CrCl ml/min)] * 1.44 = L/day o digoxin is dosed per day not hour o clearance is higher here 2. Does have CHF Cl = [(0.33 ml/kg/min *wt kg) + (0.9 *CrClml/min)] *1.44 = L/day o clearance is lower in CHF - elimination half-life, t1/2 = 36-48h o hence, wait 10-14 days (5-7 half-lives to reach ss) to take a level for the maintenance dose (MD) o w/ a LD we wont wait for ss b/c we just want to know what the conc at this dose o

if a drug affects the conc of digoxin, like quinidine, it cant be given until 10-14 days pass; quinidine changes the ss conc of digoxin, hence we wait 10-14 days after quinidine administration to check the new ss conc of digoxin

Factors that Affect Digoxin Disposition of Pharmacokinetics in the Body 1) Age physiological aging 2) Exercise temporarily alters pharmacokinetics, e.g. skeletal muscle has high levels of ATP (pump?) when beginning exercise it forces ATP (pumps?) to work, c/ing digoxin to displaces from the site & levels to appear to be higher (in the blood) after exercise, so exercise should be done after blood work 3) Dx states o CHF b/c the drug is not being distributed thru out the system b/c the heart is not pump significantly enough; affects digoxin levels if digoxin is not working b/c heart is not pumping significantly o Chronic renal failure drug is 75% cleared renally, if renal func decreases drug conc increase o Hyperthyroidism decreases drug conc b/c it is a hypermetabolic state o Hypothyroidism increases drug conc 4) Drugs o Quinidine - can affect dig conc and pharmacokinetics by 50-200%; it decreases the clearance of digoxin and decreases the Vd of digoxin, this is why there is a significant increase in digoxin o Amiodarone decreases Clearance digoxin by 70-100% & also decrease distribution by displacing digoxin from tissue binding sites; most times w/ this drug digoxin levels are being altered o Ca2+ channel blockers 1st gen: result in increased serum digoxin concentrations and toxicity (nausea, vomiting, arrhythmias). Diltiazem, Verapamil (has the greater effect) o Antibiotics tetracycline & erythromycin kills bacteria in the gut, increasing the absorption of oral tab and elixir; this doesnt affect the gel cap

Pharmacokinetics Lecture Twenty-two October 30, 2009 Adverse Effects of Digoxin (most are only seen with toxicity) - Cardiac effects: Sinus bradycardia: the SA node is still pacing the heart, but the rate has slowed down AV block: if you develop AV block, the impulse from the SA node cannot get to the bottom of the heart; when the AV node is blocked, the Purkinje fibers or ectopic foci can take over and create their own impulses or the SA node can start firing more impulses in an effort to get more impulses through; the Purkinje fibers are very excitable so this can lead to ventricular tachycardia; in 1st degree AV block most impulses get through; in 2nd degree AV block some impulses get through (a beat can be skipped); in 3rd degree AV block little to no impulses get through (multiple beats are skipped) Ventricular tachycardia or ventricular arrhythmias Supraventricular tachycardia with block: deals with anything above the Bundle of His (i.e. atrial fib); if the AV node becomes blocked, the SA node impulse cannot get through; the SA node can start firing more impulses in an effort to get more impulses through - GI toxicities: Nausea and vomiting Diarrhea Anorexia (this might be seen even if levels are normal) - CNS toxicities: Headache Fatigue Drowsiness Confusion Generalized muscle weakness Seizures and coma (in severe cases) - Ocular toxicities: Blurred vision Halo vision Yellow-green vision (the cones of the eye are affected; other colors can be seen, but yellow-green is the most common)

