Pharmacokinetics - Digoxin, Theophylline, Phenytoin
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- Created by: LBCW0502
- Created on: 13-02-19 17:10
Describe features of drugs requiring TDM
Wide inter-patient variation in clearance, influenced by a range of diseases. Narrow therapeutic range. Toxicity above therapeutic range. Ease of detection - can report a plasma concentration within an appropriate time period to be clinically useful
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Give examples of drugs which require routine monitoring
Aminoglycosides (antibiotic e.g. gentamicin). Cardiac glycosides (AF e.g. digoxin). Phosphodiesterase inhibitor (asthma e.g. theophylline). Anticonsulvants (epilepsy e.g. carbamazepine, phenytoin). Antipsychotics (mania, bipolar disorder eg. lithium)
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What is the therapeutic range?
The window for the range of concentrations at which the drug produces a therapeutic effect. Above the therapeutic window leads to toxicity and under the therapeutic window leads to sub-therapeutic dosing
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What is digoxin used to treat?
Congenital heart failure and AF
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Describe features of oral absorption
Most drugs are administered orally yet act systemically. A drug must be in solution to be absorbed. Sometimes a drug is intended to act locally (eyes, lungs etc) so systemic absorption becomes a safety issue
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Describe features of the small intestine
Absorption works best in the SI on all accounts. Large SA (microvilli 200 M^2). Good blood supply (1L blood/min compared to 150 mL/min in stomach). Permeability to drugs greater. GE is important
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What is bioavailability?
The proportion of drug that reaches the systemic circulation after oral compared to IV administration (IV = 1, 100%, other routes = <1)
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What is absolute bioavailability?
Assessed with reference to IV dose. F is measured by comparing the area under the curve (AUC) for oral against IV doses from zero to the time point for which elimination is complete. F = Dose/AUC (iv) x AUC/Dose (oral)
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State features of digoxin pharmacokinetics (1)
Incompletely absorbed. Bioavailability (F) digoxin tablets range from 0.5 to 0.9 (average of 0.63%). Most clinicians use F of 0.7-0.8 to minimise rise of overdose. Volume distribution is 7.3 L/kg (more in plasma/bloodstream).
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State features of digoxin pharmacokinetics (2)
V reduced in patients with renal disease, in hyperthyroid patients and in patients taking quinidine
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What does a graph for blood plasma concentration against time after administration show?
Absorption phase (Ka) and elimination phase (Ke). Peak plasma concentration. Blood level - time curve after single oral administration
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What is distribution? (1)
The reversible transfer of drug from one location to another within the body. Definitive information on distribution of a drug in the body requires measurements in various tissues - difficult in humans
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What is distribution? (2)
Rate and extent of distribution can however be derived from blood or plasma
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Digoxin is an example of what type of compartment model?
Two compartment model. Distribution phase ~ 35 mins. Plasma concentration time curve may be more accurately represented by a 2-compartment model
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Describe the pharmacokinetics of digoxin (1)
Distribution follows 2-compartment model (drug distributed initially into plasma). Then into tissues (pharmacological effect). Unless drug has distributed into both compartments plasma drug concentrations will not reflect drugs pharmacological effect
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Describe the pharmacokinetics of digoxin (2)
High plasma levels commonly reported if sample collected soon after dosing but do not reflect therapeutic or toxic effects. Need to wait at least 4 hrs after IV dose, 6 after oral dose
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Describe the pharmacokinetics of digoxin (3)
Digoxin 20-30% bound. Long distribution half like into cardiac tissue. Free - bound
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Describe features of digoxin metabolism
Most patients metabolise <20% dose so active metabolites are not important. 10% patients metabolise 55% dose (toxicity). About 20-30% digoxin bound plasma proteins and variation have no clinical significance
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What is clearance? (1)
Parameter that relates the rate of elimination to drug concentration. Proportionality constant. CL = Kelim/C (plasma), units (mg/h, mg/L, L/h). Values 1-1000 mL/min
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What is clearance? (2)
Clearance usually constant over therapeutic concentration range. Drug elimination systems not saturated (absolute rate of elimination is a linear function of drug's plasma concentration)
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What is clearance? (3)
Important for insuring appropriate long term drug dosing (correct steady state drug concentrations)
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How do you calculate clearance?
CL = Cl m + CL r (40-60 mL/min for healthy individuals weighing 70 kg). Total clearance for 70 kg male is 57 mL/min. With congestive HR - 23 mL/min
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What are the key parameters for digoxin?
Therapeutic concentrations (1-2 ng/mL). F (tablets) - 0.62, F (Elixir) - 0.80. Vd (steady state) - 7.3 kg/kg. Half like (elimination) - 36-48 h (in patients with normal renal function). Anephric patients (kidney not functioning) half life - 4-6 days
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How do you estimate a loading dose?
LD = (V)(Cp) / (S) (F). Where S = 1.0 (salt form - fraction of administered drug salt/ester which is active)
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What is theophylline used for?
