Module 2A Flashcards
What are frequency distribution curves
- A graphical representation of the number of patients that respond to a drug at different doses during clinical trials
- Follows normal distributions
It is binary and does not describe the magnitude of the response
- Follows normal distributions
What is binary
- Shows whether a measurable response happened or not
- Either yes or no
What is ED50
- The median effective dose
- The dose needed to produce a specific therapeutic response in 50% of patients
- Also referred to as standard or average dose
- This dose does not apply to everyone as some patients will respond to lower or higher doses then average
What is TD50
- Median toxicity dose
- The dose needed to produce a given toxicity in 50% of a group of patients
- Lethal doses observed in preclinical studies (cells and animals as we don’t test the lethal dose in humans)
- We determine this from adverse effects which are reported in clinical trials as toxicities are monitored closely and will happen before death
What is the dose-response relationship
Looks at an individuals response to a drug
Different phases of the dose-response relationship
a) Phase 1: very few target cells have been affected by the drug
b) Phase 2: Shows the linear relationship between amount of drug given and degree of response obtained
- Not all drugs have a linear relationship but most do
c) Phase 3: plateau
- No further response occurs with a higher dose
- This is as all receptors are occupied so you have already obtained 100% of the indication
- Even though there is no further response there still will be adverse effects and more signs of toxicity
What is a dosage regimen
- The goal is to attain and maintain therapeutic concentrations to treat a condition effectively
How do dosage regimens and the therapeutic range relate
- Most conditions need repeated dosing which allows for the drug plasma concentration to stay within the therapeutic range
How do we find out the dosage regimen to allow it to stay within the therapeutic range
- By using the half life (T1/2)
- We reach plateau in about 5-7 T1/2 if we give equal doses
- We need to give another dose before the minimum effective concentration is reached (steady state)
what is the goal with a dosage regimen within the therapeutic range
- A plateau drug plasma level which is steady state (CSS)
What is the therapeutic window
- The range of drug plasma concentration (Cp) which gives the desired clinical response in a patient
What are the three parts of clinical response
-onset
-intensity
-duration
Onset
the time it takes to reach the effective dose
Intensity
how strong the drug is
Duration
time drug lasts in therapeutic window
What is the therapeutic range
- A parameter which describes the dose needed to achieve the therapeutic window of a papulation
- Based on population as we don’t know the therapeutic window for a specific patient
- There are empirical dosing regimens designed to put the drug Css (steady state) in the therapeutic range
What is the therapeutic index
- The ratio of toxic plasma concentration (Cp) to effective Cp values
- Compares the amount of drug which causes the indication to the amount which causes toxicity
- A ratio and has no units
What are the ways to describe the space between effectiveness and toxicity of a drug
-Therapeutic window
- Therapeutic range
-Therapeutic index
Therapeutic Window (TW)
the range of drug plasma concentration when the drug gives the desired effect with no fear of toxicity
Therapeutic range (TR)
the range of dose where most of the population will get the desired effect with no fear of toxicity
Therapeutic index (TI)
tells us how large or small the room we have to “play” with drug dosing
What is the loading dose
- If we cant wait 5-7 half lives for the drug to reach steady state (Css)
A loading dose (LD) is how we attain the desired therapeutic concentration much faster
What is maintenance dose
- It is how we maintain the desired therapeutic concentration (Cther)
- Keep it within the therapeutic window after the loading dose
How to calculate a loading dose
Vd: volume of the body the dose distrubutes into to give Cther
Cther: therapeutic concentration
S: fraction of drug salt form which is the active drug
F: bioavailability of drug
What is Cther
therapeutic concentration (it is only a kinetic thing and only involves where the drug is going within the body)
How to calculate Css
Steady state
Cls: systemic clearance
what is maintenance dose determined by
Maintenance dose is determined by how quickly the body clears the drug
Steady state
what goes in = what comes out
How do we calculate maintenance dose
Css: Steady state concentration
Cls: systemic clearance
S: Fraction of drug salt form which is active drug
F: bioavailability of drug
Determinants of a dosage regimen
a) Activity toxicity
- Therapeutic window
- Side effects
- Toxicity
- Cp vs response
b) Pharmacokinetics:
- Absorption, distribution, metabolism, excretion
