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81 Cards in this Set
- Front
- Back
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Define Clearance (CL)
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Clearance is the intrinsic ability of the body to remove drug from the blood or plasma via its organs of elimination.
Clearance is a proportionality factor relating drug elimination to the plasma drug concentration |
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Rate of metabolism =
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Rate of metabolism = Cu x kmet
kmet = Clearance Expressed as the volume of blood or plasma from which drug is completely removed per unit of time (i.e. L/hour, L/min, or mL/min) |
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Rate of elimination =
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Rate of elimination - CL x Cp
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Why is Clearance one of the most important PK parameters?
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because the rate at which a drug is removed from the body is directly proportional to the body's ability to clear the drug from the blood
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The actual amount of drug removed from the blood depends on ...
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... the drug's concentration in the blood
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Total systemic clearance (CLs)
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The total rate of elimination of a drug from the body is the sum of all of the processes by which drug is eliminated
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Total Elimination Rate =
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Total Elimination Rate = rate of hepatic elimination + rate of renal elimination + rate of other elimination
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Total systemic clearance
CLs = |
CLs = CLh + CLr + CLother
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How does clearance relate to half-life?
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T1/2 = 0.693(Vd)/CL
So, half-life is directly related to how quickly the drug is cleared from the body It is also effected by the volume of distribution |
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What are the advantages of a "physiological approach" to clearance?
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It provides the ability to predict and approximate changes in CL and drug elimination based on changes in various physiological parameters such as enzyme activity, blood flow, plasma protein binding, and disease states.
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What is a physiological approach to clearance?
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A physiological approach to clearance is to view it as the loss of drug through an organ of elimination.
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What is extraction?
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the elimination of a drug by an organ
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The efficiency of drug extraction by an organ is characterized by the ________________.
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extraction ratio
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What does the extraction ratio compare?
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the rate of drug extraction compared with the rate at which the drug is actually presented to the organ
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Extraction ratios can be applied to _________, although most commonly with the _________ and __________.
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all organs, liver, kidney
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What are the possible values of the extraction ratio?
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the extraction ratio is a value between 0 (no drug is eliminated) and 1.0 (all drug is eliminated and no drug escapes the organ)
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What are the three classifications of extraction ratios?
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High extraction ratio (E>0.7)
Intermediate extraction ratio (E = 0.3-0.7) Low extraction ratio (E<0.3) |
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The best way to think of the Extraction Ratio is as a measure of the __________ with which an organ _______________.
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efficiency, removes drug from the blood
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Which organ usually has the higher extraction rate, the liver or the kidney?
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the liver
renal extraction is usually pretty low |
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A drug has a hepatic extraction ratio of 0.8; the hepatic blood flow is 1.0 L/minute. The plasma concentration of the drug is 10 mg/L. What is the hepatic CL of the drug, and how much is eliminated each minute?
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CLH = QH x EH
CLH = 1.0 L/minute x 0.8 = 0.8 L/minute Amount eliminated = CL x Cp Amount eliminated = 0.8 L/minute x 10 mg/L = 8 mg/minute Note: The amount of drug in the body is always changing. CL is a fixed number and does not change. The amount eliminated will change over time. |
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What is the maximum possible CL for an organ?
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*If E = 1.0, the organ will eliminate all of the drug that is presented to it
*In this case, drug elimination becomes perfusion-limited *The maximum clearance will then be equal to the blood flow to that organ (Q) |
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What are the major mechanisms of hepatic elimination of drugs?
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* Metabolic biotransformation to other compounds
* Excretion into the bile, followed by elimination through the feces * Either of these two mechanisms can act on both parent drugs and metabolites |
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What factors influence hepatic clearance?
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1. Hepatic blood flow
2. Plasma protein binding 3. Hepatic enzyme activity |
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How does hepatic blood flow effect hepatic clearnace?
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* If no perfusion, no drug can be cleared
* QH is thus a major factor in determining CLH * For high extraction ratio drugs (EH >0.7), QH is the only factor significantly determining CLH * High EH drugs are essentially perfusion-limited * CLH = QH * Low EH drugs are less subject to changes in QH |
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How does plasma protein binding effect hepatic clearance?
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* Only unbound drug is normally able to cross cell membranes, therefore only unbound drug is capable of reaching the intracellular enzymes that carry out the processes of metabolism or biliary transfer
* CLH for many drugs is highly sensitive to changes in protein binding * High EH drugs are not greatly affected by changes in protein binding * Hepatic clearance of low EH drugs is directly proportional to the fraction unbound (fu) * Decreased protein binding results in more unbound drug and allows more efficient clearance * High EH = Rate of metabolism and/or biliary elimination will alter the equilibrium between blood and liver and will “pull” even plasma-bound drug into the liver * Low EH = Rate of metabolism and/or biliary elimination will not be great enough to have a significant impact on the equilibrium between blood and liver of bound drug |
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How does hepatic enzyme activity effect hepatic clearance?
