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Exam 1 Flashcards

1
Q

Pharmacokinetics

A

Relationship between drug input and how the concentration of the drug changes with time at an active site: How the body handles the drug

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2
Q

Pharmacodynamics

A

Relationship between concentration at an active site and effects with time: how the drug affects the body

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3
Q

Systemic absorption

A

The process by which unchanged drug proceeds from the site of administration to the site of measurement within the body (often an arm vein)

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4
Q

Distribution

A

Process of reversible transfer of drug to an from the site of measurement and the peripheral tissues

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5
Q

Disposition

A

Once absorbed systemically, it is delivered by blood to all tissues including organ of elimination.

Everything that happens to the drug after it’s in the body
-Sum of all ADME actions

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6
Q

ADME

A

Absorption
Distribution
Metabolism
Excretion

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7
Q

The therapeutic window

A

-The body optimal exposure to the drug of choice
-Exposure must be high enough to elicit the desired response but must not be so high that it’s toxic
-A compromise is usually achieved between the desired effects determined by the disease stage possible adverse effects

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8
Q

Importance of PK and PD

A

-PK and PD are extensively used in the pharmaceutical industry in the rational development and marketing of a drug
-PK and PD data collected during the three phrases of a clinical trial are sued to establish safe and efficient dosage regiments

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9
Q

Pharmacokinetics pathway

A

drug release and dissolution (absorption) –> Unbound drug (Systemic circulation) –> Drug in organs/tissues, Drug in site of action (Distribution) –> Metabolism and/or excretion (Elimination)

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10
Q

Pharmacokinetic Parameters

A

Clearance
Volume of distribution
Half Life
ETC.

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11
Q

Significance of PK Parameters

A

Predict dose-concentration relationship and concentration time profiles

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12
Q

Clearance

A

The theoretical volume of blood completely cleared of drug per unit of time (mL/min, L/hr)
Clearance = Blood flow to organ x Extraction ratio

*Max clearance by an organ can be NO FASTER than the flow rate of blood to that organ
*Clearance is additive

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13
Q

Factors that alter clearance

A

Body size

Drug interactions
-Inhibition or induction of drug metabolizing enzymes

Altered organ performance
-Mainly kidney and liver
-Heart

Hypermetabolic states
-Pregnancy, Burns, Cystic fibrosis

Genetics

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14
Q

volume of distribution

A

Hypothetical volume (not physical) that drug distributes in the body
-Vd is a proportionality factor that relates the measured plasm concentration to the amount of drug in the body

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15
Q

CP(0)

A

Concentration immediately after injection

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16
Q

Factors that alter Vd

A

Body composition
Edema
Plasma and tissue protein binding
Some cases in kidney failure

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17
Q

Elimination Rate constant

A

First order pharmacokinetics
-Approximately the fraction of the total amount of drug removed per unit of time (0.25 /hr ~ 25% of drug eliminated per hour)
-Does not change with drug concentration (you won’t eliminate more drug if you infuse a higher conc)

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18
Q

Bolus

A

All of the drug is administered at once

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19
Q

Infusion

A

The drug is administered in doses over time until it reaches steady state

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20
Q

Secondary Parameters

A

Kel and T1/2 are derived from primary parameters (CL and Vd)

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21
Q

graphing PK data

A

We will primary use the linear plot which is Ln(Cp) vs time because of the straight slope (1 compartment model)
-How does the concentration of the drug change over time
*drug concentrations often decline exponentially

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22
Q

compartmental analysis

A

The body parts are lumped into one or more homogenous compartments that are kinetically connected
-Rate of drug distribution tissues/organs is determined
-Nonlinear regression analysis

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23
Q

Noncompartmental analysis

A

-Model independent
-Establishing the degree of drug exposure (AUC) and associated PK parameters (Cmax, Tmax, CL, Vd)
-Does not characterize the rate of drug distribution

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24
Q

One vs multiple compartments

A

1 compartment is a linear regression
2 compartment and 3 compartment is exponential

