Week 1 part 2 Flashcards
What is Pharmacokinetics?
The study of the changes in the concentration of a drug during the processes of absorption, distribution, metabolism, and elimination from the body (ADME)
Think what the body does to a drug once administered
What system is essential for delivery of drugs to various tissues?
Vascular system
Once drugs enter into the blood, they can either remain where? 3 things
NAME?
Where can unbound, free floating drugs enter?
Unbound drug enters organs, muscles, fats, and receptors
What 4 characteristics of a drug determine the ability to move to various sites within the body?
NAME?
What are 2 non drug properties that influence uptake?
NAME?
What sized molecules can’t pass through cell membranes?
Molecules with molecular weights greater than 100-200
Smaller molecular sized drugs (agents) cross the lipid barriers and membranes easier
Biologic membranes have small openings or pores
What are the two types of ways molecules can transport across membranes?
-
Passive
Does not require energy
Involves transfer of drug from area of high concentration to area of low concentration -
Active
Requires energy
Faster
Uses carriers that form complexes with drug molecule on the membrane surface
Can involve movement of drug against a concentration gradient i.e. low to high concentration
Many cell membranes have what 2 specialized transport mechanisms?
- Control entry
-
Control exit
Examples include –>
Sugars
Amino acids
Neurotransmitters
Metal ions
What is the terminology for the two directions ions can move in and out of cells?
Efflux
Drive substrates out of cells
Uptake
Transfer substrates into cells
What common transporter requires active energy (active) to be used?
Adenosine triphosphate binding cassette (ABC)
Active pumps requiring energy
Over 300 genes believed to code these transporters
Most act on endogenous substrates
What common transporter allows for passive transport?
Solute carrier transported (SLC)
Control passive movement of solutes down electrochemical gradient
What are most drugs salts of?
Weak acids
Weak bases
Drugs behave like a chemical in a solution when introduced to the human body
As an acid or base, drugs exist in solutions in…?
NAME?
Key points to know about ionized drugs –>
Water soluble (hydrophilic)
Unable to easily penetrate lipid cell membranes
Key points to know about nonionized drugs –>
Lipophilic
Diffuses across cell membranes like blood- brain/gastric/placental barriers
What is the meaning of pKa?
The pKa is the negative log of the equilibrium constant for the dissociation of the acid or base
The pH of a drug where 50% of the drug is ionized and the other 50% is nonionized
What determines the degree of ionization of an agent?
Acids and bases degree of ionization is determined at a particular site by the dissociation constant (pKa) of the agent and its pH gradient across the membrane
What is the relationship between pH, pKa, and Ionization for weak acids and bases?
What is ion trapping?
When an unionized drug crosses a membrane into a more acidic environment (lower pH) –> This unionized drug now becomes ionized because of this lower pH, and now that it is ionized, it can’t cross back through the membrane.
Changes in protein binding have long been theorized to ________________.
Changes in protein binding have long been theorized to influence a drugs clinical effect
What are some diseases in which you would expect lower plasma protein levels?
NAME?
Two or more highly protein-bound drugs can cause __________ _________.
Drug interactions –> Although this is rare
Drugs bound to plasma proteins become trapped within what?
Remain trapped within circulatory system
Drug-protein molecules are too large to diffuse through blood vessel membrane –> Albumin quantitatively most abundant plasma protein
Why are some drugs bound extensively to plasma proteins?
Due to innate affinity for circulating and tissue proteins
Albumin prefers to bind with what types of drugs?
Acidic, but will bind to anything else like basic or neutral drugs as well.
What proteins bind to cyclosporin and corticosteroids?
Lipoproteins bind to cyclosporine
Transcortin binds to corticosteroids
True or False
The more lipophilic a drug is, the greater its affinity for plasma proteins.
True –> Degree of protein binding of a drug is proportional to its lipid solubility
Highly lipid soluble, tends to be highly protein bound
What happens when drugs are bound to proteins?
Protein-bound drugs are not free to act on receptors, and therefore influences how a drug is distributed
High protein binding prevents drug from leaving blood to enter tissue
High protein binding results in high plasma concentrations
Protein binding sites of drugs is __________.
finite –> Adding more drug can overcome protein binding
How can bound drugs to plasma proteins dissociate?
Bond is usually weak and can dissociate as
- Plasma concentrations of drug decline
- A second drug that binds to the same protein is introduced
What is the problem with drugs that are highly protein bound (greater than 90% bound to plasma proteins)?
