Pharmacology - Lecture 3 Flashcards
Explain the difference between first-order, zero-order and dose-dependent kinetics of drug elimination.
- First order Kinetics:
Elimination rate of the drug is a constant fraction of the drug remaining in the body (rather than a constant amount of drug per hour)
- half life is constant!! - Zero Order:
Drugs that are eliminated primarily by metabolism may display zero order kinetics.
When metabolic pathways are saturated, metabolism occurs at a fixed rate and does not change in proportion to drug concentration.
** A fixed amount is metabolized per unit time**
– half life is NOT constant! - Dose dependent kinetics:
When a drug’s elimination is mediated predominantly by metabolism, its elimination will tend to follow first order kinetics when concentrations are well BELOW the Km of the metabolic enzymes, but will follow zero order kinetics at doses that greatly EXCEED the Km of the metabolic enzyme.
a) if C>km = Zero order
c/t = Vmax
List examples of commonly prescribed drugs that follow zero-order (9), first-order (2) and dose-dependent kinetics.
Zero order:
- Phenytoin***
- Ethanol ***
- Aspirin ***
4- heparin 5-phenylbutazone 6-Salicylates 7-theophylline 8-tolbutamide 9-warfarin
First Order:
1. Lidocaine, digoxin
DOSE DEPENDENT:
- Phenytoin
- Ethanol
Recognize the importance of steady-state plasma drug concentrations for maintenance therapy and describe the time course for achieving steady state with intermittent dosing or continuous infusion.
Steady State:
1. A function of dosing rate & elimination clearance
- Rate of drug administration = rate of elimination
- w/ continous I.V. infusion
- steady state attained after FOUR elimination half-lives
** eventual steady state levels depend on MAINTENANCE DOSE not loading dose*
What are primarily pharmacokinetic parameters for Elimination half life (2)?
- Clearance
2. Volume of distribution
What is the two compartment drug distribution?
What kind of kinetics does this follow?
What drugs demonstrate this? (3)Which can be an exception at high concentrations?
- Early multi exponential decay phase (distribution) when the drug is initially distributed from the central compartment, followed by a mono exponential decay phase (elimination) once it equilibrates
- Lidocaine
- digoxin
- phenytoin**
- at high concentrations follows zero order
What is the volume of distribution?
Why is this often larger than anatomically possible?
A measure of how evenly distributed a drug is in the body.
Vd is the theoretical volume of fluid into which the total drug administered would have to be diluted to produce the concentration in plasma.
Often larger due to:
- Plasma protein binding (Heparin Vd= 0.05-0.1)
- Reflects distribution in total body water
(theophylline, ethanol) - Highly lipophilic drug that redistributes into total body fat (Chloroquine 200-300)
What is the equation for volume of distribution?
How does one find initial Concentration (Co) value in:
- Two compartment distribution
- One compartment distribution
Vd = DOSE / Concentration initially
dose = amt/kg concentratin = mg/L
Vd = L/kg
Two compartment = extrapolate at time =O from the linear portion of log plasma conc. vs time
One compartment: Co is the measured concentration immediately after drug is administered
What if the minimum effective concentrations cannot be achieved?
IT TAKES how many HALF-LIVES TO REACH STEADY-STATE?
Use multiple dosing regiment
= REPETITIVE DOSING
- 4-6 half lives (multiple by 3.3 to get 90%)
** regardless if a drug is given by repetitive dosing or by continuous effusion**
If a drug takes a long time to reach therapeutic levels, then a HIGHER dose, called the _____ may be given initially before dropping down to a lower maintenance dose.
What is the purpose?
What variables are used to calculate loading dose? Equation?
- the loading dose
2. Reach therapeutic DRUG levels more QUICKLY
What variables are used to calculate loading dose? Equation?
What does the loading dose depend on? (test)
True or false: the time to reach steady state is reduced by loading dose
- Cp (peak desired concentration of drug)
Vd (volume of distribution of drug in body)
F (bioavailability) - Loading dose = Cp * Vd / F
- Loading dose is dependent on VOLUME OF DISTRIBUTION (test)
- FALSE, still takes 4-6 intervals to reach steady state
What is maintenance dosing?
What is it based on?
What is the primary determinant to calculate this maintenance dose? (equation)
- Dosing strategy to maintain a steady state of drug in the body.
- Dose is based on replacing the amount of drug cleared from the body since the previous drug administration.