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25
Non compartmental analysis
Determine the degree of exposure and derive PK parameters -No assumption about the number of compartments SHAM analysis: Slope (k) Height (Cmax) Area (Area under the curve) Moment *Tmax = time of maximum concentration
26
Pharmacists using PK in the clinical setting
-Dose adjustment based on changes in PK parameters due to patient specific conditions (Kidney/liver impairment, Age, Others) -Food effects and drug-drug interactions
27
Therapeutic Drug monitoring
Measuring drug concentration in blood to determine dosage regiment adjustment Useful when: -Drugs w narrow therapeutic windows -Patients w large Pk variability -Confirm medication adherence Criteria: -Drugs with good concentration effect relationship -No unmeasured active metabolites -Difficult in interpreting therapeutic/toxic effects based on physical exams
28
Single plasma membrane transport vs multicellular
Single = movement across the plasma membrane of a single cell Multicellular = across a series of membranes of many cells
29
Membranes Proteins and Changes in Membrane structure
Biological membranes are dynamic structures in which both proteins and lipids can move rapidly D = 10^-7/-8 cm^2/s
30
Drug transport
Movement of drugs through cell membranes *Physiologic, Physicochemical, and anatomic factors affect the rate of drug transport and determine the PK and PD of drugs
31
Transcellular
Transport that occurs through cell membranes
32
Paracellular
Transport that occurs between cells
33
Intravascular dosing
A drug is placed directly in the blood -Common methods are intra-venous or intra-arterial Steps follow IV or IA: 1. Distribution step from blood to tissue - cross capillary membrane 2. Hepatic Elimination (metabolism) step (requires transfer of drug from blood to the intracellular compartment of hepatocytes) 3. Renal Elimination (excretion) step from blood to urine - cross the glomerulus of the nephron in the kidney DME *No absorption since you are administering right to the blood
34
Extravascular dosing
Systemic routes: oral, sublingual, buccal, intramuscular, subcutaneous, dermal, pulmonary and rectal Regional routes: ventricular and parenchymal delivery to the brain, abdomen or pleural delivery ADME
35
passive diffusion
Movement of molecules from high to low concentration -Spreading of energy throughout a volume leads to an increase in entropy which is a spontaneous process
36
GI epithelium membrane barriers
Small intestine --> Folds of Kerckring, Microvilli, villi
37
Drug properties affecting drug transport across a membrane barrier
1. Molecular size 2. Lipophilicity 3. Degree of protein binding 4. Charge (degree of ionization)
38
Fick's first law
Penetration and absorption across a membrane = net rate of drug diffusion
39
Stokes Einstein eq
Calculates the diffusion coefficient
40
Qualitative prediction of absorption for drugs undergoing transcellular passive diffusion
-As the membrane surface increases, the rate of absorption increases -As the functional membrane height increases, the rate of absorption decreases -As the lipid-water partition coefficient increases, the rate of absorption increases -As molecular size increases the rate of absorption decreases -As the Cside1 increases, the rate of absorption increases -As viscosity increases, the rate of absorption decreases
41
general protein binding considerations
-only unbound, nonpolar drugs are able to cross lipid membranes because the protein bound form is too large -Unbound concentration provides the driving force for drug transport -At distribution eq, unbound concentration will be equal on both sides of the membrane
42
pH partition hypothesis
-Only un-ionized nonpolar drugs are able to cross membranes -Applies to events at equilibrium, when the unionized drug concentration is equal on both sides of the of the membrane (used to predict the influence of pH on the rates of absorption and distribution)
43
Mechanisms of drug transport
1. passive transport (for high to low) 2. Passive facilitated diffusion --> movement across the membrane is facilitated by a transporter but doesn't require ATP (One direction only) 3. Active transportation --> movement across the membrane is facilitated by a transporter but requires ATP (Drugs can move in or out of cell)
44
Glycoprotein and membrane transport
MDR1 was found to efflux many drugs that entered cancer cells -A specific glycoprotein (P-glycoprotein) was responsible -It's located in many organs and tissues and plays a major role in the hepatic secretion of drugs
45
P-Glycoprotein
Hydrophonic vaccum cleaner, which pulls substances from the lipid bilayer, expelling them to promote multi-drug resistant
46
P-gp and BCRP
-Important efflux transporters -Located: Intestine, Liver, Kidney, Blood brain barrier -P-gp is polyspecific: it can transport many different chemical substrates -Transporter expression can be altered in various diseases
47
Distribution-Part 1
1. Understand the important factors governing distribution to and from blood and other tissues of the body 2. Rate of distribution
48
Perfusion rate limited distribution
Be able to calculate and use the tissue distribution rate constant (kt) or distribution half-life to make determinations about how quickly different drug reach equilibrium in different tissues of the body 1. Perfusion rate of tissue 2. Affinity of tissue for drug (Kp) --> takes longer to load tissue Membrane offers no resistance; movement of drug into tissue is limited by blood flow
49
Permeability limited distribution
Factors governing net penetration rate across cell membranes and be able to apply them to assess permeability differences among different drugs 1. Lipophilicity 2. Fraction unionized at target pH 3. Fraction unbound in plasma 4. Drug size/radius 5. Affinity of tissue for drug --> takes longer to load tissue Membrane resistance is significant; movement of drug into tissue is slow and insensitive to changes in blood flow
50
Distribution of drugs through the vasculature
