Lecture 4: How Drugs are Eliminated (Pharmacokinetics) Flashcards
What are the main categories of Pharmacokinetics?
Absorption, Distribution, Metabolism, Excretion
Why do the effects of a drug wear off?
Because over time the drug is eliminated from the body
What are the characteristics of a drug that is absorbed faster?
It will reach its peak effect faster, but because it gets into the bloodstream faster it will be eliminated sooner and have a shorter duration of effect
What are the characteristics of a drug that has a larger dose?
It would be absorbed faster and have a higher peak effect and it would have a longer duration of action because it takes longer to be eliminated
What are the characteristics of a drug that is eliminated more quickly from the body?
It would appear to have a smaller peak effect because it being eliminated quicker
What can profile of the amount of drug in our body overtime be controlled by?
By manipulating properties of the drug or the different properties in the body
Why is it important to understand pharmacokinetic principles?
Because they define how often or how much of a drug you should be taking to be at its optimal concentration in the body
Which questions do drug parameters influence?
- How much drug should be taken?
- How often?
- how long will it take me to perceive an effect of the drug?
What are the three considerations for the route of administration of a drug?
- Convenience
- Bioavailability
- Processing
Why is convenience an important consideration for drug administration?
Because it is easier to take a medication orally vs through an injection, IV or other routes
Why is bioavailability an important consideration for drug administration?
Because difference drugs may be absorbed with different efficiency from the gut
Why is Processing an important consideration for drug administration?
Because drugs that are absorbed from the gut first encounter the liver before entering systemic circulation so there is sometimes significant processing and breakdown
Where do drugs that are absorbed in the gut go before reaching the systemic circulation?
They go through hepatic portal circulation and to the liver
Why is the liver of important consideration with drugs?
Because it is a major site of metabolism and strongly influences the bioavailability of drugs
What is First Pass Metaolism?
The amount of a drug that is processed or eliminated its first time through through the liver after it is absorbed in the gut and goes through the circulatory system
What is the inverse of bioavailability?
Extractions ratio
What is Clearance?
The volume of blood that can be cleared of a compound over a certain amount of time
Why would something have a higher clearance?
The more effectively something is removed from the blood by the liver the higher the clearance and the higher the extraction ratio
What drugs have a high extraction ratio?
Drugs that are rapidly processed by the liver
What is the meaning of a low extraction ratio?
Drugs that a poorly processes by the liver (aren’t significantly processed by the liver)
What are the six routes of administration?
- Oral
- Intravenous
- Intramuscular/subcutaneous
- Inhalation
- Sublingual
- Transdermal
What is the rate of adsorption for Oral drugs?
Slow
What can Oral drugs be affected by?
Intake of food
What can the exposure of oral drugs be influenced by?
Breakdown in the gut and processing in the liver
What is the rate of the onset of action of intravenous drugs and why?
They have a very rapid onset because it is delivered directly into the systemic system
Why is intravenous not often used?
Because it is inconvenient and requires expertise
What are the pros to intravenous injections?
- Rapid onset
* There is high control over circulating level by controlling the rate of infusion
What does the rate of absorption of intramuscular injections depend on?
Blood flow to the site
What is a common type of intramuscular injection?
Depot injections for sustained release
What are Depot injections?
Intramuscular injections that slowly dissolve for sustained release
Where is absorption in inhalation administration?
The epithelium in the lungs, and can be very rapid
What is the rate of absorption in sublingual administration?
Rapid absorption route
What does Sublingual administration bypass?
Bypasses the ‘first pass’ effects despite being taken orally
What are the benefits to Transdermal (Ointment or patch) administration?
Convenient, slow absorption and sustained exposure
What is Bioavailability?
The fraction of unprocessed/unaltered drug that reaches the systemic circulation after administration by a particular route
What is the bioavailability of IV administration?
100%
What are the very efficient route of administration in terms of bioavailability?
IV, Intramuscular (IM), and Subcutaneous (SC)
Which administration has the most variable bioavailability?