- CLEARANCE!!! most important for maintenance dosing
Maintenance Dose = CL * TC * T/F
At steady state, what replaces drug lost since the previous dose?
What is the target concentration of this dose?
- MAINTENANCE DOSE
(depends on CLE –> clearance in L/hr)
- selected in relation to expected clearance
Dosing Rate = CLe * Target Concentration
- Target concentration for maintenance dose is a value between the peak and trough
Define the following:
a) Irreversible drug removal from the plasma through an eliminating organ(s).
b) Drug distribution between plasma and tissues, a bidirectional process.
a) Elimination Clearance
b) Intercompartmental clearance
What is steady state concentration a function of?
When is it attained?
What is it independent of?
Proportional to?
- Dosing Rate & Elimination Clearance
Css= Dosing Rate * F / Clearance
- After approximately 4 half lives
- time to steady-state independent of dosage
- proportional to dose/dosage interval
- Inversely related to CL/F
In continous IV infusion, what is the steady state concentration proportional to?
Inversely related to?
What can be estimated from the infusion rate and the steady-state plasma concentration achieved?
- proportional to infusion rate
- Inversely related to CL
Infusion rate = CL x Css
- CLEARANCE
CL = Infusion / Css
1st-order elimination (or kinetics): the elimination rate of the drug is a constant _____of the drug remaining in the body per unit time (rather than a constant amount of drug per hour).
What is the equation for first order kinetics of elimination?
What drug falls in this category?
What would help you determine the elimination rate constant of the drug?
- fraction (not amount)
- dC/dt= -kC
(elimination rate constant)
- DEPENDS ON CONCENTRATION!!! - LIDOCAIN
- HALF LIFE!!!
t = 0.69/k
Drugs that are eliminated primarily by metabolism may display _____-order kinetics of elimination
When metabolic pathways are saturated, metabolism occurs at a ____ rate, i.e. it does not change in proportion to drug concentration.
What drugs fall in this category?
- zero
- fixed
Fixed amount of drug is metabolized per unit time
- not proportional to concentration
dC/dt= -K
- Phenytoin, Ethanol
True or false: half life is a hallmark of zero order kinetics.
FALSE!
Fixed amount of drug is metabolized per unit time
- not proportional to concentration
dC/dt= -K
In dose dependent kinetics,
when a drug’s elimination is mediated predominantly by metabolism, its elimination will tend to follow first-order kinetics when concentrations are well __(above/below)___ the KM of the metabolic enzymes, but will follow zero-order kinetics at doses that __(greatly below/exceed)___the KM of the metabolic enzymes
- below
- greatly exceed
First order
C> Km
dC/dt = -Vmax
Phenytoin, Ethanol, ASPIRIN becomes zero order kinetics at HIGH doses
A patient with grand mal seizures is receiving phenytoin 300 mg po per day. The phenytoin plasma level is 9.5 mg/ml (therapeutic range 10-20 mg/ml). The dose of phenytoin is increased to 500 mg po per day and one week later the patient presents with lethargy and ataxia. A repeat phenytoin plasma level is now 30 mg/ml. Which of the following best explains this clinical picture?
a) Phenytoin follows first-order kinetics of elimination.
b) The bioavailability of phenytoin has decreased.
c) Saturation of metabolic pathways resulted in toxic levels.
d) The Vmax for phenytoin metabolism has increased.
e) The renal clearance of phenytoin has decreased.
C
Which of the following is true when a drug exhibits zero-order kinetics of elimination?
A constant FRACTION of the drug is eliminated per unit time.
A constant fraction of the volume of distribution is cleared of drug.
A constant amount of drug is eliminated per unit time.
A constant half-life of elimination is observed.
A constant oral bioavailability is seen regardless of the dose.
A constant amount of drug is eliminated per unit time.
What is:
1. Volume of plasma cleared
of drug per unit time.
- Drug elimination may occur through the kidneys, the liver, the lung, and other organs.
- Equal to the sum of all these individual and simultaneously occurring organ clearances:
- Elimination Clearance
Units are ml/min or L/hr (“flow”)
- Total Clearance
CLtotal = CLrenal + CLhepatic + CLother
What is the elimination half life ?
What is this a function of? 2 values)
Time to eliminate 50% of the body content of the drug
- function of CLEARANCE and VOLUME OF DISTRIBUTION
t= 0.69Vd/ CL
Which of the following is considered a “primary” pharmacokinetic parameter?