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* The ability to clear drugs from the blood is clearly related to the degree of enzyme activity present within the liver ( Clint )
* Enzyme activity can be influenced by many factors, particularly drugs and disease states * Low extraction ratio drugs are more affected by changes in hepatic enzyme activity than are drugs with high extraction ratios |
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Summarize the relative influence blood flow, protein binding, and hepatic enzyme activity have on drugs with high and low hepatic extraction ratios.
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* Blood flow is the major factor influencing high E drugs and will only effect low E drugs in extreme situations.
* Protein binding has a major effect on low E drugs and will effect high E drugs only in extreme situations * Hepatic enzyme activity has a major effect on low E drugs and will effect high E drugs only in extreme situations |
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Oral Bioavailability and the Hepatic Extraction Ratio
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* Oral bioavailability (F) = 1 – EH
* Any drug with a high hepatic extraction ratio automatically has a low oral bioavailability |
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Renal Clearance
Rate of excretion = |
Rate of excretion = rate of filtration + rate of secretion - rate of reabsorption
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Renal Clearance: Glomerular Filtration
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* Approximately 20-25% of cardiac output (~1.1 L/min) goes to the kidneys, with about 10% of that being filtered at the glomerulus
* GFR (glomerular filtration rate) is the rate at which plasma water is filtered * For a 70 kg, 20 year old male, this is about 120 mL/min |
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Rate of filtration for renally excreted drugs
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Rate of filtration = GFR x fu x Cplasma
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For a drug that is 100% unbound and completely filtered, the renal extraction ratio is only about 0.11.
Why is the renal extraction ratio so low? |
* If a drug is only filtered at the glomerulus, and all filtered drug is excreted into the urine, then the rate of renal excretion is equal to the GFR
* This is analogous to CLH = QH when EH = 1.0 However, only about 10% of what passes through the kidney is filtered through the glomerulus |
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What is the MAXIMUM renal extraction ratio
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0.11
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Renal Clearance: Active Secretion
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* Filtration always occurs but this process has low drug extraction capabilities, especially if the drug is partially bound within the blood
* Active mechanisms exist for secreting anions and cations * These processes are located predominantly in the proximal tubule * Secretion is inferred when renal clearance is greater than GFR x fraction unbound |
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Renal Clearance: Reabsorption
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* Reabsorption occurs all along the nephron, and is associated with the reabsorption of water that is filtered at the glomerulus
* As the water is removed, drug becomes more concentrated in the filtrate * Movement across biological membranes = permeability x surface area x concentration difference * Alteration in drug concentration along the renal tubule is a major driving force for reabsorption, which is usually passive in nature * Therefore, permeability is a major limiting factor in determining drug reabsorption |
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What factors influence renal clearance?
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1. Renal blood flow
2. Molecular weight of the drug 3. Plasma protein binding 4. Affinity of a drug for secretory transport mechanisms 5. Ability of a drug to cross membranes 6. Urine flow rates |
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How does renal blood flow effect renal clearance?
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Changes in renal blood flow influence rates of filtration, secretion, and reabsorption
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How does the molecular weight of a drug effect renal clearance of the drug?
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Large compounds of MW > 20,000 (e.g. proteins) are not capable of being filtered at the glomerulus and are also not highly secreted
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How does plasma protein binding effect renal clearance?
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* Because large proteins are not filtered at the glomerulus, neither are drugs which are highly protein bound
* Filtration rate for many drugs therefore depends on the degree of protein binding * Protein binding may also affect secretion rates |
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How does affinity of a drug for secretory transport mechanisms effect renal clearance?
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The more affinity a drug has for secretory transport mechanisms, the more of of that drug will be secreted by the kidney.
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How does ability of a drug to cross membranes effect renal clearance?
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* Reabsorption is a largely passive process driven by concentration gradients within the renal tubule
* Drugs which are lipophilic and un-ionized are able to follow gradients through the tubular membranes and are more likely to be reabsorbed * Water-soluble, ionized drugs are trapped within the lumen of the tubule and are excreted |
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How does urine flow rate effect renal clearance?
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* Changes in urine flow rate can influence renal clearance of drugs which are highly reabsorbed
* Increasing urine flow rates can also increase renal excretion of such drugs |
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What are four consequences of metabolism other than inactivation and elimination?
