4 and 5 - Pharmacokinetics Flashcards
Define absorption
The absorption of a drug is simply the movement of an agent from the site of administration into the circulation. The extent to which a drug reaches the circulation is in part impacted by the method of drug delivery or route of administration.
Define enteral administration
drug delivery via the gastrointestinal (GI) tract
What are the types of enteral administration?
- Oral
- Sublingual and buccal
- Rectal
What are the pros and cons to oral administration
Pros = relatively safe, convenient, and economical
Cons = since drugs administered via this route will encounter various GI environmental components (digestive enzymes, low gastric pH, variability in propulsion, food, other drugs), challenges exist to overcome these components for drugs to be therapeutic
What are the pros and cons to sublingual and buccal administration?
Pros = This route allows for lipid soluble drugs to be absorbed across the oral mucous membrane and directly into venous blood
More pros = This direct absorption into the venous blood avoids metabolism by the liver.
No cons for this type
What are the pros and cons to rectal drug administration?
Pros = Allows delivery of an agent to an unconscious/vomiting patient, allows for approximately half of the drug to avoid metabolism by the liver
Cons = drug administration by this route can be incomplete and cause significant irritation
And who the hell wants a rectal drug? No one.
Define parenteral administration
Parenteral administration: drug delivery via a route that does not involve the GI tract. This route of administration requires piercing the skin.
What are the different types of parenteral administration?
- Intravenous (IV)
- Intramuscular (IM)
- Subcutaneous (SC)
- Intrathecal
- Epidural
What are the pros and cons of IV drugs?
Pros = rapid administration, bioavailability reaches 100%, accurate dosing
Cons = once administration has occurred there is no “recalling” the drug.
What are the pros and cons of IM drugs?
Cons = The absorption from the site of injection is dependent upon blood blow to the site therefore exercise and fat distribution can significantly impact absorption.
No pros listed
What are the pros and cons of SC drugs?
Pros = This method allows for constant absorption at a relatively slow rate
No cons listed
What are intrathecal drugs?
Administration via an injection into the subarachnoid space for delivery of drugs into the central nervous system.
What are epidural drugs?
Administration of drugs via an injection into the epidural space.
When a drug enters the body, it must cross biological membranes in order to function - how does it cross membranes?
Crossing these membranes can occur either by passive membrane diffusion or by facilitation from a carrier molecule. The majority of drugs cross membranes via simply passive diffusion down a concentration gradient.
Describe the differences between the ionized and non-ionized forms of drugs in the body
Drugs in the body will exist as a mixture of two forms. These forms include an ionized (electrically charged) and a non-ionized (uncharged) form.
What form of the drug (ionized or non-ionized) can pass through membranes?
It is only the non-ionized form that is able to readily cross lipid membranes.
What determines the ratio of ionized to non-ionized forms of the drug?
- pH of the fluid in which the drug is dissolved
- pKa (pH at which 50% of the drug is ionized and 50% is non-ionized)
What will happen if the pKa is greater than the pH?
The drug will exist predominantly in the protonated form
What will happen if the pH is greater than the pKa?
The unprotonated form will predominate
We know that the non-ionized drugs can cross membranes, but what does this mean in terms of protonation in acid drugs?
A protonated weak acid (HA) is uncharged (non-ionized) and can readily cross membranes
A deprotonated acid (H+) and A-) cannot easily cross a membrane
What about the protonation of bases?
A base (B) in the unprotonated form can easily move across membranes
The protonated form of a base (HB+) will not move across the membrane easily
Give a summary of acids, bases and protonation
Non-ionized = Easy movers
- Protonated acid
- Unprotonated base
Remember: “NIPAUB”
Ionized = No movement
- Protonated base
- Unprotonated acid
Define drug distribution
The process by which a drug leaves the circulation and enters the tissues perfused by the blood
What are the four factors that impact drug distribution?
1 - Cardiovascular factors
2 - Tissue binding
3 - Drug molecule size
4 - Lipid solubility
What types of cardiovascular factors affect drug distribution in the body?
- Proportion of cardiac output
- Regional blood flow
- Capillary permeability
- Binding to plasma proteins
What is biotransformation?
: Biotransformation reactions or metabolism of drugs can be categorized as Phase I and Phase II biotransformation. These reactions can convert
a parent compound into an active or inactive metabolite.
What is phase I biotransformation?