Conceptualized to have an unexpected intensification of effect if they are displaced from plasma proteins
Examples: warfarin, phenytoin, propranolol, Propofol, fentanyl and analogs, diazepam
No clinically relevant examples of changes in drug disposition or effects can be clearly ascribed to changes in plasma protein binding. The idea that a drug displaced from plasma proteins increases the unbound drug concentration, increases the drug effect, and perhaps produces toxicity seems a simple and obvious mechanism. Unfortunately, this simple theory, which is appropriate for a test tube, does not work in the body, which is an open system capable of eliminating unbound drugs.
What can occur if bound drugs to plasma proteins are rapidly displaced but only occupy less than 90% of these plasma proteins?
Have little change in free active fractions that they are considered not a concern
Only a concern if greater than 90% of the drug is occupied by plasma proteins
No clinically relevant examples of changes in drug disposition or effects can be clearly ascribed to changes in plasma protein binding. The idea that a drug displaced from plasma proteins increases the unbound drug concentration, increases the drug effect, and perhaps produces toxicity seems a simple and obvious mechanism. Unfortunately, this simple theory, which is appropriate for a test tube, does not work in the body, which is an open system capable of eliminating unbound drugs.
Bioavailability of a drug at its effect site is different based on the ____________ _____ _______________.
route of administration –> Each route of administration has advantages and disadvantages
What route of administration is the most rapid and predictable?
Parenteral –> Route of choice for anesthetists
- Intravenous injections allows for rapid and accurate delivery
- Exact method of achieving the desired effect from agents delivered
What is considered enteral route of administration?
Enteral means related to the intestines. The term enteral medication describes medications that are administered into the gastrointestinal tract including orally (PO), rectally (PR), or through a tube such as a nasogastric (NG) tube, nasointestinal (NI) tube, or percutaneous endoscopic gastrostomy (PEG) tube.
What are some good things to remember when administering medications enterally?
They are –>
- Relatively inexpensive
- Lower bioavailability
- Slow absorption
- Presystemic elimination
- Elimination of drug by GI system before drug reaches systemic circulation via –>
Stomach acids
Enzymes in GI wall
Liver biotransformation
- First-pass hepatic effect –> Hepatic extraction and metabolism of drug
What is the bioavailability of intravenous drugs?
1
What is the bioavailability of inhalation agents?
5-100%
What are some drugs that undergo substantial first pass elimination?
What medications are administered via inhalation?
Bronchodilators and antibiotics are administered via devices to move aerosols into the alveolar sacs
Volatile Anesthetics administered through lungs
Large surface area
What route of administration is generally chosen for sustained release agents?
Transdermal (topical) administration –>
Usually water soluble and lipid soluble
Water soluble to penetrate hair follicles and sweat ducts
Lipid soluble to traverse the skin (penetrate the skin) and exert effect at receptors
What is Bioavailability?
Extent to which a drug reaches its effect site after introduced to the body
Rate of systemic absorption establishes a drugs duration of action and intensity
What are some factors that influence bioavailability?
Factors that influence bioavailability
- Lipid solubility
- Solubility in aqueous and organic solvents
- Molecular weight
- pH
- pKa
- Blood flow
What are some environmental factors that influence bioavailability?
Environmental factors that influence bioavailability
- Age
- Sex pathology
- pH
- Blood flow
- Temperature
What routes of administration do we observe first pass metabolism or presystemic metabolism?
May occur when drug administered orally or rectally
Metabolism occurs in the intestinal wall or liver prior to drug entering systemic circulation
- Venous draining from most portions of GI tract enter portal circulation
What are the four enzyme systems associated with first pass effect?
NAME?
What is it called when a drug is administered in an inactive form, and needs to be activated after administration by the body in order to function correctly?
Prodrugs converted to active form in liver
- Common prodrugs include dolasteron, amlodipine, levodopa, and quinapril
What are compartment models good for determining?
Depict the body as composed of distinct sections that represent theoretic spaces with calculated volumes
Useful for predicting serum concentrations and changes in drug concentrations in other tissues
What is the single compartment model good for explaining?
Single-compartment model represents the entire body
Single-compartment model is sufficient to describe the action of many drugs
DOES NOT generally explain the kinetics of lipid-soluble anesthetic drugs
When is the two compartment model used for explaining drugs effects?
Two-compartment model is typically used to simplify and explain pharmacokinetic concepts that can be extrapolated to more complex models
Conceptual representations of two separate volumes in which a quantitative change in drug concentration occurs
What are the two compartments of the two compartment model theory?