c) Clinical factors
- State of patient: age, weight, condition, other disease states
- Management of therapy: multiple drug therapy
- Convenience of regimen
- Compliance
d) Other factors
- Route of administration
- Dosage fomr
- Tolerance- dependence
- Pharmacogenetics
- Drug interactions
- Cost
What is the LADMER system
- Liberation, administration, distribution, metabolism, elimination, response
What is pharmacokinetics
- Drug movement in the body
- Linear PK (pharmacokinetics)= proportional increase in Cp with increased dose
- Non linear PK = disproportional increase of Cp with increased dose (this leads to unpredictable response of a drug
Explain each pharmacokinetic process
a) Absorption: Drug moving from site of administration to systemic circulation
b) Distribution: where it goes in the body
c) Metabolism: changes drug to inactivate and or make it more likely for excretion
d) Excretion: drug leaves the body
Why do we need pharmacokinetics
- It allows us to predict a drugs plasma concertation without starting from scratch
- Can use formulas to predict variables in patients and these variables can be from both the drug and the patient
Explain plasma concentration vs time curve
- Adjustable elements of the dosage range which determine the shape including
Amount of drug, route of administration, dosing interval and formulation
What are factors related to drug effect
- Cmax, Tmax, AUC, Css, TW, T1/2
- Determined by primary PK parameters
What is MTC
- Min toxic concentration
What is MEC
- Min effective concentration
What are the primary PK parameters
- They are determined by physiology
- All constants that don’t change with the dose of the drug (in linear PK conditions)
a) Absorption rate constant (Ka)
b) Oral bioavailability
c) Renal clearance (ClR)
d) Hepatic clearance (ClH)
e) volume of distribution
- All constants that don’t change with the dose of the drug (in linear PK conditions)
Absorption rate constant (Ka)
- Determined by blood flow at absorption site, gastric emptying, GIT motility
Oral bioavailability
- Determined by gastric emptying, acid secretion, enzymatic activity, GIT motility
Hepatic clearance (ClH)
- Determined by hepatic blood flow (Qh), binding in blood (Fu(b)), intrinsic clearance (Clint)
- Liver clearance
Renal Clearance (ClR)
- Determined by renal blood flow (fu(b)), active secretion/ reabsorption, urine pH and flow, glomerular filtration
- Kidney clearance
Volume of distribution (Vd)
- Determined by fu(b), tissue binding, partitioning tissue perfusion, body composition and size,
- Vd is a characteristic of a drug
- Affected by physiology
What are the secondary PK parameter
a) Elimination half life
- T 1/2 = 0.5 0.693 x volume of distribution/ systemic clearance
b) Elimination rate constant
- K = systemic clearance/ volume of distribution
c) Fraction excreted unchanged
- Fe= renal clearance/ systemic clearance
What are the derived Pk parameters
- Area under the curve (IV)
- Steady state concentration
- Area under the curve (oral)
- Average plateau concentration(IV)
- Tmax,/ Cmax
What is pharmacodynamics
- What the drug is doing to the body
- Tells us what happens at the drug receptor and this can be connected to a clinical effect
Relationship between PK and PD
PD couldnt happen without PK and it can happen anywhere in the table but usually during the distribution phase
Do Pharmacokinetics happen at the same or different times
- ADME all happen at the same time after absorption occurs but all separate processes
How does pharmacokinetics connect to the clinical response
- PK assumes there is a relationship btw drug plasma concentration and the drug concentration at the receptor
Explain absorption
- Process by which unchanged drug is released from the dosage form and proceeds from administration site into the systemic circulation
- Most drugs need to absorb to work
What does the rate of absorption tell us about a drugs onset of action
- The faster rate means faster onset
What are the 4 parameters that describe absorption
a) Absorption rate constant (Ka): a primary PK parameter describing the rate of absorption
b) Bioavailability (F): a primary PK parameter which describes the extent of absorption
- The amount of drug available at the site of action
c) Cmax: a descriptive PK parameter for extent of absorption
- The max concentration reached
d) Tmax: a descriptive PK parameter for rate of absorption
- The time when Cmax happens
Absorption rate constant (Ka)
a primary PK parameter describing the rate of absorption
Bioavailability (F)
a primary PK parameter which describes the extent of absorption
- The amount of drug available at the site of action
Cmax:
a descriptive PK parameter for extent of absorption
The max concentration reached
Tmax
a descriptive PK parameter for rate of absorption
- The time when Cmax happens
Does absorption occur when a drug is administered Intravenously
- No because with absorption the site of action to the blood but with IV the drug goes directly into the blood
