Professional Documents
Culture Documents
Pharmacokinetics
Pharmacokinetics
Clinical Pharmacokinetics
The science of the rate of movement of drugs within biological systems, as affected by the absorption, distribution, metabolism, and elimination of medications
Absorption
Must be able to get medications into the patients body Drug characteristics that affect absorption:
Molecular weight, ionization, solubility, & formulation
concentration
IV Oral Rectal
Distribution
Membrane permeability
cross membranes to site of action
Lipophilicity of drug
lipophilic drugs accumulate in adipose tissue
Volume of distribution
Volume of Distribution
Therefore the dose required to give a certain plasma concentration can be determined if the VD for that drug is known. The VD is not a real volume; it is more a reflection of how a drug will distribute throughout the body depending on several physicochemical properties, e.g. solubility, charge, size, etc.
Examples
Drug VD Warfarin VD = 8L Theophylline, Ethanol VD = 30L Chloroquine VD = 15000L Comments Reflects a high degree of plasma protein binding. Represents distribution in total body water. Shows highly lipophilic molecules which sequester into total body fat.
Pediatric Distribution
Body Composition
total body water & extracellular fluid adipose tissue & skeletal muscle
Protein Binding
albumin, bilirubin, 1-acid glycoprotein
Tissue Binding
compositional changes
Metabolism
Drugs and toxins are seen as foreign to patients bodies Drugs can undergo metabolism in the lungs, blood, and liver Body works to convert drugs to less active forms and increase water solubility to enhance elimination
Metabolism
Liver - primary route of drug metabolism Liver may be used to convert pro-drugs (inactive) to an active state Types of reactions
Phase I (Cytochrome P450 system) Phase II
Phase I reactions
Cytochrome P450 system Located within the endoplasmic reticulum of hepatocytes Through electron transport chain, a drug bound to the CYP450 system undergoes oxidation or reduction Enzyme induction Drug interactions
Phase II reactions
Polar group is conjugated to the drug Results in increased polarity of the drug Types of reactions
Glycine conjugation Glucuronide conjugation Sulfate conjugation
Elimination
Pulmonary = expired in the air Bile = excreted in feces
enterohepatic circulation
Renal
glomerular filtration tubular reabsorption tubular secretion
Pediatric Elimination
Glomerular filtration matures in relation to age, adult values reached by 3 yrs of age Neonate = decreased renal blood flow, glomerular filtration, & tubular function yields prolonged elimination of medications Aminoglycosides, cephalosporins, penicillins = longer dosing interval
Pharmacokinetic Principles
Steady State: the amount of drug administered is equal to the amount of drug eliminated within one dosing interval resulting in a plateau or constant serum drug level Drugs with short half-life reach steady state rapidly; drugs with long half-life take days to weeks to reach steady state
Linear Pharmacokinetics
Linear = rate of elimination is proportional to amount of drug present Dosage increases result in proportional increase in plasma drug levels
120 100
concentration
80 60 40 20 0 dose
Nonlinear Pharmacokinetics
Nonlinear = rate of elimination is constant regardless of amount of drug present Dosage increases saturate binding sites and result in nonproportional increase/decrease in drug levels
50 45 40 35 30 25 20 15 10 5 0 dose
concentration
Michaelis-Menten Kinetics
Follows linear kinetics until enzymes become saturated Enzymes responsible for metabolism /elimination become saturated resulting in non-proportional increase in drug levels
30
concentration
25 20 15 10 5 0 dose phenytoin
Pharmacodynamics
Study of the biochemical and physiologic processes underlying drug action
Mechanism of drug action
Drug-receptor interaction
Pharmacodynamics
What the drug does to the body
Cellular level General
Drug Actions
Most drugs bind to cellular receptors
Initiate biochemical reactions Pharmacological effect is due to the alteration of an intrinsic physiologic process and not the creation of a new process
Drug Receptors
Proteins or glycoproteins
Present on cell surface, on an organelle within the cell, or in the cytoplasm Finite number of receptors in a given cell
Receptor mediated responses plateau upon saturation of all receptors
Drug Receptors
Action occurs when drug binds to receptor and this action may be:
Ion channel is opened or closed Second messenger is activated
cAMP, cGMP, Ca++, inositol phosphates, etc. Initiates a series of chemical reactions
Drug Receptor
Affinity
Refers to the strength of binding between a drug and receptor Number of occupied receptors is a function of a balance between bound and free drug
Drug Receptor
Dissociation constant (KD)
Measure of a drugs affinity for a given receptor Defined as the concentration of drug required in solution to achieve 50% occupancy of its receptors
Drug Receptors
Agonist
Drugs which alter the physiology of a cell by binding to plasma membrane or intracellular receptors
Partial agonist
A drug which does not produce maximal effect even when all of the receptors are occupied
Drug Receptors
Antagonists
Inhibit or block responses caused by agonists
Competitive antagonist
Competes with an agonist for receptors High doses of an agonist can generally overcome antagonist
Drug Receptors
Noncompetitive antagonist
Binds to a site other than the agonist-binding domain Induces a conformation change in the receptor such that the agonist no longer recognizes the agonist binding site. High doses of an agonist do not overcome the antagonist in this situation
Drug Receptors
Irreversible Antagonist
Bind permanently to the receptor binding site therefore they can not be overcome with agonist
Pharmacodynamics
Definitions
Definitions
Efficacy
Degree to which a drug is able to produce the desired response
Potency
Amount of drug required to produce 50% of the maximal response the drug is capable of inducing Used to compare compounds within classes of drugs
Definitions
Effective Concentration 50% (ED50)
Concentration of the drug which induces a specified clinical effect in 50% of subjects
Definitions
Therapeutic Index
Measure of the safety of a drug Calculation: LD50/ED50
Margin of Safety
Margin between the therapeutic and lethal doses of a drug
Dose-Response Relationship
Drug induced responses are not an all or none phenomenon Increase in dose may:
Increase therapeutic response Increase risk of toxicity
Clinical Practice
What must one consider when one is prescribing drugs to a critically ill infant or child???
Clinical Practice
Select appropriate drug for clinical indication Select appropriate dose
Consider pathophysiologic processes in patient such as hepatic or renal dysfunction Consider developmental and maturational changes in organ systems and the subsequent effect on PK and PD
Clinical Practice
Other factors
Drug-drug interaction
Altered absorption Inhibition of metabolism Enhanced metabolism Protein binding competition Altered excretion
Clinical Practice
Other factors (cont)
Drug-food interaction
NG or NJ feeds
Continuous vs. intermittent Site of optimal drug absorption in GI tract must be considered
Substrate deficiencies
Exhaustion of stores Metabolic stress
Effect of Disease on PD
Up regulation of receptors Down regulation of receptors
Decreased number of drug receptors
Effect of Disease on PD
Altered response due to:
Acid-base status Electrolyte abnormalities Altered intravascular volume Tolerance
Know the appropriate time to measure the concentration If the serum concentration is low, know how to safely achieve the desired level Be sure the level is not drawn from the same line in which the drug is administered Be sure drug is administered over the appropriate time AND Treat the patient, not the drug level
REMEMBER
No drug produces a single effect!!!