Management of Adverse Effects of Digoxin - If these side effects occur we should HOLD the Digoxin and decide whether or not to start it at a lower dose - If toxicity occurs we first need to look at how long ago it was that the patient took the dose - If someone has just recently taken the dose of Digoxin we can give Questran or Colestipol to bind the Digoxin in the GI tract; we should take the Digoxin drug level the next day (or at minimum 6 hours if it is given PO); if we begin to see signs and symptoms of toxicity we will take a level that same day; if we know a patient has taken too much Digoxin, even if they are not exhibiting signs and symptoms, we want to go ahead and give Questran just to be safe - If we take a Digoxin level and the concentration is too high we will hold that dose for the day and start the patient back on the Digoxin the next day (the dosage may need to be decreased) - If the dose of Digoxin is already in systemic circulation, and the levels are too high, but the patient is not experiencing signs and symptoms of toxicity, we can give IV potassium chloride (infused at 10 mEq/hr; it is usually diluted to 20 mEq/L) if the patient is showing signs and symptoms of toxicity; we will not give a patient potassium if the potassium level is greater than 5 mEq/L; if the patient is in 2nd or 3rd degree AV block, even if the potassium is in normal range, we will not give potassium because slight changes in potassium can be dangerous in these situations - If the patient has nausea and vomiting we can give them something for the N/V and hold the dose - If the patient develops sinus bradycardia or AV block we can give the patient Atropine; if the patient develops 1st degree AV block and the potassium level is < 5 mEq/L we can give potassium chloride; if the patient has 2nd or 3rd degree AV block we give Atropine; we do not give potassium chloride even if the potassium level is less than 5 mEq/L because even a little bit of potassium can exacerbate an arrhythmia - If the patient develops ventricular tachycardia, and the potassium level is less than 5 mEq/L give IV potassium chloride infused at 10 mEq/hr (diluted to 20 mEq/L); in emergencies, some sources say to infuse it at 20 mEq/hr (diluted to 40 mEq/L); we can also add Lidocaine (Xylocaine) or Phenytoin - We should continue to treat any problems associated with toxicity, even if Digoxin levels return back to normal ranges - We will only use Digibind in severe situations; in practice, Digibind is not used that often; Digibind works to decrease Digoxin levels systemically; it does not work in the intestine thus it should not be used after a recent dose -

Digoxin Dosing - Use: MD = (Cl x C x T)/(S x F), where: Cl is in L/d C is in mcg/L T = 1 day MD should come out to be mcg/day

Pharmacokinetics Lecture Twenty-three November 2, 2009 Example: JA is a 59 y.o. black male. He is 510 and weighs 165 lbs (75 kg); he has been diagnosed with CHF; according to his lab sheet he has a SCr of 1.1 mg/dL; serum Digoxin concentration is 1.5 mcg/L; S = 1; T = 1 day; F = 0.7; what is the maintenance dose for a Digoxin tablet? 1. IBW = 50 + (2.3 x 10) = 73 kg

2. CrCl = ((140 59) x 73)/(72 x 1.1) = 74.6591 ml/min

3. Cl = (0.33 x IBW) + (0.9 x CrCl) = (0.33 x 73) + (0.9 x 74.6591) = 91.2832 ml/min x 1.44 = 131.4478 L/day

4. MD = (Cl x C x T)/(S x F) = (131.4478 x 1.5 x 1)/(1 x 0.7) = 281.6739 mcg Answer: MD = 281.6739 mcg

Example: Now lets say that the patient cannot take the tablet; the F for the elixir is 0.8; what dose of Digoxin elixir could we give? 1. (281.6739 mcg x 0.7)/0.8 = 246.4647 mcg Answer: MD = 246.4647 mcg

Pharmacokinetics Lecture Twenty-four November 4, 2009

Theophylline
-

Theophylline is used in the management of asthma and COPD COPD is broken down into chronic bronchitis and emphysema; these diseases present in different ways; some sources consider severe asthma as a form of COPD (asthma is normally not considered to be a form of COPD); severe asthma, especially in pediatric patients, can cause a patient to go to the ICU; asthma can be life threatening We normally use beta 2 agonists in the management of asthma
Bronchiole

Beta 2 Receptor
Adenyl cyclase

Muscarinic receptor

cGMP

Stimulation

ATP

cAMP

Blockade

Direct dilation/relaxation Mast Cell

Granules containing histamine, serotonin, and slow reactive substance of anaphylaxis

These substances cause vasoconstriction and increased

Bronchioles have beta 2 receptors; beta 2 receptors in the bronchioles are not really controlled by CNS responses; normally, beta 2 receptors are stimulated by circulating norepinephrine/epinephrine; normal bronchiole relaxation is not controlled by the CS because it needs to happen at all times; however, the CNS is involved in breathing because there are respiratory control centers in the brain