Two-compartment model
- Central compartment
10% of body mass in adults
Receives approx. 75% of cardiac output
Called vessel-rich group
Intravascular fluid and the highly perfused tissues such as heart, lungs, brain, liver, and kidneys
- Peripheral compartment
90% of body mass in adults
Receives approx. 25% of cardiac output
Vessel-poor group
Muscle, fat, and bone
What compartment theory states that each compartments has a different rate at which a drug is distributed to them?
Two-compartment model
What compartment theory states that there are not true anatomic areas?
Two-compartment model
According to the two compartment model, how do drugs leave the central compartment so they can enter the peripheral compartment?
Drug leaves central compartment by distribution into tissues via metabolism and excretion
What is alpha half life?
Two compartment model
- After intravenous bolus, high blood flow organs have largest amount of drug
- Highly perfused tissues equilibrate
- As blood flows through less perfused organs, drug deposits in vessel-poor group
- Concentration rises slowly, not as high as vessel-rich group
- Serum concentration drops due to distribution, this fall in plasma concentration is described as alpha half-life
Once the body equilibrates and the drug begins to leave the central compartment and enter the peripheral compartment –> When plasma concentration drops below tissue concentration, drug moves from highly perfused tissue and enters plasma serum allowing for redistribution (moves back to central)
What compartment must the drug be in for clearance from the body to take place?
Drug enters central compartment for clearance from body
What is the volume of distribution? What is the formula?
Volume of distribution = Vd
Proportional expression that relates the amount of drug in the body to the serum concentration
Calculated by dividing the dose of the drug administered intravenously by the plasma concentration before elimination occurs
Volume of distribution= Dose of drug/Plasma concentration of drug
What is considered a large volume of distribution? What does this mean?
A large Vd (>0.6L/kg) implies that drug is widely distributed and likely lipid soluble
What is considered a small volume of distribution? What does this mean?
A small Vd (<0.4L/kg) implies drug is largely contained in the plasma and likely water soluble
What are some factors that influence volume of distribution?
Factors that may alter expected distribution volumes
Size, carrier molecules, disease states, fluid shifts
Vd with a infusion differs than bolus injection, compartments eventually are in equilibrium
Affinity of a drug is intimately related to what?
Affinity of a drug for a specific macromolecular component of the cell and its intrinsic activity are intimately related to its chemical structure
Rigid relationship
- Minor alterations may result in major changes
Manipulation of structure-activity relationships frequently lead to synthesis of therapeutic agents quite different in therapeutic effects and side effects
What is Stereochemistry?
A carbon containing compound usually exists as stereoisomers –> Molecules with the same chemical bonds but different configurations in their fixed spatial arrangements. A specific configuration is achieved either by the presence of double bonds, where there is no freedom of rotation, or by chiral centers, around which varying groups are arranged in a specific sequence.
What are chiral centers?
Chiral centers are therefore formed by a carbon atom with four different asymmetric substituents. A molecule with one chiral carbon can have two stereoisomers; however, as the number of carbons in a molecule increases, so does the number of its potential stereoisomers.
What are enantiomers?
Two compounds that are enantiomers of each other have the same physical properties, except for the direction in which they rotate polarized light
Ex –>
- D(−) ephedrine, with a relative potency of 36, is used to a large extent as an anti-asthmatic and, by an anesthesia professional, as a pressor amine to restore low blood pressure in the operating arena.
- L(+) pseudoephedrine, with a relative potency of 7, is used primarily as a nasal decongestant. These drugs therefore have varying activities and potencies, rendering them ideal for varying situations.
What does a plasma concentration curve show?
Depiction of declining plasma concentration of a drug over time after intravenous injection into the central compartment.
What is the difference between the alpha and beta phase on the plasma concentration curve?
Highly lipid soluble drugs have a steep slope in the ⺠phase, showing rapid fall in plasma level
- Demonstrates ability of drugs to cross membrane lipid bilayers and distribute to peripheral compartment rapidly
Î’eta phase is slower, shows a exponential drop in concentration due to elimination
- The elimination phase of the plot aids in determining elimination half-life of drugs
What is the steady state of a drug?
Theoretically occurs when stable plasma concentration of drug is achieved
All body compartments have had ample opportunity to equilibrate with drug
Drug amount being eliminated is equal to the amount being added to the system
Can concentrations of a drug vary from organ to organ if steady state has been achieved?
YES –> Concentrations may vary from organ to organ (this is normal), but are not changing
What is another name for drug biotransformation?
Metabolism
What is the main organ responsible for metabolism? How does this occur?