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1. Active
Various prodrugs, procainamide, benzodiazepines, many others 2. Toxic Acetaminophen is metabolized to a toxic quinone intermediate 3. Inhibitory Metabolites can inhibit the subsequent metabolism of the parent drug or act as an antagonist at the same site of action 4. Capable of Displacement Metabolites may displace parent drug by competing for plasma and/or tissue binding sites * Therefore, the PK of metabolites may be as, or even more important than, those of the parent drug * Metabolites may themselves be metabolized multiple times |
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Describe a once compartment model.
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Think of the body as a tank or a bucket (for Vd) with a drug filter or drain (for CL).
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True or False:
CL is the half-life of a drug. |
False
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What assumptions must be made when using the one compartment model?
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1. The drug distributes and comes to equilibrium immediately.
2. No drug is eliminated during the drug administration time. |
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Describe first-order elimination.
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* 1st order kinetics indicates that the CL system for drug removal is working well below its maximal capacity and is NOT saturated.
* 1st order kinetics indicates that drug concentrations fall by a constant fraction (Ke). * 1st order indicates the rate is determined by conc. The result is a constant fraction of drug is lost in a given time. |
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How are ke and t1/2 secondary PK parameters?
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they are dependent on the primary PK parameters CL and Vd.
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Volume of distribution (Vd)
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a theoretical volume necessary to account for observed concentrations produced following administration of a known quantity of drug (L)
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What is the importance of drug clearance (CL)?
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it is the body’s capacity to remove drug
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What is the apparent volume of distribution?
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A measure of drug concentration in the plasma/blood. It is necessary to have a volume to relate the concentration to dose.
Vd = dose /concentration |
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Vd and Concentration at time 0
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Conc at time 0 (C0) = 100mg/Vd
or C0 = Dose/Vd or C = Dose/Vd (if pre-existing conc) or Vd = Dose/C0 |
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What is the 5 t1/2 rule?
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It takes 5 t-1/2s for a drug to be "completely" eliminated.
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True or False:
The one compartment model assumes that the dose distributes instantly and that no drug is eliminated during administration. |
True
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Which of the following descriptions of Vd is FALSE?
A. A change in Vd will cause a change in CL. B. A change in Vd will cause a change in t-1/2. C. Vd = Dose/C0 for a IV bolus dose. |
A.
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Define Zero-order elimination.
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Zero-order means that a CONSTANT AMOUNT is lost over time. This occurs when drug metabolism becomes saturated. Zero-order elimination is NOT COMMON (phenytoin is an example).
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Elimination rate constant
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* CL/V is the elimination rate constant, ke (hr-1).
* Since ke depends totally upon CL and V (ke=CL/V), it is called a “secondary” PK parameter. CL and V are primary PK parameters. Thus, a change in V or CL will affect ke, but a change in V or CL will not affect the other primary PK parameter. |
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Describe the effects of Vd and CL on the rate of elimination.
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Changing Vd only…
Drug 1 CL = 1 L/h V = 10 L fastest Drug 2 CL = 1 L/h V = 100 L slower Drug 3 CL = 1 L/h V = 1000 L slowest Now changing CL only… Drug 4 CL = 10 L/h V = 1000 L slowest Drug 5 CL = 100 L/h V = 1000 L faster Drug 6 CL = 1000 L/h V = 1000 L fastest So, the rate that drug concentrations fall depends both on the CL and the total volume (Vd). |
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Differences between single IV bolus dose and infusion
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* IV bolus is a single rapid dose vs. IV infusion is constant drug input into the body
*For an IV bolus there is an initial conc at time 0; dose/Vd with two assumptions vs. IV infusion where the conc at time 0 is not relevant for constant drug input *With an IV bolus Conc in plasma fall after C0 vs. IV infusion where concentrations build up during the constant drug input |
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Define steady-state and the time to steady state for a constant infusion regimen.
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* Steady state is the condition where the rate of drug administration (R0) is equal
to the rate of drug elimination (rate in = rate out). *Steady-state corresponds to a plateau on the concentration/time curve. * Css = R0/CL *The steady state concentration is a function of the drug administration rate (R0) and CL only. * The time to steady state is the amount of time it takes to reach steady state and is approimately 5 t-1/2s. |
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What are two major reasons to use a constant IV infusion?
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1. If a drug has a very short half-life and would therefore require very frequent dosing in order to maintain concentrations in the desired range.
2. Due to the severity of the disease state that we are attempting to treat, it is critically important to maintain a constant, therapeutic drug concentration in order to maintain the desired pharmacologic effect. |
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Infusion rate
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* The rate at which a continuous infusion is administered.