that deal with the rate of respiration and hypoxic drive (hypoxic drive deals with how deep we breathe) m, Stimulation of beta receptors causes the activation of adenyl cyclase; adenyl cyclase then converts ATP into cyclic AMP; cyclic AMP can do two things: it can inhibit mast cell degranulation and cause direct bronchodilation; mast cells have granules containing histamine, serotonin, slow reactive substance of anaphylaxis, and other things; when the mast cell is stimulated, these granules are released further causing the release of histamine, serotonin, and slow reactive substance of anaphylaxis into circulation; if degranulation of mast cells is inhibited, these substances will not be released; these substances cause increased mucous production and bronchiole constriction; cyclic AMP can also directly cause bronchiole relaxation Beta 2 agonists are a mainstay in the management of asthma Patients with chronic bronchitis have a lot of mucous production; they usually have a cough that is productive; these patients often present like patients who have CHF (both of these patients are usually overweight and have a productive cough); we usually treat chronic bronchitis with anticholinergic drugs in order to decrease mucous production; anticholinergic drugs used include: Tiotropium (Spiriva), Ipratropium (Atrovent), Ipratropium/Albuterol (Combivent) The bronchioles also have muscarinic receptors; muscarinic receptors are stimulated by acetylcholine; this causes the stimulation of guanyl cyclase; guanyl cyclase converts GTP to cyclic GMP; cyclic GMP stimulates the degranulation of mast cells, thus it increases the histamine response and causes vasoconstriction; anticholinergic drugs block these receptors causing inhibition of mast cell degranulation Short acting beta 2 agonists are used in emergency situations (they are rescue inhalers); they include Albuterol, (Levalbuterol) Xopenex; long acting beta 2 agonists are not used in emergency situations Salmeterol (Serevent); short acting beta agonists work quicker, but do not work as long; long acting beta agonists take longer to work but work longer; LONG ACTING BETA 2 AGONISTS SHOULD NOT BE USED IN EMERGENCY SITUATIONS; long acting beta 2 agonists can be used in patients with exercise-induced asthma, but they should be given well before the patient exercises; overtime, people can develop tolerance to beta 2 agonists Other drugs, such as mast cell stabilizers like Montelukast (Singulair), can prevent degranulation of mast cells; these drugs are used to prevent asthmatic attacks; they should not be used in an acute asthmatic attack; antihistamines and anticholinergics can help in acute asthmatic attacks; leukotriene inhibitors, such as Accolate and Zyflo can also be used We can also use steroids in the management of asthma; steroids inhibit the release of leukotrienes and inhibit prostaglandin synthesis; overtime, steroids can help patients who have become tolerant to beta 2 agonists because they increase the number and sensitivity of beta receptors thus making beta 2 agonists more

effective; if we give a beta 2 agonist and a steroid together, we give the beta agonist first in order to open up the airways (the beta 2 agonist will increase the surface area so there is more room for the steroid to work); inhaled steroids should not be used in an acute asthma attack; if a steroid is used for an acute asthma attack, it should be given IV; asthma attacks are caused by airway constriction and inflammation; steroids are the best thing to use for inflammation Inhaler puffs should be spaced out by 1 minute (or at least 30 seconds) cAMP is broken down by phosphodiesterase; Theophylline inhibits phosphodiesterase thus increasing the levels of cAMP; Theophylline is a methylxanthine; methylxanthines have the ability to directly relax smooth muscle (particularly in the respiratory tract; it can dilate pulmonary arteries and reduce pulmonary hypertension); Theophylline is a CNS stimulant; it stimulates parts of the respiratory centers found in the medulla and pons; stimulation of these areas makes the body more sensitive to CO 2 ; when CO 2 levels get too high we breathe faster to get rid of excess CO 2 ; Theophylline will cause faster breathing even though CO 2 levels are normal due to its ability to stimulate respiratory centers in the brain making them more sensitive to CO 2 ; in a nutshell, Theophylline stimulates breathing Theophylline also inhibits PDE found in the GI tract (PDE is not just found in the lungs); cAMP in the GI tract causes increased gastric acid production and inhibiting PDE in this area will increase the amount of cAMP Pharmacokinetics of Theophylline Absorption: Theophylline is very well absorbed; when taken orally, the F is pretty much 1 no matter what dosage form you use (ER tablet, ER capsule, elixir); the different formulations can slow the rate of absorption though Bioavailability (deals with rate and extent of absorption): ER formulations v. regular release formulations; foods high in fiber can inhibit absorption of Theophylline; if parents are giving it to children, they should be careful about sprinkling the capsules over cereals high in fiber; antacids can decrease the absorption of Theophylline (this can be overcome by giving Theophylline one hour before, or two to three hours after antacids); when we give Theophylline IV we give it as Aminophylline; Aminophylline is 80% Theophylline so the S is 0.8; we do not measure Aminophylline levels in the blood, we measure Theophylline levels Time of day: Theophylline is best absorbed between the hours of 5 am and 11 pm; the best time to give Theophylline is between the hours of 8 am 8 pm or 9 am 9 pm The therapeutic concentration of Theophylline is 10-20 mg/L

