Drug Effectiveness
Dose-response (DR) curve: Depicts the relation between drug dose and magnitude of drug effect Drugs can have more than one effect Drugs vary in effectiveness
Different sites of action Different affinities for receptors
Dose-Effect Curves
Therapeutic Index
This is a figure of two different dose response curves. You can obtain a different dose response curve for any system that the drug effects. When you vary the drug, this is the Independent variable, what you are measuring is the % of individuals responding to the drug. Here we see the drugs effects on hypnosis and death. Notice that the effective dose for 50 % of the people is 100 mg and if you double the dose to 200 mg then 1 % of your subjects die. Thus, if you want to use this drug to hypnotize 99 % of your subjects, in the process you will kill 2-3 % of your subjects.
Pharmacokinetics
Drug molecules interact with target sites to effect the nervous system
The drug must be absorbed into the bloodstream and then carried to the target site(s)
Pharmacokinetics is the study of drug absorption, distribution within body, and drug elimination over time.
Absorption depends on the route of administration Drug distribution depends on how soluble the drug molecule is in fat (to pass through membranes) and on the extent to which the drug binds to blood proteins (albumin) Drug elimination is accomplished by excretion into urine and/or by inactivation by enzymes in the liver
Overview
Pharmacokinetics
DISPOSITION OF DRUGS
The disposition of chemicals entering the body (from C.D. Klaassen, Casarett and Doulls Toxicology, 5th ed., New York: McGraw-Hill, 1996).
Routes of Administration
Routes of Administration:Orally: Rectally: Inhalation: Absorption through mucous membranes: Topical: Parenterally:
Intravenous: Intramuscular: Subcutaneous:
Routes of Administration
Membranes
Types of Membranes: Cell Membranes: This barrier is permeable to many drug molecules but not to others, depending on their lipid solubility. Small pores, 8 angstroms, permit small molecules such as alcohol and water to pass through. Walls of Capillaries: Pores between the cells are larger than most drug molecules, allowing them to pass freely, without lipid solubility being a factor. Blood/Brain Barrier: This barrier provides a protective environment for the brain. Speed of transport across this barrier is limited by the lipid solubility of the psychoactive molecule. Placental Barrier: This barrier separates two distinct human beings but is very permeable to lipid soluble drugs.
Drug Distribution
Dependent upon its route of administration and target area, every drug has to be absorbed, by diffusion, through a variety of bodily tissue. Tissue is composed of cells which are encompassed within membranes, consisting of 3 layers, 2 layers of water-soluble complex lipid molecules (phospholipid) and a layer of liquid lipid, sandwiched within these layers. Suspended within the layers are large proteins, with some, such as receptors, transversing all 3 layers. The permeability of a cell membrane, for a specific drug, depends on a ratio of its water to lipid solubility. Within the body, drugs may exist as a mixture of two interchangeable forms, either water (ionized-charged) or lipid (nonionized) soluble. The concentration of two forms depends on characteristics of the drug molecule (pKa, pH at which 50% of the drug is ionized) and the pH of fluid in which it is dissolved. In water soluble form, drugs cannot pass through lipid membranes, but to reach their target area, they must permeate a variety of types of membranes.
Pharmacokinetics vs Pharmacodynamicsconcept
Fluoxetine increases plasma concentrations of amitriptyline. This is a pharmacokinetic drug interaction.
Fluoxetine inhibits the metabolism of amitriptyline and increases the plasma concentration of amitriptytline.
Pharmacokinetics vs Pharmacodynamicsconcept
If fluoxetine is given with tramadol serotonin syndrom can result. This is a pharmacodynamic drug interaction.
Fluoxetine and tramadol both increase availability of serotonin leading to the possibility of serotonin overload This happens without a change in the concentration of either drug.
Basic Parameters
In the next few slides the basic concepts and paramaters will be described and explained.
In pharmacokinetics the body is represented as a single or multiple compartments in to which the drug is distributed.
Some of the parameters are therefore a little abstract as we know the body is much more complicated !
Volume 100 L
Clearance 10 L/hr
Clearance = 10 L/hr Volume of Distribution = 100 L What is the Elimination Rate Constant (k) ?
CL = kV
If V increases then k must decrease as CL is constant
Important Concepts
VD is a theoretical Volume and determines the loading dose. Clearance is a constant and determines the maintenance dose. CL = kVD. CL and VD are independent variables. k is a dependent variable.
Volume of Distribution
An abstract concept
Gives information on HOW the drug is distributed in the body
Loading Dose
Dose = Cp(Target) x Vd
Question
What is the loading dose required for drug A if; Target concentration is 10 mg/L Vd is 0.75 L/kg Patients weight is 75 kg
Answer is on the next slide
Dose = Target Concentration x VD Vd = 0.75 L/kg x 75 kg = 56.25 L Target Conc. = 10 mg/L Dose = 10 mg/L x 56.25 L = 565 mg This would probably be rounded to 560 or even 500 mg.
Clearance (CL)
Ability of organs of elimination (e.g. kidney, liver) to clear drug from the bloodstream. Volume of fluid which is completely cleared of drug per unit time. Units are in L/hr or L/hr/kg Pharmacokinetic term used in determination of maintenance doses.
Clearance
Volume of blood in a defined region of the body that is cleared of a drug in a unit time. Clearance is a more useful concept in reality than t 1/2 or kel since it takes into account blood flow rate. Clearance varies with body weight. Also varies with degree of protein binding.
Clearance
Rate of elimination = kel D,
Remembering that C = D/Vd And therefore D= C Vd Rate of elimination = kel C Vd Rate of elimination for whole body = CLT C Combining the two, CLT C = kel C Vd and simplifying gives: CLT = kel Vd
Question
What maintenance dose is required for drug A if; Target average SS concentration is 10 mg/L CL of drug A is 0.015 L/kg/hr Patient weighs 75 kg
Answer on next slide.