Phase I biotransformation includes oxidative, reductive and hydrolytic reactions. The result of these reactions is to generate a more polar molecule by exposing a functional group on the parent compound. This can render the compound a substrate for Phase II biotransformation
What is the rate limiting step in phase I biotransformation?
The rate limiting step in Phase I biotransformation is mediated by a group of enzymes expressed in the endoplasmic reticulum of cells. These enzymes are referred to as cytochrome P450s (CYP) and many isoforms of the enzymes exist.
What is phase II biotransformation?
Phase II reactions yield a more water soluble conjugated product that is transported into the bile caniculi and eventually into the bile duct to be excreted with the feces; or back into the blood to be excreted by the kidneys. These reactions include glucuronidation, sulfation, acetylation, glutathione conjugation, glycine conjugation, methylation, and water conjugation.
What are the main sites of biotransformation?
- GI tract
- Lungs
- Skin
- Kidneys
- Brain
- Liver ***
Although all these organs play a significant role in metabolism, it is the liver that serves as the primary metabolizing organ in the body
Why is the liver the metabolizing?
This is due in part to the vascular architecture and high level of metabolizing enzyme expression.
What is the first pass effect?
The anatomical orientation of the vasculature in relationship to the gastrointestinal organs (see figure below) creates a challenge when delivering drugs via an oral route. A large percentage of a drug absorbed by the stomach or intestine will initially be carried to the liver by the portal vein. Thus, most of the orally administered drug will be exposed to metabolizing enzymes in the liver before distributing to the entire body. As a result, a large amount of drug can be inactivated prior to reaching the intended target.
What are the two main routes of drug elimination?
- Renal excretion
- Fecal excretion
Describe renal excretion
- Renal excretion is the primary mechanism of drug elimination
- Excretion requires a conversion of the compound to a more polar form
What factors contribute to the amount of drug that is eliminated via the kidneys?
- Glomerular filtration rate
- Binding to plasma proteins
- Alkalinization or acidification of urine
What are the two mechanisms by which drugs are excreted in the feces?
- Drugs can be excreted into the bile during the digestive process of hepatic secretion
- Drugs can be removed from the circulation by GI enterocytes and secreted directly into the lumen of the GI tract
What is one implication to fecal excretion of drugs?
Due to the large number of transport proteins present in the GI tract, many compounds are subject to re-absorption by the intestine and thus undergo enterohepatic circulation
Define “volume of distribution”
Volume of distribution (V) can be defined as the measure of space in the body available to contain the drug.
What is the equation for V?
V = (amount of drug in body)/(concentration of drug in blood)
What does V mean in terms of distribution in the body?
- The larger the volume of distribution, the greater the extent to which the drug distributes to extravascular tissue
Describe a situation in which a drug has a V which is close to the blood volume in the body (6 L)
If the volume of distribution is calculated to be close to the blood volume (i.e. 6 L) it would suggest that the majority of the drugs is located within the vasculature.
Describe a situation in which a drug has a V which is 100x greater than the blood volume
If a drug was to have a very large volume of distribution (i.e. 15,000 L), it would suggest that the majority of the drug is located in extravascular compartments, such as fat
Define clearance
- Clearance (CL) is the rate of elimination in relation to drug concentration. CL is expressed as mL/min/kg and this value helps determine the capacity for drug removal by organs.
What are the two types of clearance kinetics?
- Zero-order elimination
- First-order elimination
Define zero-order elimination
A specific amount of drug is eliminated over a period of time. The elimination process is at capacity or is saturated. The process is independent of the drug concentration. Practically, zero-order kinetics is observable when the bodies capacity to eliminate a drug is saturated and is referred to as capacity-limited elimination.
Define capacity-limited elimination
A point at which the concentration of drug has saturated the elimination capacity or capabilities of the system. This will mimic zero-order kinetics. This is important in that if the dosing rate is greater than the elimination rate, the drug concentration will continue to increase in the blood. This could lead to dangerous toxic effects. This is particularly relevant for drugs such as phenytoin, aspirin and alcohol
Define first-order elimination
Clearance is constant over the range of drug concentrations in the body because the system is not saturated. This is the case for a majority of drugs. Practically, first-order kinetics is observed with the metabolizing organ has excess capacity to eliminate a drug and is only limited by the flow of blood to that organ or flow-dependent elimination.
Define flow-limited elimination
An organ has a high capacity or is not saturated by the drug concentration. The kinetics would mimic first-order. The limiting factor for elimination of a drug is the blood flow to that organ. Thus the greater the blood flow, the greater the extent of elimination. This is noted with a drug like propranolol. The oral dose is 20-30x greater than the IV dose. This is because the rate of drug delivery to the liver after oral absorption is very high. Following flow through the liver, a large fraction of drug is metabolized and eliminated.