Drugs distribute rapidly in the blood through networks of fine capillaries, diffusing either through (transcellular lipophilic pathway) or between (paracellular) capillary endothelial cells to tissue spaces (extravasation) filled with interstitial fluid
51
Factors determining drug distribution
1. Delivery to tissues by blood (perfusion rate) 2. Capillary permeability (transcellular/paracellular) *smaller capillary width leads to better diffusion 3. Binding in blood 4. Binding in tissues 5. Partitioning into fat
52
Perfusion
Delivery of drug to tissue by blood flow
53
Permeability
Ability of drug to pass through membranes
54
Is distribution a reversible process?
Yes it is Rate (expressed in terms of Kt or T1/2) Extent (typically expressed in terms of an apparent volume of distribution)
55
first order
[A]f = [A]0e^-kt
56
Rate of presentation
The product of blood flow (Q) and the arterial blood concentration (Ca)
57
Rate of leaving
The product of blood flow (Q) and the venous blood concentration (Cv)
58
Net rate of extravasation
Q (Ca - Cv)
59
Distribution rate constant
A measure of how quickly the drug would leave the tissue if the arterial concentration would drop to zero *Analogous to the elimination rate constant
60
Distribution half life
How long it takes half the drug to distribute through the tissue
61
Distribution take-home lesson
A drug leaves slowly from tissue for which it has a high affinity and that is poorly perfused
62
Why can a drug have greater entry into the membrane despite being less unionized?
The presence of specific transporters can allows for the more ionized drug to cross the membrane faster
63
Apparent volume of distribution
In order to get the desired plasma concentration of the drug how much volume of fluid do you need to distribute the initial concentration of drug *varies widely for different drugs *rarely corresponds to a real physiological volume due to plasma and tissue binding effects
64
Plasma vs Serum
Plasma = Proteins Serum = No proteins
65
Factors that Volume of distribution depends on
1. Drug can be bound in blood by plasma proteins (glyco or lipoproteins) or blood cells 2. Drug can be bound in tissues by a variety of tissue components
66
Unbound fraction of drug in plasma
Main concern with plasma protein binding is related to the variability within and among patients Unbound concentration is more important in defining efficacy of therapeutics. The unbound fraction also varies greatly for different drugs -Drugs with fu<0.1 are highly bound -Drugs with fu>0.9 are weakly bound
67
Plasma protein binding
-Depends on affinity of the protein for the drug -The unoccupied protein concentration depends on the the total protein concentration -The protein binding site is not saturated at drug therapeutic concentrations
68
Tissue distribution
We assume: 1. Only unbound drug can enter or leave the plasma and tissue 2. Unbound concentration in plasma and tissue are equal -The magnitude of V critically depends on binding of drug to plasma proteins and tissue components
69
If both plasma and tissue binding are relevant
39L --> Lipophilic 14L --> Hydrophilic Assuming a Value for Vtw that distributes into (either of the two categories above) allows us to estimate FUt
70
Kinetics of IV Bolus Dose
An IV bolus dose is a rapid IV injection of a therapeutic dose of a drug Pros: -Elevated concentration of drug in blood can be quickly achieved -Immediate bioavailability Cons: -Rapid onset but need ot dose frequently if the 1/2 life is short -An IV bolus dose can often be given only in an inpatient setting
71
Kinetic difference between an IV bolus dose and other drug formulations
An oral dose has a slower onset than that of an IV bolus dose -Bioavailability can be reduced -It can easily be given in an outpatient setting An IV continuous infusion has a lower onset than that of an IV bolus dose but one can maintain and precisely control drug levels -Often implies a controlled response -Bioavailability = 1 -Generally an infusion is only given in the inpatient setting A multiple dose regimen is given usally via mouth, it has a lower onset than that of an IV bolus dose but one can maintain drug levels -There can be bioavailability issues -Generally given in outpatient
72
The fundamental pharmacokinetic assumption
Drug plasma concentration, C, is proportional to the concentration of free drug Cu at the site of action and thus to the observed clinical effects -This means that drug distribution has reached eqm -There is no saturation occuring
73
AUC
measure of the extent of drug exposure (C1 + C2) / 2
74
Drug input
Determined by the dosage regimen
75
Drug output
-Determined from the distribution volume -Alwats characterized by an elimination rate
76
Excretion
Minor players -Via the bile (biliary excretion) -Via the lungs (pulmonary excretion) Major player -Via the kidney (renal excretion) -Most drugs are excreted through the kidnehys Metabolism: 1. Biotransformation is mainly by the liver (oxidation/reduction by CYP450, hydrolysis, conjugation) 2. Major elimination mechanism of drugs from the body
77
Common metabolic reactions
Oxidation, reduction. hydrolysis, and conjugation -Metabolites may undergo secondary (further) metabolism Oxidation, reduction, and hydrolysis are phase 1 reactions Conjugations are phase 2 reactions
78
Rate of drug elimination
Clearance * drug conc Clearance is the proportionality factor allowing us to relate drug elimination rate to drug concentration in the plasma
79
Rate of extraction
1. Mass balance 2. Mass balance normalized to rate of entry 3. Mass balance normalized to entering concentration
80
fractional rate of elimination
Rate of elimination is directly proportional to the amount of A present -Defines a first order process -The kinetic constant is exactly the fractional rate of elimination and it is expressed in T^-1
81
Total Clearance
Total elimination from the body calculated with AUC

Pharmacokinetics (1 decks)

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