Pharmacokinetics Lecture Twenty-five November 9, 2009 Distribution of Theophylline - When Theophylline gets into systemic circulation it is distributed very rapidly - Theophylline does not distribute to adipose tissue very well; IBW should be used to calculate Theophylline dosages; there will be situations where we should use the actual body weight as opposed to the IBW; these situations include anorexia and hypermetabolic states, such as hyperthyroidism; we always use the lower of the ABW or IBW (most times IBW will be lower) - Vd = 0.5 L/kg (it can be as low as 0.33 or as high as 0.7 L/kg - Theophylline can be given PO or IV; it is not given IM - We can give a loading dose and a maintenance dose (MD can be PO, continuous infusion, or IV maintenance dose); if we give an IV maintenance dose the T will be 8, 12, or 24 hours; if we give a continuous infusion, T is always equal to 1 - We do not use the intermittent infusion equation when we dose Theophylline (we do not use the Cmax, Cmin, etc) - When we give IV Aminophylline, we have to infuse it over at least one hour (almost like an intermittent infusion) because adverse reactions are associated with rapid infusion - LD = (Vd x C)/(S x F) - MD = (Cl x C x T)/(S x F) Elimination of Theophylline - Theophylline is primarily metabolized; only 10-15% of the drug is excreted renally unchanged (this renal excretion is insignificant so we look at Theophylline as just being metabolized) - If the liver begins to fail, the clearance of Theophylline begins to decrease causing blood concentrations to increase - Theophylline Cl = 0.04 L/kg/hr - The life of Theophylline (in a nonsmoking individual) = 8 hours; clearance increases in patients who smoke - One of the minor metabolites of Theophylline is caffeine; caffeine has similar effects to Theophylline; some hospitals will give neonates caffeine for apnea - Adverse effects: GI effects: Theophylline increases secretion of stomach acid (caffeine also does this) leading to ulcers; patients with GERD can experience increased reflux when they take Theophylline; it can also lead to GERD; Theophylline also causes nausea and vomiting (this usually only occurs when the patient is toxic), abdominal pain, and loss of appetite CNS effects: HA, irritability, nervousness/anxiety, restlessness, insomnia; these things normally occur with higher drug levels, but these effects can

be seen in a patient that is not toxic; in cases of severe toxicity, seizures may be present Cardiovascular effects: tachycardia, ventricular arrhythmias Miscellaneous adverse effects associated with rapid IV infusion: hypotension, flushing, dizziness, fainting, and bradycardia; for class purposes, we infuse Aminophylline over 1 hour Factors that affect Theophylline clearance: Age decreases clearance; in the elderly, renal clearance decreases by 40%; liver function also begins to decline; children do not conjugate well, but Theophylline is not conjugated; Theophylline goes through Phase I metabolism (P450 enzymes); pediatric patients have about 80% of their CYP450 enzymes when they are born; they have faster heart rates so clearance is faster Smoking increases the clearance of Theophylline by 60% (this also depends on the individual); a person who smokes will need a higher dose; in practice, we give the patient the regular dose based on population parameters; once we figure out how the patient handles the drug we can individualize the dose In liver cirrhosis or hepatic insufficiency Theophylline clearance decreases by about 50%, thus concentration will increase; albumin levels decrease in liver cirrhosis because albumin is produced in the liver; if the liver has cirrhosis it cannot repair itself like it normally would if it was not diseased CHF can decrease the clearance of Theophylline; 1,500 ml of blood circulates through the liver per minute; this is roughly 25% of the cardiac output; CHF decreases CO causing decreased blood flow to the liver and kidneys; if blood flow to the liver is decreased, Theophylline metabolism is decreased causing decreased clearance; if heart failure is being treated appropriately, we do not need to be worried about Theophylline clearance About 1,000-1,200 mls of blood passes through the kidney per minute; this is roughly 20% of the cardiac output Based on size, the brain receives the most blood; the heart also receives a lot of blood through the coronary arteries Thyroid disease: in hyperthyroidism metabolism increases so the drug is cleared a lot faster (concentration decreases); in hypothyroidism metabolism decreases the drug is cleared a lot slower (concentration increases) Other hypermetabolic states, such as cystic fibrosis, fever (when the fever is under control the clearance will go back to normal; dosage changes should not be made because of a fever) Drugs: Drugs that decrease the clearance (increase concentration) of Theophylline: Cimetidine, quinolones (Cipro), macrolide antibiotics (Erythromycin; Erythromycin can also decrease absorption because it

increases GI motility); some drugs, such as Tacrine, compete for the same metabolism binding site as Theophylline Drugs that increase the clearance (decrease concentration) of Theophylline: these drugs stimulate hepatic microsomal enzymes; they include: anticonvulsants (Phenytoin), barbiturates (Phenobarbital), Rifampin

