L4 Pharmacokinetics Flashcards
Pharmacokinetics is described as ADME. What does this acronym stand for?
Absorption
Distribution
Metabolism
Excretion
pharmacokinetics refers to:
the processes occurring within the body that affects how much drug will reach the site of action and impact the pharmacodynamic effects.
1) drug absorbed and travels to target tisue
2) drug is eliminated
What is key about pharmacokinetics and their peak effect?
Drugs in the body do not reach their peak effect instantaneously.
They have a duration of action where they are effective and then are eventually eliminated and the duration of action can be controlled/altered
Understanding what controls absorption and elimination (pharmacokinetics) is extremely important in order to:
Maximize the amount of time that the drug is present in an optimal concentration
- How much drug should be taken
- How often
- How long it will take to perceive the effect of a drug
What three questions are important for pharmacokinetics?
- How much drug should be taken
- How often
- How long will it take for the effect of the drug to be percieved
What is steady state and steady state concentration?
- Steady State:
- Attained after approx 4 half-times
- time to steady state independent of dosage
- ie in a region where, if drug is taken in regular intervals, the drug is maintained within some relative effective range where drug is at optimal range to deliver therapeutic outcome
- Steady-State Concentration
- Proportional to dose/dosage interval
- Proportion to F/CL (Apparent total clearance of the drug from plasma after. oral administration)
What is the most important consideration when considering how to manipulate the absorption of a drug?
Route of administration
What are three factors to consider when talking about routes of administration?
- Convenience
- easier to take medication orally (vs injection/IV etc)
- Bioavailability
- Dif drugs may be absorbed with dif efficiency from the gut
- Depending on route of administration dif drugs may be absorbed with dif efficiency
- Processing
- Hepatic portal circulation is a major consideration
- drugs ingested orally are absorbed in the gut where they enter the Hepatic portal system where they are processed in the liver prior to entering systemic circulation
- This means that some drugs (like pro-drugs) can be processed into an active form OR be broken down before they can elicit their effect
- Hepatic portal circulation is a major consideration
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
i. e. The first pass effect is a phenomenon in which a drug gets metabolized at a specific location in the body that results in a reduced concentration of the active drug upon reaching its site of action or the systemic circulation - strongly influences the bioavailability of many drugs
- eg oral route of administration:
- hepatic portal vein
- processed in liver
- enters circulatory system
*
How do you calculate Extraction Ratio?
Extraction ratio = Clearance (by Liver) / Blood flow
Clearance describes the volume of blood that can be cleared of a compound over time; the more effectively a drug is removed from the blood = higher clearance = higher extraction ratio
Would drugs that are effectively processed by the liver have a high extraction ratio or a low extraction ratio?
High.
Drugs that are effectively processed by the liver have a high extraction ratio while drugs that are not effectively processed have low extraction ratio
Routes of Administration:
Oral:
- Rate of absorption?
- Drug Exposure?
- Rate of absorption?
- typically rate of absorption is slow and affected by intake of food
- Drug Exposure?
- Exposure of drug may be influenced by breakdown in the gut, processing in the liver (variable btwn individuals)
Routes of Administration:
Intravenous:
- Rate of absorption?
- Delivered directly into systemic circulation = rapid onset of action
- High control over circulating level by controlling the rate of infusion or amount injected
- inconvenient
Routes of Administration:
Intramuscular/subcutaneous:
- Rate of absorption?
Routes of Administration:
Intramuscular/subcutaneous:
- Rate of absorption?
- Depends on blood flow to site
- Common to use “depot” preparations (slowly dissolving) for sustained release
Routes of Administration:
Inhalation
- Rate of absorption?
Routes of Administration:
Inhalation
- Rate of absorption?
- through epithelium in the lungs = can be very rapid
Routes of Administration:
Sublingual:
Rate of absorption?
Rapid absorption route, also bypasses ‘first pass’ effects despite taking orally
Routes of Administration:
Transdermal (ointment or patch)
- Rate of absorption?