Oral administration because of first pass
What does Distribution refer to?
How a drug or substance is partitioned into different body compartments after it is absorbed
What does the distribution of a drug have an influence on?
The effective concentration of a drug in the body and its lifetime of the drug in the body
What are the two key factors to drug distribution?
- Binding to plasma proteins
* Drug accumulation in tissues
What do drugs circulate in the equilibrium between?
Free and bound to some globulin in the bloodstream
Which drugs are considered pharmacologically active in terms of free and bound?
Only free drugs
Why are only free concentrations of drugs considered pharmacologically active?
Because bound drugs are unable to interact with the receptor
What are the characteristics of drugs that are highly bound to blood globulins?
They have a long lifetime in the body but have a smaller concentration that is able to interact with receptors
What kind of drugs is drug accumulation favored for?
Drugs that are lipophilic
Which tissues can accumulate a drug more readily?
More highly perfused tissues
Why can highly lipophilic drugs accumulate in tissues?
Because they can easily cross cell membranes
What is the meaning of a high volume of concentration?
The drug will have a high concentration in body compartments relative to the bloodstream
What is the meaning of a low volume of concentration?
A drug is restricted to the bloodstream and does not distribute to the compartments well
What drugs will have a VOD close to blood volume?
Drugs that a restricted to the circulation/plasma
What kind of drugs will have a high volume of distribution?
Drugs that distributes throughout the entire body water
Why would a drug have a really large VOD?
Because the drug is highly lipophilic and accumulates in fat tissue
How can drugs that a poorly lipid soluble distribute?
Through extracellular fluid
What would cause a drug to be entirely restricted to the blood circulation or plasma?
Because it is bound to plasma proteins
What is Single compartment distribution?
When a drug is contained within a single compartment
What is drug elimination like in single compartment distribution?
The drug concentration decreases with exponential decay
What occurs after administration in multiple compartment distribution?
The drug distributes into multiple compartments (blood and tissue)
How does elimination work in multiple compartment distribution?
The drug concentration in the blood can be eliminated but the reservoir (other compartments) can prolong the lifetime of the drug in the body
How does the distribution of a drug into compartments affect the rate at which it is eliminated?
Drugs that move into compartments from the bloodstream are eliminated at a lesser rate than those that do not
What is Biotransformation?
Drug metabolism in the liver
What are the key mechanisms leading to elimination?
Metabolism in the liver and excretion (kidney/gut)
What does metabolism in the liver involve?
Phase 1 and Phase 2
What occurs in Phase 1?
Mixed Function Oxidase system (CYP family enzymes) generate oxidative modifications of drugs
What occurs in Phase 2?
Conjugation of parent compound or Phase 1 product with large polar adducts to make the product more prone to excretion
What is the most important CYP?
CYP3A4
What kinds of drugs can be excreted?
Modified and unmodified
How many CYP genes can metabolize a drug?
Multiple
What leads to individual differences in how we respond to drugs?
Genetic variation in CYP enzymes
What can cause Hepatotoxicity?
When sometimes toxic/reactive intermediates are formed by CYP proteins interacting with drugs
Why is it possible to overdose on acetaminophen?
If there is a shortage of phase 2 compounds then a lot of it gets processed into intermediate forms by phase 1 this can cause cell death in the liver
What are the primary routes for excretion after metabolism?
- Bile/Feces
* Urine
How are Biotransformed drugs excreted through urine and feces?
Drugs in the liver are incorporated into bile and secreted into the gut
Why don’t drugs in bile become reablsorbed?
Modifications add large polar adducts and make the drugs more polar and less prone to be reabsorbed in the digestive tract
How do excreted drugs make it to the urine?
The drug passes through glomerular filtration or is actively secreted into the renal tubule
What is overall drug elimination described by?
A half life
How is a higher concentration of a drug affected by elimination?
A higher concentration of a drug has a high rate of elimination
What is Capacity Limited elimination?
When the concentrations of a drug are much higher than the affinity of a key enzyme involved in their elimination