To relax smooth muscles of bronchioles. Used to treat bronchial asthma and other respiratory diseases. Water solubility theophylline v poor (1%). Only given parenterally as aminophylline (2:1, theophylline and ethylenediamine). Some orals
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What is the association between theophylline serum concentrations and toxicity? (1)
>10 mg/L (nausea, insomnia, headache, nervousness - minor/mainly transient). >20 mg/mL (nausea, vomiting, diarrhoea, insomnia, irritability, headaches, tremor - potentially serious)
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What is the association between theophylline serum concentrations and toxicity? (2)
>35 mg/mL (cardiac arrhythmias, cardio-respiratory arrest, seizures - life threatening)
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What is volume of distribution?
Proportionality constant relating the amount of drug in the body to the drug concentration in plasma. V is not a physiological volume. Never < blood or plasma but it can be much larger than total body water volume (42 L) for some drugs
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What is apparent volume of distribution? (1)
Reflection of the amount of drug in the blood after all the drug has been absorbed. Concentration in plasma after distribution of dose administered is complete and indicates extend of tissue distribution
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What is apparent volume of distribution? (2)
Magnitude V provides extent of drug distribution but not location of drug. If drug is held in bloodstream it will have small volume of distribution. If very little drug remains in bloodstream/has large volume of distribution (L or L/kg)
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How can the fraction of drug in the body (plasma) be estimated?
Can estimate fraction of drug in and outside of systemic circulation if plasma volume (Vp) and volume of distribution (Vd) are known. V = Dose/Co (Co - amount in plasma at t0). Dose/amount of drug administered. Larger V/smaller fraction in plasma
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How do you calculate apparent volume of distribution?
V = amount of drug in the body / concentration measured in blood. Immediately after IV dose is administered, amount of drug in body is equal to dose (V = D/Co)
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What is the average volume distribution for theophylline?
0.5 L/kg. Increased in patients with cirrhosis/chronic respiratory acidosis and in premature babies. Theophylline has limited distribution into adipose tissue. V is reduced in clinically obese patients (if expressed L/kg body weight)
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What are the key parameters for theophylline?
Therapeutic concentrations (10-20 ug/mL). F (tablets) - 100% (iv), V (steady state) - 0.48 L/kg. CL - 0.04 L/Hr/kg. Half life (elimination) - 6-8 hr. Total body weight needs to be used for obese patients rather than 70 kg male
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What is elimination half life (t 1/2)?
Time taken for plasma concentration to decrease by half (50%). Time for plasma concentration to fall after dosing is stopped e.g. if patient has overdosed. Frequency of dosing interval
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Based on knowledge of half-life how long will it take for theophylline to reach steady state?
~ 40 hours
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How do you calculate elimination half life?
t 1/2 = 0.693 / k el (independent of concentration, property of first order process)
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The half life of elimination of a drug (and its residence in the body) depends on what?
Both its clearance and its volume of distribution. t 1/2 is proportional to V and inversely proportional to CL. t 1/2 = (0.693 x V) / CL
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Describe features of theophylline metabolism (1)
Theophylline is metabolised in the liver. Major pathway begins with 8-hydroxylation to 1,3-dimethyluric acid. N-dimethylation also takes place to form 1-methyluric acid and 3-methylxanthine. In neonates, 1/3 of dose is converted to caffeine
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Describe features of theophylline metabolism (2)
Average adult half life - 6-8 hours (but marked individual variation). (95% lost in 5 half lives, 99% lost in 7 half lives/complete)
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What is clearance equal to?
Q (blood flow). K el = CL/V (K el is the fraction of the V which will be cleared of drug per unit time)
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Give examples of disease states which affect theophylline clearance
Smoking history, congestive heart failure, acute pulmonary oedema, hepatic cirrhosis, severe obstructive pulmonary disease, obesity
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How do you calculate maintenance dose?
Maintenance dose = (CL)(Cpass ave)(τ) / (S)(F) where τ is the dosing interval (tau)
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What is phenytoin used for? (1)
As an anticonvulsant but also for certain types of cardiac arrhythmias. Usually administered orally as single or divided doses 200-400 mg/day. When rapid therapeutic effect required loading dose 15 mg/kg used by oral or IV route
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What is phenytoin used for? (2)
Intramuscular has slow and erratic absorption
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What is the bioavailability for phenytoin?
90% (absorption is slow and variable). 90% bound to proteins (binding affected and substantially lower - in those with renal/hepatic disease, neonates and in the third trimester of pregnancy)
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Describe features of phenytoin metabolism (1)
Metabolised in liver by oxidation. But hepatic mixed function oxidase system has limited capacity and can become saturated at concentrations within the target range. Dose dependent PK
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Describe features of phenytoin metabolism (2)
As plasma concentration rises metabolic capacity is exceeded and clearance and elimination falls
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Which drug has zero order kinetics?