Define half life
The time it takes for the concentration of a drug in the plasma to decrease by 50% and is expressed in units of time
What is half life dependent on?
Volume of distribution and clearance
What is the equation for half life?
t(1/2) = (0.693 x V)/CL
If clearance increases, half-life…
Decreases
takes less time to rid the body of the drug
If volume of distribution increases, half-life…
Increases
takes more time to rid the body of the drug
Define the drug accumulation factor
Accumulation of drugs in the body will be detectable if the dosing interval is shorter than four half-lives. So, accumulation is inversely proportional to the fraction of drug lost with each dosing interval. This number will predict the ratio of the steady-state concentration to the dose seen following the first dose.
Define bioavailability
the amount of drug that reaches the systemic circulation. The bioavailability of a drug administered IV will be 100%; while all other routes of administration will result in a decreased bioavailability
What factors affect the bioavailability of a drug?
- Clearance
- Hepatic blood flow
- Extent of absorption
There is a sequence of two equations which allow you to calculate bioavailability using the information above
ER = CL/Q
ER = extraction ratio CL = Clearance Q = Hepatic blood flow
F = f x (1-ER)
F = bioavailability f = extent of absorption (gut)
Describe the target concentration and its relationship to the MEC and MEC
A. The goal of drug delivery is to reach a plasma concentration that produces the desired therapeutic effect. The target concentration (TC) falls between the minimum effective concentration (MEC) for the desired effect and the minimum effective concentration (MEC) for the adverse or toxic effect
What do we call this range of drug concentrations?
The concentration range between these two points (MEC and MEC) is referred to as the therapeutic window
Define steady state concentration
C(ss)
The point during a dosing regimen when elimination of a drug is equal to the bioavailability of the drug
What is the equation of steady state concentration?
C(ss) = dosing rate/CL
What is the goal of the C(ss) - steady state concentration?
C. The goal is to have the C(ss) within the therapeutic window.
How will changing or altering the drug clearance impact the C(ss)?
Changing or altering drug clearance will impact the Css.
For example, if the CL of a drug decreases then the Css will increase
How will changing or altering the dosing rate impact the C(ss)?
Changing or altering the dosing rate will impact C(ss).
If CL is constant and the dosing rate increases (see slide set for comparison of steady state concentrations with different doses, slide 37) there will be an increase in C(ss).
What is the relationship between C(ss) and half life?
F. Reaching Css will always take approximately 4-5 half-lives
Why does it take 4-5 half lives to reach a steady state?
Following 4-5 half-lives, the amount of drug from the first dose is negligible. The time it takes to reach C(ss) is independent of the dose or dosing rate but is dependent upon the half-life. The longer the half-life, the longer it will take to reach the C(ss).
What is a maintenance dose?
Dose needed to maintain steady state concentrations. In order to achieve this, enough drug must be administered to replace the amount of drug lost in the proceeding dose. In order to determine a maintenance dose, the dosing rate at steady state must be determined. Further if the dose is administered via a route other than IV, the bioavailability must be taken into account.
How do you calculate a steady state dosing rate?
Dosing rate(ss) = CL x TC
TC = target concentration
It is different for oral route…
Dosing rate(oral) = Dosing rate (ss)/F(oral)
Remember - F = bioavailability
Once you have calculated the dosing rate, how do you calculate the maintenance dose?
Maintenance dose = dosing rate x dosing interval
What is a loading dose?
An initial dose that can be given in order to achieve the target concentration rapidly. This is useful when using drugs with a long half-life and reaching a therapeutic concentration is necessary prior to the time needed to reach steady state. However, a large loading dose may be toxic and thus need to be divided into multiple smaller doses or infused over a period of time.
How do you calculate loading dose?
LD = (V x TC)/F
LD = loading dose V = volume of distribution TC = target dose F = bioavailability
Main point from slides on pKa and pH…
If the pH is less than the pKa of a drug, the protonated form predominates. If the pH is greater than the pKa, the unprotonated form predominates.
Weak acids are protonated (HA) in the lower pH of the stomach, whereas weak bases are non-protonated (B) in the higher pH of the intestines.
MAIN CONCEPT: Therefore, weak acids are more readily absorbed from the stomach than are weak bases, and
Weak bases are absorbed more readily from the intestines than from the stomach.
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