Main organ is liver
- Other metabolism pathways include –> plasma, lungs, GI tract, kidneys, heart, brain, and skin
Enzyme-catalyzed change in chemical structure of agent
Involves multiple pathways
What is the goal of metabolism?
Goal of metabolism is to alter lipid-soluble agents into more water-soluble forms
- This allows the kidneys to eliminate agent from body
- Metabolism usually leads to transformation of active drug into inactive metabolites
What are some consequences of metabolism?
Consequences can occur
- Could metabolize into an active drug with same or new activity
- Converted from inactive prodrug to active form
What is first order kinetics? What drugs follow this process?
Drug is cleared at a rate proportional to the amount of drug present in the plasma –> Fraction of total drug is metabolized in a set time period. Most drug eliminated per time unit occurs with highest concentrations
Most drugs administered in therapeutic doses follow first-order kinetics
What is zero order kinetics?
Drugs like alcohol follow zero-order kinetics
At therapeutic levels, they exceed body’s ability to excrete or metabolize them
Enzyme system for elimination is saturated
A constant amount of drug is cleared regardless of the plasma concentration, different from the percentage cleared with first-order kinetics
Amount of agent cleared per unit of time is the same amount, independent of plasma concentration
*Picture is of first order kinetics but the one on the right (log first order kinetics graph) is what zero order looks like if the y axis wasn’t written as a log scale.
What are the phases of metabolism?
Phase I
- Oxidative, reduction and hydrolysis reactions
- Generally results in increased polarity of molecule, transforms lipid-soluble compound to water-soluble
- Oxidative and reduction catalyzed by cytochrome P-450 system enzymes
Phase II
- Conjugation reactions
- Drug or metabolite is conjugated with an endogenous substrate
- Synthesizes new compound by donating a functional group from an endogenous acid
- New compound is the conjugate of the drug or drug product of phase I reaction
What are the results of a drug molecule after undergoing phase I metabolism?
Result of phase I reaction is a more polar compound easily excreted by kidneys
- Phase I reactions, through placement of hydroxy or carboxy groups on drug, enable phase II reactions to occur
- NEEDS functional group to progress to phase II metabolism.
True of False?
Many times drugs can completely bypass the first stage of metabolism and proceed with stage II?
True –>
Many drugs already possess an appropriate functional group for conjugation and do note need to be modified by a prior phase I reaction to be conjugated
What is enzyme induction?
Increased enzyme activity created by enzymatic stimulation over a period of time
Alcohol is an example
- When ingested chronically it induces enzymatic activity
- System therefore can break down more agent that uses the same enzymatic system for biotransformation
- Leads to reduced half-lives
When more enzymes are created in order to eliminate increasing amounts of a drug
What is enzyme inhibition?
Usually occurs through exposure to certain drugs and chemicals
- Leads to accumulation of substrate agent
- Causes elevated plasma levels and potentially greater activity and toxicity
Enzymes are inhibited, therefore drugs can’t be metabolized leading to high levels in the plasma
What does it mean when someone refers to a drugs half life?
Time necessary for the plasma content of a drug to drop to half of its prevailing concentration after a rapid bolus injection
The amount of drug remaining in the body is related to the number of ____________ that have passed.
half-lives
At what percentage is a drug determined to be fully eliminated? How many half lives?
Drug is regarded as fully eliminated when approximately 95% has been eliminated
Usually occurs in 4-5 half-lives
What will happen if a drug is given in intervals shorter than its elimination?
Drug accumulation can occur –> Can lead to overdose and potential adverse effects
- This is why knowing a drugs half life is important when dosing at intervals.
How is context sensitive half time different from half life?
Time to halving of the blood concentration after termination of drug administration by an infusion designed to maintain a constant concentration
- Accounts for continuous infusions or repeated dosing-induced changes in drug behavior
Key difference is that half time refers to a bolus dose while context sensitive half time refers to continuous infusions or repeated doses.
What is a flaw in context sensitive half time?
A flaw includes that it describes only the time to a 50% decrease in central compartment concentration
- This may not be the decrement in drug level required to achieve recovery
- More widespread application is necessary before determining usefulness
What is relative decrement times?
Within context sensitive half time –> Time needed for 80-90% decreases in inhalation anesthetic concentration
- Major differences in elimination rates for desflurane, sevoflurane, and isoflurane occur in the last 20% of the elimination process
What is drug clearance?
The volume of plasma completely cleared of drug by metabolism and excretion per unit of time
- Governed by properties of the drug and the body’s ability to eliminate it
What is drug clearance directly proportional to?
Directly proportional to the dose
- Increased dose = increased clearance
What is drug clearance inversely proportional to?