* R0 or RA = dose / dosing frequency |
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Fraction of SS attained at time t
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(1-e-ke*t)
Note: This value varies between 0 and 1 |
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To calculate concentrations prior to reaching steady state
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Use:
Ct = Css * (1-e-ke*t) or Ct = R0/CL * (1-e-ke*t) |
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Does Vd influence Css, ke, t-1/2, and/or the time to reach steady state?
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Vd does not influence Css (R0/CL). Vd influences ke (CL/Vd) and t-1/2, and therefore, the time to reach SS (can think of as, how long it takes to “fill the tank”).
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Conceptually, Css and AUC depends on the “dose input” and “dose removal (CL)” only. So, how does Vd efect the drug concentration/time curve.
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Vd alters the shape of the drug concentration time profile…
Drug 1 CL = 1 L/h V = 10 L fast Drug 2 CL = 1 L/h V = 100 L slower Drug 3 CL = 1 L/h V = 1000 L slowest |
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Conceptually, Css and AUC depends on the “dose input” and “dose removal (CL)” only. So, how does CL efect the drug concentration/time curve.
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Drug 4 CL = 10 L/h V = 1000 L slow
Drug 5 CL = 100 L/h V = 1000 L fast Drug 6 CL = 1000 L/h V = 1000 L fastest |
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Vd is considered the _______ parameter...it tells us the ________.
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loading dose, the dose needed to “fill the tank”
dose = Vd*desired conc |
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CL is considered the ______________ parameter…it tells us the ________________.
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maintenance dose, “keep the tank full”
dose rate = CL*Css |
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What do you need to figure out when calculating concentrations after stopping an infusion?
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what the concentration in the plasma is at the termination of the infusion and then treat it like C2=C1*e-ke*t
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Stopping the Infusion After Reaching Steady-State
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After reaching steady-state, the concentration in the plasma
will be R0/CL. Therefore, it we substitute this in for C1 in the first-order equation that we developed for IV bolus: Ct = R0/CL* (e-ke*t) R0/CL is the Css concentration (e-ke*t) is the fraction of the Css remaining at time t |
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Stopping the Infusion Prior to Reaching Steady-State
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What is the concentration in the plasma from an infusion prior to reaching SS?
Ct1 = R0/CL * (1-e-ke*t1) If we substitute this into the Ct2 = Ct1 * e-ke*t: Ct2 = R0/CL * (1-e-ke*t1) * (e-ke*t) Where t1 is the length of the infusion and t2 is the time after stopping the infusion. |
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How do we determine if drug is eliminated during the bolus input?
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we can assume no drug is eliminated during the bolus if the bolus is at least 6 times faster than the elimination half-life
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What can we do if the second assumption of the bolus model isn't met a.k.a the bolus administration is not at least 6 times faster than the elimination 1/2 life?
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we can use a short infusion equation instead of bolus equations so we can account for drug loss during the infusion
Ct =R0/CL * (1-e-ke*t) |
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After the short infusion is stopped, how do we calculate the drug concentration at a given time?
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C1 = C0 * (e-ke*t)
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How do you calculate drug concentrations in a situation where an IV bolus is administered and an infusion is started at the same time?
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Cplasma = Cld + C inf
Where: CLD = drug level from the original loading dose (use bolus model)…used to “fill the tank” Cinf = drug level from the drug infusion (use infusion model)…used to “maintain the concentration” Concentrations from a loading dose and infusion are calculated separately, then added together |
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When is the short infusion model used?
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when t-1/2 is not 6 times longer than t-in and it accounts for drug loss during the infusion
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True of false:
The eventual Css concentration for an infusion only depends on the rate of administration, R0 and CL. |
True
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Which of the following about Vd is FALSE?
It affects Ke, so it affects t-1/2, so it affects the time to reach SS. It affects Ke, so it affects 1-e-ke*t, so it affects the fraction of SS attained at time t. It affects the Css concentration. It is considered the “loading dose” parameter. |
It affects the Css concentration
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When would you use short infusion equations instead of a bolus equations?
Never. Always. When the drug administration time is not 6 times faster than the half-life. When the CL equals the half-life. |
When the drug administration time is not 6 times faster than the half-life.
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Generally, how are concentrations calculated after a loading dose and an infusion?
Multiply the concentration from the loading dose with the concentration from the infusion. Subtract the concentration from the loading dose with the concentration from the infusion. Divide the concentration from the loading dose with the concentration from the infusion. Add the concentration from the loading dose with the concentration from the infusion. |
Add the concentration from the loading dose with the concentration from the infusion.
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