If I was giving a drug IV and then switched it to an oral tablet would you give the same amount
- No because absorption needs to occur now which would lower the amount which reaches the blood
Explain distribution
- The reversible transfer of drug between systemic circulation and the tissue
- Happens in a constant equilibrium
- Most drugs need to be distributed to the tissues in order to work
What is BioPhase
- The effect site of the drug
What are the 2 parameters that describe distribution
a) Volume of distribution (VD)
- A measure of the extent of distribution
b) Fraction unbound (FU(B))
- A measure of the extent of distribution
What is the volume of distribution
D= amount (Dose) / plasma concentration (C0)
- Tells us how much drug is available in the tissue
- Represents the apparent volume the drug is distributed into the tissues that would give the same concentration as it is in the blood plasma
- Drugs vary widely in the volume of distribution
VD equation
What do distribution properties relate to
- Body composition
- Tissue perfusion
- Binding in both tissue and plasma
What is fraction unbound
- Drugs are promiscuous and can bind to other receptors which can create complexes which now cant act on the target site or be eliminated
- A complex are often to large to cross plasma membranes to become trapped in the blood stream (they also prevent binding to a receptor)
- Expressed as a %
Equation for fraction unbound
What is elimination
- Both metabolism and excretion
- It is the irreversible removal of drug from the body by all drug mechanisms
- Can start right after the drug enters the systemic circulation
What is a metabolite
- Drug + enzyme
What is metabolism
- The irreversible removal of a drug by a chemical conversion to an inactive metabolite
- Biotransformation
What is excretion
- Irreversible removal of intact (parent) drug
How are elimination and dosage regimen connected
- Systemic clearance determines that steady state of a dosage regimen
- Need to know the variables that affect CLs to determine dosage regimen
Css equation
Css: Concentration of drug at steady state
What is systemic clearance
- Liver (CLh) and kidney (CLr) are the main clearance mechanisms
- The sum of all clearance mechanisms
What is and determines hepatic clearance
- Liver clearance
- Determined by
a) Hepatic blood flow (Qh) - Most important
b) Fraction of drug unbound (F(U)B)) - Only the unbound is cleared from the liver
c) Intrinsic clearance (Clint) - The max ability of the drug to be removed from the liver in absence of anything impeding blood flow and no protein binding occurring
- Where metabolism occurs
- Determined by
What is and determines renal clearance (ClR)
- Kidney clearance
- All of the drugs unbound are filtered
- Determined by
a) Glomerular filtration (GFR) - Move drug blood
- Makes filtrate (what becomes the urine)
b) Tubular secretion (TS) - Moves the drug back from filtrate
- Blood and reduces drug serum concentration
c) Tubular reabsorption (TR) - Move drug blood
- Makes filtrate
A)What is half life (T1/2)
- The amount of time it takes for a drugs serum concentration to be decreased by half
- Systemic clearance needs to take half life into account also
how to calculate half life
What determines Half life
- The time it takes to reach steady state concentration (Css)
The dosing interval that allows for the appropriate Css
What is the elimination rate (K)
- The fraction of drug that is eliminated per unit of time
- Describes elimination and takes distribution into account as they occur at the same time
Equation for elimination rate (K)
How do polarized epithelia related to PK
a) All PK processes need drugs to move across polarized epithelia in the functional unit of the organ
- Liver: acinus
- Intestine: villus
- Kidney: nephron
b) Drugs don’t have the ability to squeeze between cells such as in diapedesis and rather they have to cross the cells themselves between tight junctions between the polarized epithelia
- Transporters and enzymes in the polarized epithelia determines what gets across
Different ways to transport across polarized epithelia
i. Transcellular: through the cell
ii. Paracellular: through tight junctions
a) Passive diffusion
b) Endo/ exocytosis
c) Carrier mediated
- Active
- Facilitated diffusion
How do we know how a drug will cross polarized epithelia
- We know what qualities a drug need to undergo passive diffusion (small, non ionized, lipid soluble), passive diffusion is the easiest as it will do it itself
- Transport it dependent on size, ionization, and solubility of the drug
- This is why protein binding effects distribution of drugs
What are transporters
- Move things within the body
- 10% of human genome codes for them
- Also move nutrients and other ions across polarized epithelia
- example is bile salt export pumps: transports bile salts from hepatocytes for bile excretion, (if another drug inhibits BSEP the toxic level of bile salts is possible)