Convenient, slow absorption and sustained exposure
Define bioavailability
Fraction of unprocessed/unaltered drug that reaches the systemic circulation after administration by a particular route
eg if you administer 100mg to somebody, how much actually reaches systemic circulation
Given the route of administration, give it’s:
- Bioavailability (%)
- Characteristics
Intravenous (IV)
Given the route of administration, give it’s:
- Bioavailability (%)
- 100 (by definition)
- Characteristics
- Most rapid onset
Intravenous (IV)
Given the route of administration, give it’s:
- Bioavailability (%)
- Characteristics
Intramuscular
Given the route of administration, give it’s:
- Bioavailability (%)
- 75-100
- Characteristics
- Large volumes often feasible; may be painful
Intramuscular
Given the route of administration, give it’s:
- Bioavailability (%)
- Characteristics
Subcutaneous
Given the route of administration, give it’s:
- Bioavailability (%)
- 75-100
- Characteristics
- Smaller volumes than IM; may be painful
Subcutaneous
Given the route of administration, give it’s:
- Bioavailability (%)
- Characteristics
Oral (PO)
Given the route of administration, give it’s:
- Bioavailability (%)
- 5- <100
- Characteristics
- most convenient; first pass effect may be important
Oral (PO)
Given the route of administration, give it’s:
- Bioavailability (%)
- Characteristics
Rectal (PR)
Given the route of administration, give it’s:
- Bioavailability (%)
- 30 - <100
- Characteristics
- Less first-pass effect than oral
Rectal (PR)
Given the route of administration, give it’s:
- Bioavailability (%)
- Characteristics
Inhalation
Given the route of administration, give it’s:
- Bioavailability (%)
- 5 - <100
- Characteristics
- Often very rapid onset
Inhalation
Given the route of administration, give it’s:
- Bioavailability (%)
- Characteristics
Transdermal
Given the route of administration, give it’s:
- Bioavailability (%)
- 80 - <100
- Characteristics
- Usually very slow absorption; used for lack of first-pass effect; prolonged duration of action
Transdermal
What does distribution refer to in pharmacokinetics?
How a drug/substance is partitioned into different body ‘compartments’ after it is absorbed
The distribution of a drug can have a big influence on:
(2)
- the effective concentration of a drug in the body
- the lifetime of the drug in the body
What are two key factors of distribution?
- Binding to plasma proteins:
- drugs will circulated in an equilibrium between ‘free’ and ‘bound’
- usually only one ‘free’ fraction is considered to be pharmacologically active
- some drugs are highly bound
- Drug accumulation in tissues
- Accumulation is favoured for drugs that are lipophilic
- more highly perfused tissues can accumulate a drug more readily than tissues with poor perfusion
- Key parameter is Volume of Distribution
Why is the binding of drugs to plasma proteins important?
- drugs will circulate in an equilibrium between ‘free’ and ‘bound’
- usually only one ‘free’ fraction is considered to be pharmacologically active (has pharmacodynamic effect)
- some drugs are highly bound
- longer lifetime but smaller concentration of the drug is able to interact with the desired receptor
Why is drug accumulation in tissues important to distribution?
- Accumulation is favoured for drugs that are lipophilic (easily cross cell membranes)
- more highly perfused (blood flow) tissues can accumulate a drug more readily than tissues with poor perfusion
- Key parameter is Volume of Distribution
How do you calculate the Volume of Distribution?
Volume of distribution = (Total amount of drug in the body) / [drug]*
*drug concentration can mean in blood, plasma, serum, unbound… but should be defined in whatever source you’re reading
What is the “volume of distribution”?
A concept, not a real volume
- provides a relative comparison of how well different drugs are distributed into tissues
- Drugs with a high volume of distribution are well distributed
- Drugs with a low volume of distribution are poorly distributed
How will the VOD of drugs that are restricted to the circulation/plasma compare to blood volume? Why?