Answer
Maintenance Dose = CL x CpSSav
CL = 0.015 L/hr/kg x 75 = 1.125 L/hr Dose = 1.125 L/hr x 10 mg/L = 11.25 mg/hr So will need 11.25 x 24 mg per day = 270 mg
Half-Life and k
Half-life is the time taken for the drug concentration to fall to half its original value The elimination rate constant (k) is the fraction of drug in the body which is removed per unit time.
Drug Half-Life
Half-Life
C = Co e - kt C/Co = 0.50 for half of the original amount 0.50 = e k t
ln 0.50 = -k t -0.693 = -k t
t 1/2 = 0.693 / k
Drug Elimination
C KC t dC KC dt Kt C t C 0e
Drug Concentration
C1
Exponential decay
C2
dC/dt C = -k.C
Time
Log Concn.
C0
C0/2 t1/2 t1/2 t1/2
Time
Time to eliminate ~ 4 t1/2
Integrating:
Cp2 = Cp1
-kt .e
Logarithmic transform:
lnC2= lnC1 - kt
Elimination Half-Life:
t1/2 = ln2/k
t1/2 = 0.693/k
Steady-State
Steady-state occurs after a drug has been given for approximately five elimination half-lives. At steady-state the rate of drug administration equals the rate of elimination and plasma concentration - time curves found after each dose should be approximately superimposable.
194
200
75
50
C
Cpav
t
Four half lives to reach steady state
Therapeutic Index
Therapeutic index = toxic dose/effective dose
This is a measure of a drugs safety
A large number = a wide margin of safety A small number = a small margin of safety
2) tubular reabsorption/secretion - acidification/alkalinization, - active transport, competitive/saturable, organic acids/bases - protein binding
Metabolism - minor
Portal circulation
Gut
Therapeutic Window
Useful range of concentration over which a drug is therapeutically beneficial. Therapeutic window may vary from patient to patient Drugs with narrow therapeutic windows require smaller and more frequent doses or a different method of administration Drugs with slow elimination rates may rapidly accumulate to toxic levels.can choose to give one large initial dose, following only with small doses
Distribution
Rate & Extent depend upon
Chemical structure of drug Rate of blood flow Ease of transport through membrane Binding of drug to proteins in blood Elimination processes
Partition Coefficients: ratio of solubility of a drug in water or in an aqueous buffer to its solubility in a lipophilic, non-polar solvent pH and ionization: Ion Trapping
Renal Elimination
Glomerular filtration: molecules below 20 kDa pass into filtrate. Drug must be free, not protein bound. Tubular secretion/reabsorption: Active transport. Followed by passive and active. DP=D + P. As D transported, shift in equilibrium to release more free D. Drugs with high lipid solubility are reabsorbed passively and therefore slowly excreted. Idea of ion trapping can be used to increase excretion rate---traps drug in filtrate.
% Bound
Renal failure, inflammation, fasting, malnutrition can have effect on plasma protein binding. Competition from other drugs can also affect % bound.
An Example
Warfarin (anticoagulant) protein bound ~98% Therefore, for a 5 mg dose, only 0.1 mg of drug is free in the body to work! If patient takes normal dose of aspirin at same time (normally occupies 50% of binding sites), the aspirin displaces warfarin so that 96% of the warfarin dose is protein-bound; thus, 0.2 mg warfarin free; thus, doubles the injested dose
Volume of Distribution
C = D/V
Vd is the apparent volume of distribution C= [drug] in plasma at some time D= total [drug] in system
Vd gives one as estimate of how well the drug is distributed. Vd < 0.071 L/kg indicate the drug is mainly in the circulatory system. Vd > 0.071 L/kg indicate the drug has entered specific tissues.
C = Co - kt
ln C = ln Co - kt
First-Order Kinetics
To reiterate: Comparison
Zero Order Elimination
[drug] decreases linearly with time Rate of elimination is constant Rate of elimination is independent of [drug] No true t 1/2
AUC: IV Administration
AUC
For IV bolus, the AUC represents the total amount of drug that reaches the circulatory system in a given time. Dose = CLT AUC
Bioavailability
The fraction of the dose of a drug (F) that enters the general circulatory system, F= amt. of drug that enters systemic circul. Dose administered F = AUC/Dose
Bioavailability
A concept for oral administration Useful to compare two different drugs or different dosage forms of same drug
Rate of absorption depends, in part, on rate of dissolution (which in turn is dependent on chemical structure, pH, partition coefficient, surface area of absorbing region, etc.) Also firstpass metabolism is a determining factor
Rowlands Equation
F = 1-E = 1-Clhep LBF This very useful equation calculates the magnitude of the effect of the livers 1st pass of an oral dose and, more precisely, to predict it from and i.v. test. Thus, if E < 0.10, then, clearly, bioavailability F > 0.90.
P450 Interactions
Substrate: Is the drug metabolized via a specific hepatic isoenzyme? Inhibitor: does a specific drug inhibit a specific hepatic isoenzyme?
Would expect this to interfere with drug inactivation
Drug-CYP Interactions
Enzyme (CYP) Substrate Inhibitor
Cimetidine Thiotepa Fluoxetine
Inducer
Tobacco smoke Phenobarbital
1A2
2B6 2C19
Prednisone
http://www.georgetown.edu/departments/pharmacology/clinlist.html
Drug Enantioners
A drug molecule may be organized in such a way that the same atoms are mirror images
Enantioners represent drug molecules that are structurally different (spatial configutation)
Different physical properties
Light rotation (levo = left; dextro = right) Melting points