Inversely related to the agent’s half-life and concentration in central compartment
- Increased half life = decreased clearance
- Increased concentration in central compartment = decreased clearance
What are the two main organs that perform clearance?
Two main organs for clearance
- Hepatic
- Renal
What determines clearance rate? What is the formula?
Determined by blood flow (Q) to organs, as well as ability to extract drug from bloodstream, extraction ratio (E)
Formula –>
Clearance= QxE
What are the two types of hepatic clearance?
Typically perfusion-dependent elimination or capacity-dependent elimination
What is perfusion dependent hepatic clearance? What is the extraction ratio?
Perfusion dependent –> Hepatic blood flow for these agents far outweighs enzymatic activity in clearing them from the body, so a decrease in hepatic blood flow decreases the rate of clearance, and a high perfusion state leads to faster clearance. This is termed perfusion-dependent elimination.
Extraction ratio greater than 0.7
What is capacity dependent perfusion? What is the extraction ratio?
Capacity dependent –> Hepatic enzymes and the degree of protein binding. When a low extraction rate exists only a small fraction of the agent is removed per unit of time, and changes in hepatic perfusion do not have significant effect on hepatic clearance. Clearance of these drugs depends on hepatic enzymes and the degree of protein binding. Therefore alterations such as enzyme induction or suppression cause a change in the elimination of these drugs from the body.
Enzyme induction = increase in clearance
Enzyme inhibition = decrease in clearance
Decrease in protein binding = increase in clearance
Increase in protein binding = decrease in clearance
Extraction ration less than 0.3 or less rely on capacity-dependent elimination
What type of drug molecules do the kidneys excrete?
Water-soluble molecules
Amount of drug available to the renal tubule for elimination is dependent on what 2 things?
NAME?
True or False
Lipid soluble drugs are easily excreted by the kindeys?
False –> Do not efficiently excrete lipid-soluble agents
- Lipid-soluble molecules are reabsorbed from the renal tubules back into the systemic circulation
How do pharmacokinetics change in the elderly?
Elderly
- Decreased renal function
- Liver blood flow decreases
- Increase in fat compartment, leading to an increased volume of distribution –> Accumulation of lipid-soluble agents
How do pharmacokinetics change in Neonates?
Neonates
- Poor renal function in first year of life
- Lack ability to metabolize certain agents due to immature liver enzyme system
How do pharmacokinetics change between genders? What are some examples?
- Female patients have 20-30% greater sensitivity to commonly used muscle relaxants
- Male patients more sensitive to Propofol, and may require reduction in dose by as much as 30%
- Female patients emerge faster than male patient
- Females three times as likely to experience recall under general anesthesia
- Females more sensitive to some opioid effects
- Gender differences noted to be more pronounced in premenopausal woman –> This suggests hormonal mechanisms may be a major contributing factor
How do pharmacokinetics change in a hypothermic patient?
Hypothermia
- Metabolism and clearance delayed for almost all drugs
How do pharmacokinetics change in a hyperthermic patient?
Fever/hyperthermia
- Metabolism and clearance increased
How do pharmacokinetics change in certain disease states?
Chronic kidney disease
- CKD is known to impair clearance and elimination of drugs and their metabolites. Uremic toxins, inflammatory cytokines, and parathyroid hormone, which are common in CKD, may be implicated. Altered plasma protein binding of drugs and the activity of several drug-metabolizing enzymes and drug transporters have also been shown to be impaired in chronic renal failure
Hepatic disease
- In cirrhosis, all pharmacokinetic phases may be affected, including absorption, distribution, metabolism, and elimination of the drug. Some changes include high portosystemic pressure, which impedes GI absorption. Less first-Â pass effect in the diseased liver leads to a higher bioavailability of highly extracted drugs administered orally. The Vd for highly protein-Â bound drugs may be changed secondary to the lowered production of albumin and other plasma proteins. Water-soluble drugs may also exhibit an altered Vd due to volume overload and ascites in patients with cirrhosis. Drug metabolism and elimination are reduced due to impairment of drug-metabolizing enzymes. Phase I mechanisms are affected to a greater extent than phase II processes.
Spinal cord injury
- An increase in the volume distribution of ketamine disproportional to increases in clearance in spinal cord injury in patients in the intensive care unit, leading to a longer than expected half-life for the drug, again placing the patients at risk for overdose.
What is Pharmacogenetics?
Study of variations in human genes that influence various responses to drug therapy
What is Pharmacogenomics?
Involves the identification of drug response markers at the level of disease drug metabolism, or drug targets