Drugs that are restricted to the circulation/plasma will have a VOD close tot he blood volume (eg Heparin VOD ~3.5L/70kg)
Because of high propensity to bind plasma proteins
How can drugs that are poorly lipid soluble be distributed? VOD?
Poorly lipid soluble can distribute through the ECF (VOD ~14L/70kg)
Drugs that distribute throughout the entire body will have a ________ VOD
Drugs that distribute throughout the entire body will have a large VOD (>35L/70kg)
Drugs with a really large VOD (eg _________) is usually because the drug is highly ______ and ________ in ________
Drugs with a really large VOD (eg chloroquine) is usually because the drug is highly lipophilic and accumulates in fat tissue
Distribution affects ________
Distribution affects elimination
What is single compartment distribution?
How does this relate to elimination?
The drug is contained within a single compartment
- If an elimination pathway is present, (B) the drug concentration decreases with exponential decay kinetics (the rate of elimination depends on the concentration of the drug)
- when the concentration is high the slope is steep and as the concentration decreases, the slope smooths (see graph)
What is multiple compartment distribution and how does it affect elimination?
- After administration, the drug distributes into multiple compartments (‘blood’ ‘tissue’)
- If 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
- before drug can be eliminated, must return from the extracellular compartments into the blood
- reduces rate of elimination
- Reservoirs prolong the lifetime of drug in the body
What is biotransformation?
Processes of metabolism in the liver
In general, metabolism in the liver is divided into:
Phase 1
- mixed function oxidase system (CYP family enzymes)
- generate oxidative modifications of drugs (convert methyl to hydroxyl groups (hydroxylation, dehydrogenation etc)
Phase 2
- Conjugation of parent compound, or phase 1 product with large polar adducts to make the product more prone to excretion
- (Phase one and two don’t necessarily happen sequentially)*
What is involved in Phase 1 of Liver metabolism of a drug?
Phase 1
- mixed function oxidase system (CYP family enzymes)
- generate oxidative modifications of drugs (convert methyl to hydroxyl groups (hydroxylation, dehydrogenation etc))
What is involved in phase 2 of liver metabolism?
Phase 2
Conjugation of parent compound, or phase 1 product with large polar adducts to make the product more prone to excretion
- polar adducts make them very difficult to reabsorb
- very hydrophilic
- can’t easily cross cell membranes
- end up stuck in whatever compartment they “end up in” end up being excreted
What is the most important enzyme in elimination of drugs from the body (most frequently involved)?
CYP3A4/5
What are five key points about drug elimination?
- Phase 1 and Phase 2 do not need to occur “in order”
- unmodified drugs can be excreted
- Multiple CYP enzymes can metabolize a drug
- genetic variation in CYP enzymes leads to individual differences in how we respond to drugs
- CYP3A4 is the most widely expressed CYP in liver and (together with glucuronosyltransferase UGT1) metabolize ~75% of therapeutic drugs
- Sometimes toxic/reactive intermediates are formed, which can lead to hepatotoxicity
What are two primary routes of drug excretion?
-
Bile/Feces
-
Biotransformed drugs in the liver are incorporated into bile and secreted into the gut
- modifications (large polar adducts) make these drugs more polar and less prone to be reabsorbed in the digestive tract
-
Biotransformed drugs in the liver are incorporated into bile and secreted into the gut
-
Urine
- Drug passes through the glomerular filtration, or is actively secreted in to the renal tubule and excreted in urine
Drug elimination is typically described by a half-life, what does this mean?
The enzyme and systems mediated drug elimination are not saturated. An exponential decay equation can be used to describe elimination
What does capacity-limited elimination mean?
The enzymes involved in the metabolism of the drug and its elimination are saturated
- The concentrations of the drug reach such a high level that the enzymes are working at their maximal rate to process it = constant rate of elimination vs a rate that depends on [drug]
Capacity-limited saturated rate of elimination
