Pharmacotherapeuties: Intro to pharmacokinetics and pharmacodynamics Flashcards
What is “pharmacokinetics”?
How the body acts on the drug.
The study of absorption, distribution, metabolism, and excretion (ADME) of a drug.
Describes the relationship between dose and response.
Used to determine a rational population dosing regimen which will include age and disease-specific recommendations.
What is “pharmacodynamics”?
How the drug acts on the body.
The relationship between the concentration of a drug at the site of action and the size or magnitude of it’s effect.
Mechanism of action… It studies the mechanism of action and the physiological effects of the drug.
Receptor concept… Receptors are thought to play an important role as to how a drug interacts with the body.
Explain “GI absorption”.
When an extravascular (oral, rectal, etc) drug is taken it will be absorbed by the GI tract.
Weak acids will absorb more rapidly in low pH and bases will absorb more rapidly at high pHs.
For example, the stomach is acidic and acid drugs are unionized in the stomach and they will have an increased absorption. Unionized drugs can cross barriers easer than ionized dugs therefore ionized drugs are more rapidly absorbed than unionized drugs.
The amount of time that the drug takes to be absorbed will depend on the dosage of the formulation.
Explain passage into systemic circulation.
Passage is affected by:
-Concentration gradients- higher at administration site; the drug will move from an area of high concentration to an area of low concentration in an attempt to make all areas equal.
- membrane surface area (passive diffusion)- the larger the area, the faster the passive diffusion will take place
- drug permeability (size, lipophilicity, charge)- unionized drugs can cross barriers and are more rapidly absorbed than ionized drugs; weak acids absorb quicker at lower pH and weak bases absorb more quickly at high pH.
- blood flow- facilitates diffusion and passage of drugs through membranes; areas of high blood flow will have a greater passage for diffusion.
protein-binding- drugs not protein-bound can passively pass through membranes; high or unbound fractions of the drug allow for greater passage through membranes
What is “distribution”?
Movement of a drug from one area in the body to another.
It is reversible.
Once a drug is absorbed it needs to be distributed by systemic circulation otherwise there would be no effect; it would sit there and do nothing.
Can be categorized in to “Rate of distribution” and “extent of distribution”.
What is “rate of distribution”?
The speed by which a drug exits one body area and enters another.
Affected by:
-Tissue perfusion: well-perfused areas will have rapid drug take-up. If a drug is able to cross a membrane easily, it’s rate of membrane penetration is only limited by the rate of transportation; for example, areas with
-Blood flow-well-perfused tissues will ahve rapid drug take-up and drugs will also distribute out of these tissues more rapidly.
What is “extent of distribution”?
Ultimately, where the drug goes.
“Unbound” or “free” drugs are normally transported through cell membranes where they exert their effect.
Albumin binds to acidic drugs.
Acid-glycoprotein (AAG) binds to basic drugs
Protein-binding plays a role in the extent of distribution, there are 2 general mechanisms that can change the degree of protein-landing:
1) Involves changes in plasma protein concentrations: if the plasma protein concentration is increased, there will be more binding sites available; this leads to less free drugs as a result and results in less drug effect and vice versa.
A lower plasma concentration ultimately leads to an increase of drug effect because there is now more free drug.
2) Changing of binding affinity- if binding affinity is decreased then there will be less bound drug and more free drug leading to an increased drug effect or toxicity.
It is affected by:
What is “extent of distribution”?
Tissue binding
- extensive binding can lead to drug tissue concentrations much high than plasma concentrations
- such binding usually occurs with proteins of phospholipids
Molecular weight
- large, hydrophilic molecules do not crass membranes easily
- the distribution of very large hydrophilic molecules (such as proteins) is limited to extracellular spaces due to their size and polarity restricting movement throughout the body
Free drug concentration (what actually has what we call “pharmacological effect”) is more closely related to pharmacologic activity than is the total drug concentration.
What is “volume of distribution”?
Balance between plasma and tissue-binding
Highly plasma protein-bound drugs have small volumes of distribution because the drug is trapped in plasma. So if a drug is highly bound by plasma proteins the drug will be trapped in the plasma and will not be able to distribute out; the measured concentration of the drug in the plasma will be high and the drug will have a small apparent volume of distribution.
Highly tissue-bound drugs have large volumes of distribution because the drug is pulled from plasma. If a drug is bound by tissue then it will be pulled from the plasma and distributed out; the measured concentration of the drug in the plasma will be decreased and the drug will have a large apparent volume of distribution.
If drugs are highly bound to plasma proteins and to tissue, the volume of distribution will depend on whichever binding site dominates.
What is “elimination”?
The process of removing drug from the body.
Changes in drug concentration after distribution is a result of removal of drug from the body.
There are 2 processes of elimination:
1) Metabolism
2) Excretion
Explain “metabolism”.
Converts drug from parent molecule to chemical derivatives.
Metabolized drugs are broken down into metabolites and then excreted.
Not all drugs are metabolized
-excreted as parent compound or “excreted unchanged”
What are the sites of metabolism?
Metabolism provides a mechanism for removing undesirable, foreign compounds from the body.
Metabolism can produce compounds that are inactive or the process can produce compounds that are pharmacologically active or toxic.
The liver is the primary site of metabolism; the liver metabolizes drugs in to polar metabolites which allow the kidneys to eliminate them.
Other sites of metabolism (aside from the liver= extrahepatic) include:
- intestine
- kidney
- lung
- skin
What are the “phases of metabolism”?
Phase 1
- either add a polar group or an un-marked one; is the resulting molecules are highly polar it can be excreted
- phase 1 reactions can lead to inactive or active products
- oxidation, reduction, hydrolysis
- involves p-450
- conversion of lipophilic molecules to polar molecules
- involve OH or NH2 groups
- CYP 3A4 involved in metabolism of 50% of drugs (1A2, 2C9, 2C9T, 2C6, and 2E1 are also important enzymes in drug metabolism)
Phase 2 (Conjugation Reactions)
- usually involves functional group from phase I reaction; basically stage II reactions result in larger inactive molecules
- addition of glucuronic acid, sulfuric acid, acetic acid or an amino acid to make more polar molecules
- the kidneys can excrete these highly polar molecules
What factors affect drug metabolism?
When an enzyme is inhibited the response is faster than when it is induced because it takes more time because we have to wait for new enzymes to be made.
- inhibition of enzymes: quick occurrence (quick onset)
- induction of enzymes: slower response (slow onset)
- species
- disease states
- dosage and route of administration (oral routes undergo fast-pass metabolism whereas other routes bypass first-pass metabolism also by increasing the dose you can increase the concentration leading to saturated metabolic pathways… In acetaminophen overdose, the congestion pathway is saturated and hepatotoxicity can occur)
- nutritional status (low protein leads to amino acid deficiencies which can result in decreased oxidation reactions)
- age (children have not fully developed their metabolic pathways; elderly have declined metabolic capabilities therefore slower drug elimination= increased plasma drug levels)
- gender (in some cases women may metabolize drugs faster than men (for example, diazepam and tylenol)
Explain the link genetics and metabolism.
Genetics
- differences in functional enzymes–> they have an effect on metabolisms
- acetylation rates: determined by amounts of N-acetyltransferase (fast accelerators vs. slow accelerators)
Genetics will play a role in the metabolism in some meds.
