Flashcards in Pharmacokinetics Deck (60):
What are the mechanisms of drug permeation?
Aqueous diffusion (par acellular pathway), lipid diffusion (transcellular pathway), special carrier, endo/exocytosis
transfer of a drug from its site of administration to the blood stream
What is the level of absorption for IV drugs?
Complete, 100%, because the entire dose reaches the systemic circulation
Maximum convenience, but absorption may be slower and less complete than with other routes
First Pass Effect
Effect where ingested drugs are fractionally metabolized in the gut all and liver before reaching circulation
The drug enters systemic circulation directly from under the tongue. Drug bypasses the first pass effect. Enteral route
There is a partial avoidance of the first pass effect. Enteral route
IV, intramuscular, subcutaneous (below skin) and intradermal (in skin)
What is the solubility of nonionized molecules?
Liposoluble and can diffuse through the cell membrane
What is the solubility of ionized molecules?
Low liposolubility and have difficulty passing through the membrane
For weak acids, which form will permeate through the membranes?
The uncharged (protonated) form (HA)
What is permeating for weak bases?
The uncharged form (unprotanted) will permeate while the charges form will not
Conceptually, what does the Henderson Hasselbach Equation tell you?
Tells you that the ratio between unprotonated and protonated forms is based on pH and PK
Weak acids are excreted better in_________, weak bases are excreted faster in ___________.
Alkaline urine, acidic urine
According to the HH equation, when pH=PK
Unprotonated concentration=protonated concentration
For each unit of pH above the pK...
The unprotonated concentration will be ten time the protonated concentration
For each unit of pH below the PK....
The protonated concentration will be ten time the unprotonated concentration
Why does most drug absorption occur in the small intestine?
Because of its large surface area. Any factor that accelerated gastric emptying will increase the rate of drug absorption
How does blood flow affect absorption?
Increased blood flow will increase absorption
Transporter protein responsible for transporting several drugs across cell membranes. Reduced drug absorption.
Fraction of administered dose of a drug that reaches the systemic circulation
How do you determine bioavailability?
Compare the area under the curve of a particular route with the AUC after IV infection (should be 100%)
what factors can affect bioavailability?
Drug formulation, chemical instability, food and drug interactions, first pass metabolism, drug solubility, P-glycoprotein
Contain the same active ingredient and are identical in concentration, dosage form, and route of administration
When two pharmaceutically equivalent drugs have nearly superimposable concentration time plots
What is the point of looking at bioequivalence?
If two drugs are bioequivalent, one can safely replace the other
Process by which a drug leave the blood stream and enters the extracellular fluid or the cells of the tissues
What determined drug distribution?
Blood flow, capillary permeability, tissue volume, drug binding, drug hydrophobicity
Which parts of the body receive the drugs first/get most of the drugs?
Vessel rich groups that get lots of blood (brain, liver, kidney...) then it foes to the muscles
What do acidic drugs bind to?
What do basic drugs bind to?
What increases the risk of bilirubin encephalopathy?
Displacement of unconjugated bilirubin from albumin by sulfonamide drugs
Warfarin and plasma protein concerns
Warfarin is highly bound to albumin and only a small fraction is free. Sulfonamide so will displace warfarin causing a significant increase in the plasma level of free warfarin--->increase bleeding
What are the only drugs that can cross the blood-brain barrier?
Lipid soluble due to tight binding of zonula occludens
Metabolism of Drugs
Most lipid soluble drugs are not easily excreted because they can be reabsorbed easily. They must undergo a biotransformation that will make them more polar and inactive metabolites which can be easily excreted
What reactions are involved in drug metabolism?
Phase I and phase II reactions
Phase I reactions:
Oxidations, reduction, decarboxylations, deamination, hydrolytic reactions. Usually result in polar, inactive metabolites
Pharmacologically inactive compounds that are designed to maximize the amount of active species that reaches the site of action
Drug that is bio activated by metabolism to an active anticancer metabolite
How are Prodrugs usually converted into active metabolites?
Through hydrolysis of an ester or amide linkage
Phase II Reactions
Conjugation reactions that form a covalent bond between the drug molecule and something else (amino acid, sulfate, etc...)
What is the main site of drug metabolism?
Where are the enzyme systems for phase I reactions located?
Where are the enzyme systems for phase II reactions located?
What system catalyzes most phase I reactions?
What are the three main xenobiotic receptors?
Aryl hydrocarbon receptor (AhR)
Pregnane X receptor (PXR)
Constitutive lay active receptor (CAR)
Drugs will bind to xenobiotic receptors which activates the receptor, allowing it to translocation to the nucleus and bind to the promotes of various enzymes
What are the clinical consequences of enzyme induction?
A drug can increase its own metabolism, a drug can increase the metabolism of a coadministered drug (can reduce plasma concentrations below therapeutic levels)
What drugs inhibit cytochromes P450?
Amidodarone, cimetidine, ketoconazole,erythromycin, chloramphenicol, grapefruit juice
Inhibit P-glycoproteins which can lead to increased serum levels of drugs (e.g., digoxin) that are excreted by P-glycoprotein
What else can transcriptionally regulate P-glycoprotein?
What is the most common factor responsible for variations drug responses?
There is a genetic variation in enzymes that catalyze drug metabolism
What does grapefruit juice inhibit?
CYP3A4 and P-glycoprotein in the small intestine
What is the most common mechanism of drug excretion?
Renal excretion (a small number are excreted in the bile)
Volume of distribution
A measure of the apparent space in the body available to contain the drug
Measure of the body's ability to eliminate the drug
The fraction of the drug that is absorbed into the systemic circulation
Volume of distribution formula
Vd=amount of drug in body/plasma drug concentration. Theoretical with no real life application.
Schedule of drug administration to maintain specific range of drug plasma concentration over a long period of time