Lecture 4- Intro to Pharmacokinetics Flashcards
What happens after you administer a drug?
- The drug needs to be absorbed and travel in the body to reach its target tissue
- Overtime the effects of the drug wears off because the drug is eliminated from the body
What is a theraputic window?
a concentration range where the drug will have it’s desired effects
What are the 3 important considerations in terms of routes of administration?
- Convenience (route of adminstration)
- Bioavailability (different drugs may be absorbed with different efficiency from the gut)
- Processing in the hepatic portal circulation (drugs absorbed from the gut first encounter the liver before entering systemic circulation for significant breakdown)
The higher the bioavailability, the ____ the steady state concentration
higher
The higher the clearane, the ____ the steady state concentration
lower
What is first pass metabolism?
- Refers to the amount of a drug that is processed or eliminated during its first pass through the liver before being distributed to the circulatory system
- The liver strongly influences the bioavailabilty of many drugs
What is the extraction ratio?
clearance (liver)/blood flow
- The more that’s cleared from the blood going through the liver, the ____ the extraction ratio
- The more weakly a drug is cleared from the blood going through the liver, the ____ the extraction ratio
higher; lower
Are statins (prodrugs) high or low extraction ratio drugs?
high extraction
What is the rate of absorption for oral administration of a drug?
- it is slow and affected by intake of food and pH
- most common
What is the rate of absorption for intravenous administration of a drug?
- very rapid onset action as it is directly delivered into systemic circulation
- high control over circulating level by controlling the amount injected and the rate of infusion
What is the rate of absorption for intramuscular/subcutaneous adminstration of a drug?
- depends on the blood flow to site as it is injected into muscle or jsut below the skin
What is the rate of absorption for inhalation admistration of a drug?
- absorption is through the epithelium in the lungs and is rapid
What is the rate of absorption in sublingual admistration of a drug?
- rapid absorption
- also bypasses the “first pass” metabolism effect
What is the rate of absorption for a transdermal adminstration of a drug?
- ointment or patch
- slow absorption and is sustained exposure
What does bioavailability mean?
- it is a fraction of unprocessed/unalterted drug that reaches the systemic circulation after administration by a particular route.
Which 2 methods of drug administration fluctuate the most when it comes to bioavailability?
inhaled and oral
What are the 2 key factors in influencing the effective concentration and the lifetime of a drug in the body?
Binding to plasma proteins
* drugs will circulate in an equilibrium between “free” and bound
* usually only the free fraction is considered to be pharmacologically active
Drug accumulation in tissues
* accumulation is favored for drugs that are lipophillic (these drugs can accumulate in fat and have a long lifetime in fat)
* more highly perfused tissues can accumulate a drug more readily than tissues with poor perfusion
What is volume of distribution?
- is the total amount of drug in your body divided by the concentration of the drug in your plasma.
Does this refer to large or small distribution of volume?
* some drugs find their way to all parts of your body, so you will have a lot of the drug in your body but just a small amount in your blood
large volume distribution
Des this refer to large or small volume of distribution?
* Some drugs don’t escape your bloodstream, so the amount of drug in your body is proportional to the amount of the drug that’s in your bloodstream
smaller volume of distribution
How will the VOD of drugs that are restricted to the circulation/plasma compare to blood volume?
- drugs that are restrictred to the circulation/plasma (often because of high propensity to bind plasma proteins) will have a VOD close to the blood/plasma volume (i.e., heparin)
How can drugs that are poorly lipid soluble be distributed?
they can be distributed through the extracellular fluid; high VOD
Drugs that distribute throughout the entire body water will have a ____ VOD (i.e., ehtal and phenytoin)
large
Drugs with a large VOD (ie, ____) is usually because the drug is highly ____ and accumulates in fat tissue.
chloroquine (common anti-malarial drug); lipophillic
What is single compartent distribution?
- if an elimination pathway is present (B), the drug concentration decreases with exponential decay kinetics (the rate of elimination depends on the concentration of drug)
What is single compartent distribution?
- if an elimination pathway is present (B), the drug concentration decreases with exponential decay kinetics (the rate of elimination depends on the concentration of drug)
What is multiple compartment distribution?
- after adminstration, the drug distributes into multiple compartments (such as blood and tissue)
- if an elimination pathway is present (D), the drug concentration in the blood determines the rate of elimination but the reservoir of drug in the tissues can prolong the lifetime of the drug in the body
What is biotransformation?
mechanisms for metabolism in the liver
How many phases does metabolism in the liver involve?
2
What is phase 1 of the metabolism in the liver?
- mixed function oxidase system (CYP enzymes) which generates oxidative modification of drugs through hydroxylation, dehydrogenation, etc
What is phase 2 of the metabolism in the liver?
conjugation of parent compound or phase 1 product with large polar adducts to make the product more prone to excretion
What is CYP and which 2 enzymes metabolize most drugs?
- CYP is cytochrome P.450 oxidase enzyme
- 2 most common ones are CYP3A4 and CYP2D6
Phase 1 and phase 2 ____ need to occur in order/sequence
do not
Where does phase 1 and phase 2 happen in the body?
liver
Can multiple CYP enzyme metabolize a drug, often more than one pathway?
yes
____ variation in CYP enzymes leads to individual differences in how we respond to drugs
genetic
____ is the most widely expressed CYP in liver and metabolize ~75% of theraputic drugs
CYP3A4
The formation of toxic/reactive intermediates is known as ____
hepatotoxicity.
What are the 2 main routes of drug excretion?
- Bile/feces
- urine
How are drugs excreted through bile/feces?
- biotransformed drugs in the liver are incorporated into bile and secreted into the gut.
- modifications which are large polar adducts,make the drugs more polar and less prone to accumulate in tissue or reabsorbed in the digestive tract.
How are drugs excreted through urine?
- drug passes from the blood through glomerular filtration or is actively secreted into the renal tubule and excreted in urine
Drug elimination is typically described by a half-life, what does this mean?
It means that the enzymes and systems mediating drug elimination are not saturated and an exponential decay equation can be used to describe elimination.
What is the following description known as?
* elimination is capacity limited meaning that enzymes involved in elimination are saturated and rate-limiting. This is because ethanol concentrations are much higher than the affinity of a key enzyme involved in their elimination
Capacity-limited elimination