Phenytoin - constant rate of elimination irrespective of plasma concentration (saturation or capacity limited)
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Which drug has first order kinetics?
Digoxin - rate of elimination proportional to plasma concentration. Constant fraction of drug eliminated per unit time
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What are the key parameters for phenytoin?
Therapeutic concentrations (10-20 ug/mL). (F) - 0.9-1.0. V (steady state) - 0.65 L/kg. CL and t 1/2 (concentration dependent). Vm - 7 mg/kg/day. Km - 4 mg/L
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What are the drug-drug interactions with phenytoin? (1)
Drugs may increase phenytoin blood concentration - acute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, cimetidine, diazepam, disulfiram, fluoxetine, isoniazid, tolbutamide, trazodone
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What are the drug-drug interactions with phenytoin? (2)
Decrease phenytoin blood concentration - carbamazepine, chronic alcohol use
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What are the drug-drug interactions with phenytoin? (3)
Ingestion times of phenytoin and antacid preparations containing calcium need to be staggered in patients with phenytoin concentration to prevent absorption problems
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What are the drug-drug interactions with phenytoin? (4)
Drugs which may either increase or decrease phenytoin serum levels include - phenobarbital, sodium valproate and valproic acid
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What is lithium used for?
Prescribed for depressive disorder, mechanism of action is mood stabilising, used for acute control panic attacks
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Describe features of lithium absorption
Different oral formulations vary in bioavailability. Change in formulation needs careful monitoring. Complete absorption across gut occurs within 8 h, peak occurs 2-4 h after an oral dose. Sustained release more consistent absorption characteristics
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Describe features of lithium distribution (1)
After absorption, rapid distribution to the central compartment and then slower distribution to the rest of the body water space. Distribution complete 6-10 h after dosing. Lithium not distributed into adipose tissue/doesn't bind to plasma proteins
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Describe features of lithium distribution (2)
It is evenly distributed among several tissue compartments (lithium concentration is higher in oral fluid and in the thyroid than in serum)
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What are the key parameters for lithium?
F is >95%, with no plasma protein binding. Half life - 10-35 h (average 22 h). V (0.5-1.1 L/kg). CL (0.012 - 0.03 L/h/kg)
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Describe features of lithium metabolism
Elimination half life varies being 8-20 h in young adults with normal kidney function. 80% lithium reabsorbed in proximal tubule kidney. In elderly/renal function impaired half-life - 30-40 h. Steady state plasma by 2-5 days after starting dose
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Describe features of lithium clearance (1)
Lithium is not metabolised. It is filtered by the glomeruli/eliminated renally as the free ion. Small amounts are eliminated via sweat, saliva and faeces. Lithium is excreted almost entirely in urine
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Describe features of lithium clearance (2)
Clearance is directly proportional to glomerular filtration rate and renal blood flow
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How does the body handle lithium?
Three-fold (water balance, sodium balance, renal function). Decreased water balanced results in increased serum Li concentrations. Decreased sodium balanced results in increased serum Li conc. Renal function influences serum Li conc.
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Describe features of monitoring approach (1)
Important to monitor when commencing on treatment to optimise dosing. Monitor concentration 12 h after previous dose when distribution stabilised. Alterations in diet (e.g. low salt, slimming diets) or physical inactivity (e.g. excessive sweating)
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Describe features of monitoring approach (2)
Medical illnesses (e.g. renal dysfunction, diarrhoea or vomiting) may impact on effectiveness of drug
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What is the toxicity profile for digoxin?
Nausea, vomiting, anorexia, bradycardia, ventricular arrhythmias
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What is the toxicity profile for theophylline?
Link to degree of accumulation
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What is the toxicity profile for phenytoin?
Nystagmus, ataxia, lethargy, gingival, hyperplasia, osteomalacia
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What is the toxicity profile for lithium?
Life threatening > 3.5 mmoles/L, vomiting, diarrhoea, anorexia, muscle weakness, ataxia, drowsiness, tremor (extremities/jaw), seizures, renal failure, dehydration, circulatory failure, coma
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What are the plasma concentration ranges for digoxin, theophylline, phenytoin and lithium?
0.8-2 ug/L. 10-20 mg/L (toxicity >20 mg/L). 10-20 mg/L. 0.4-1.0 mmoles/L
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Other cards in this set
Card 2
Front
Give examples of drugs which require routine monitoring
Back
Aminoglycosides (antibiotic e.g. gentamicin). Cardiac glycosides (AF e.g. digoxin). Phosphodiesterase inhibitor (asthma e.g. theophylline). Anticonsulvants (epilepsy e.g. carbamazepine, phenytoin). Antipsychotics (mania, bipolar disorder eg. lithium)
Card 3
Front
What is the therapeutic range?
Back
Card 4
Front
What is digoxin used to treat?
Back
Card 5
Front
Describe features of oral absorption
Back
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