Kinetics Dr. Scott 11/13/09 SCENARIO Pt has been taking an over the counter bronchial dilator Primatene tab or mist. Which would be a bigger problem when looking at systemic effects? - The tablet because the it has a greater systemic absorption & thus more adverse effects taking this po formulation versus mist - we prefer someone to use the mist, it is formulated to work more topically in the lungs, there will be some systemic absorption but the person will feel better faster - albuterol also has systemic effects TA 30 yo female 142lbs comes in, & has been taking primatene mist w/ no relief, has had wheezing & SOB for the past 3 hours, she has never been to the doctor for asthma, theyve just been taking otc products. Labs: SCr 1.1., BUN 19, Na 138 K 4.2 Problem #1 The physician wants to give a LD of theophylline (aminophylline) 650 mg to maintain conc 15mg/L. Do you agree or disagree with this dose? Solution: Theophylline LD 650mg, S= 0.8, F = 1, Conc 10-20mg/L, t1/2 = 8hr, Vd = 0.5L/kg, 1) find wt, 142lbs/2.2. = 64.545 2) find Vd, Vd = 0.5kg/L*64.545kg = 32.273L 3) LD = (Vd*Conc)/(S*F); Conc = (LD*S*F)/Vd = (650mg*0.8*1)/(32.273L) = 16.113mg/L, yes we agree with that dose; it is in btwn the range of 10-20mg/L Problem #2 The physician comes back and says, after the LD start a continuous infusion dose that will maintain a conc of 15mg/L? MD = (Cl*Conc*)/(S*F) 1) Cl = 0.04L/kg/hr *wt = 0.04L/kg/hr*64.545kg = 2.582L/hr o we dont calculate CrCl for this drug b/c it is not significantly cleared renally, only 10-15%; using CrCl in this pt wont help o if a drug is metabolized and it has an active metabolic most times the metabolite will be excreted really unchanged, in this situation renal clearance is important; e.g. Prozac has an active metabolite which is probably excreted renal and if it has a longer half life than a primary drug then this is a problem; most drugs once broken down are more hydrophilic and thus renally excreted o there are exceptions to the rule, a drug could be broken down to an active metabolite and may be conjugated

if a drug active and is broken down to an active metabolite and the person is experiencing hepatic cirrhosis; the drug effect will stay the same but stay longer b/c the liver has not completely broken down and active metabolite conc will increase o if parent drug was inactive then there may be a decreased in effect b/c there is a slower turn over from inactive drug to active drug [slower metabolism] but excretion is still at the same rate; in this situation we need to change the drug e.g. enalapril has to be converted to enalaprat, if pt has hepatic failure and liver func is declined the conversion of the drug is less but renal Cl is the same so any drug changed is still excreted at the same rate 2) MD = (Cl*Conc*)/(S*F) = (2.582L/hr*15mg/L*1hr)/(0.8*1) = 48.413mg; 48mg/hr will be given continuous infusion o Problem #3 Physician wants the drug conc 10 hr after start of infusion; LD was given at 7 am and continuous infusion at 8am. The eq we need to use is C = [(LD*S*F)/(Vd)*(e-kt) ]+ [((MD*S*F)/(Cl*)) * (1-e-kt) but we have to find the value of k first: 1) Cl = Vd*k, k = Cl/Vd = 2.582L/hr 32.273L = 0.08hr-1 2) C = [16.113mg/L* (e-0.08*10hr)] + [14.872 * (1-e-0.08 *10hr)] = [16.113mg/L * .499] + [14.872 * (1.499)] = 7.240 + 8.190 = 15.43 = class said 15.49 o (Refers to drawing) if conc was taken 1 hr after infusion our peak conc was 16.113 at 8 am; if continuous infusion is started immediately at the end of LD we can say the t (time values) for both parts of the equation is the same b/c after 1 hr the LD peak conc begins to decline we use the end of the LD to start the time b/c thus is the time before that was continuous infusion Factor of decline (e-kt) o at t = 0, conc = 1 o at ss it = 0 Factor of incline (1-e-kt), o at t = 0, conc = 0 b/c no drug has accumulated o at ss it = 1 o C= [(LD*S*F)/(Vd)*(e-kt)]+ [((MD*S*F)/(Cl*)) * (1-e-kt), the bolded part of the equation was found in problem #1.