The loading dose The elimination half-life The elimination clearance The Vmax and the Km The infusion rate
Elimination clearance
Propranolol has a half-life of elimination (t½) of 4 hours and is prescribed to a patient at a dose of 20 mg orally every 6 hours. How long will it take to reach 90% of the steady-state plasma level with continuous therapy?
A. 6 hours B. 9 hours C. 13 hours D. 18 hours E. 26 hours
C. 13 hours
4 * 3.3 = 13 hours
(20 mg is a distractor)
Why is there DOSE ADJUSTMENT IN RENAL INSUFFICIENCY?
Daily drug dose must be reduced by the ratio of _____ over expected _____
Impaired renal function often results in reduced clearance of drugs that are eliminated primarily by the kidneys.
- measured clearance in renal failure (CLRF)
- ormal, average clearance (CLN).
Dosing RateRF = Dosing RateNormal x CLr/CLn
In renal insufficiency, the dosing rate can be reduced by what? (2)
1 . reducing the dose,
- increasing the dosing interval
- BOTH
What is creatinine clearance?
What does it measure?
What can it be used for?
What equation can be used for this?
How is this different in females?
Creatinine clearance rate (CrCL) is the volume of blood plasma that is cleared of creatinine per unit time and is the most commonly used measure for approximating the glomerular filtration rate (GFR).
CrCL is not the same as clearance of a drug (it is clearance of creatine)—it only provides a relative measure of how well the kidney is functioning.
It can be used to adjust drug dosing in a patient with renal failure.
Cockcroft & Gault formula
CrCL = (140-age) (body wt. KG) / 72(seem Cr in mg/dl)
** reduce estimates by 15% in females
What are 3 determinants of HEPATIC drug clearance?
1.Hepatic Blood Flow
(Rate of drug delivery to the eliminating organ)
- Plasma Protein Binding
(Fraction of drug available for clearance) - Intrinsic Clearance
(Hepatocellular metabolism and/or biliary excretion)
Rowland’s equation
What is restrictive hepatic clearance?
What do drugs that fall into this category have very little of when given orally?
What has a GREAT effect on these drugs?
What drugs follow this clearance?(2)
- Drugs with low hepatic extraction
(Q»f*CLin) - Little first pass metabolism
- Change in BINDING or DRUG METABOLISM/excretion
(flow has little influence)
capacity limited clearance
- WARFARIN, PHENYTOIN
CYP2C9 (responsible for metabolism of S-warfarin) genotyping may identify a subgroup of patients who have difficulty at induction of warfarin therapy and are potentially at a higher risk of bleeding complications.
- can easily overdose the patient
PHENYTOIN: high amount is protein bound so in hypoalbuminemia there is less bound, and more can be cleared
What is the equation for restrictive hepatic clearance?
What is the equation for non-restrictive?
CLh = f * CLint
CLh = Q
What is non-restrictive hepatic clearance?
What has a GREAT effect on these drugs?
What conditions pose a problem for this clearance?
What drugs follow this clearance?(2)
- Drugs with HIGH hepatic excretion
CLh = Q
- FLOW has great effect,
- alterations in binding or intrinsic clearance is much lower - Flow dependent clearance –> problem in conditions that REDUCE hepatic blood flow (CHF, hypotension)
- Lidocaine, propranolol
Hepatic blood flow may be reduced in older patients or in those with liver disease or heart failure. Maintenance doses must be decreased in these patients to compensate for decreased clearance.
Beta-Blockers as a class can reduce hepatic blood flow and therefore decrease lidocaine clearance.
- propranolol (beta blocker) can inhibit blood flow and inhibit its OWN metabolism
What drugs have high bioavailability?
Low?
- Warfarin, phenytoin, theophylline, or digitoxin
- lidocain
- Propranolol
t1/2 represents the elimination half life, and only reflects rate of drug clearance when the volume of distribution is constant. What disease state appears to reduce both the apparent volume of distribution and the clearance of lidocain?
CHF
- so the t half life may appear normal and may be misleading in the choice of proper infusion rate
- the reduced volume of distribution also requires a reduction in the loading doses
What is unique about phenytoin, aspirin, and ethyl alcohol?
Follow dose dependent kinetics of elimination
low dose = 1st order
high dose = zero order (metabolic pathways saturated)
What is the following:
regimen where drug is administered at regular intervals to achieve a steady state plasma concentration.
Maintenance Dosing
- once steady state reached –> maintenance dose matches the amount cleared
