1
Q
involves understanding bioavailability factor (F), AUC, Cmax, Tmax, Volume of distribution, clearance, first-order kinetics and elimination half-life
A
PHARMACOKINETICS
2
Q
plasma drug concentration for ORALLY administered drugs at time 0
A
drug concentration 0
3
Q
the TOTAL DRUG ABSORBED is represented by ____
A
AREA UNDER THE CURVE
4
Q
PEAK concentration
A
Cmax
5
Q
the time it takes to reach the peak concentration
A
Tmax
6
Q
PLASMA PROTEIN:
* NOT AVAILABLE to produce biologic effect
A
BOUND DRUG
7
Q
PLASMA PROTEIN:
* AVAILABLE for action
A
UNBOUND DRUG
8
Q
an important indicator of drugs’ ability to produce biological effect
A
UNBOUND DRUG
9
Q
the time it takes to reach MEC
A
ONSET
10
Q
the time within the MEC
A
DURATION OF ACTION
11
Q
a kinetic parameter that measures the RATE and EXTENT of systemic absorption
A
BIOAVAILABILITY
12
Q
BIOAVAILABILITY
for INTRAvascular route
A
F = 1
13
Q
BIOAVAILABILITY
for EXTRAvascular route
A
F < 1
14
Q
PHARMACOKINETIC PARAMETERS
- determines BOTH RATE and EXTENT
- it is the MOST VARIABLE parameter
A
Cmax (peak concentration)
15
Q
PHARMACOKINETIC PARAMETERS
determines the RATE
A
Tmax (peak time)
16
Q
PHARMACOKINETIC PARAMETERS
determines the EXTENT
A
AUC
17
Q
it is the proportion of a drug substance available for biologic absorption
A
BIOAVAILABILITY FACTOR
18
Q
FORMULA for Bioavailability factor
A
F = dose of drug that reaches the blood / dose of drug administered
19
Q
- is the extent of drug absorbed upon EXTRAVASCULAR administration in comparison to the dose size of a standard administered by the SAME ROUT (commonly ORAL route)
- ORAL vs ORAL
A
RELATIVE bioavailability
20
Q
FORMULA for RELATIVE bioavailability
A
generic / innovator (branded)
generic over dose / innovator (branded) over dose – used when different dose are given
21
Q
RELATIVE bioavailability
it is recognized as the REFERENCE STANDARD
A
INNOVATOR / BRANDED
22
Q
- is the extent or fraction of drug absorbed upon extravascular administration in comparison to the dose size administered
- ORAL vs IV
A
ABSOLUTE bioavailability
23
Q
FORMULA for ABSOLUTE bioavailability
A
oral / IV
oral over oral dose / IV over IV dose
24
Q
ABSOLUTE bioavailability
what is the REFERENCE STANDARD
A
IV
25
* expresses the period of time required for the concentration of a drug to **decrease by one half**
* is the time required to **decrease the initial dose** of drug by **50%**
* in **first order kinetics**, it is **CONSTANT**
* it also predicts the time it takes to **reach** the **steaady state concentration**
* it is also used as the **basis** for **dose interval**
HALF LIFE
26
# **HALF LIFE**
how many **half lives** would it take to **reach** the **steady state levels**
4-5 half lives
27
# **HALF LIFE**
what is the amount of the concetration at 4 & 5 half life
4.32
6.65
28
it is the **velocity** with which it occurs
rate of chemical reaction
29
it is the way in which the concentration of a drug or reactant in a chemical reaction **affects** the **rate**
order of a reaction
30
# **RATE AND ORDERS OF REACTION**
* **AMOUNT** is constant
* has a tendency to be **SATURATED**
ZERO ORDER
31
# **RATE AND ORDERS OF REACTION**
* **FRACTION** is CONSTANT
* **dependent** to the **current concentration**
FIRST ORDER
32
# **IDENTIFY THE ROUTE AND COMPARTMENT TYPE**
* **absorption** rate constant, ka
* **distribution** rate constant
* **elimination** rate constant, k
TWO compartment
EXTRAvascular
33
# **IDENTIFY THE ROUTE AND COMPARTMENT TYPE**
* **elimination** rate constant
ONE compartment
INTRAvascular
| NO absorption - IV
NO distribution - one compartment
34
# **FORMULA**
ELIMINATION RATE CONSTANT:
**zero order**
C1 - C2 / t2 - t1
35
# **FORMULA**
ELIMINATION RATE CONSTANT:
**first order**
lnC1 - lnC2 / t2 - t1
36
# **RATE AND ORDERS OF REACTION**
* **CONSTANT AMOUNT** of drug removed
* **INDEPENDENT** on the remaining maount of drug
* **half-life** is **NOT** constant
ZERO ORDER
37
# **RATE AND ORDERS OF REACTION**
* **CONSTANT FRACTION** of drug removed
* **DEPENDENT** on the remaining amount of drug
* **half-life** is **CONSTANT**
FIRST ORDER
38
the study of **how drugs move through the body**— covering **absorption**, **distribution**, **metabolism**, and **excretion** (ADME)
pharmacokinetics
39
* the **SIMPLEST** and **MOST DIRECT ROUTE** for studying pharmacokinetics
* ENTIRE dose is delivered **directly** into the bloodstream, **bypassing absorption**
* **RAPID** achievement of therapeutic drug levels -- useful in **emergencies**
IV BOLUS
40
# **IV BOLUS | CLINICAL RELEVANCE**
____ in **septic shock**
antibiotics
41
# **IV BOLUS | CLINICAL RELEVANCE**
____ in **acute myocardial infarction**
antiarryhtmics
42
# **IV BOLUS | CLINICAL RELEVANCE**
____ for seizures
anticonvulsants
43
* the body is treated as **SINGLE, UNIFORM** compartment where the drug **distributes INSTANTLY**
* it is an **open system**, meaning the drug can enter and leave
* also known as the **WELL-STIRRED MODEL** because the drug is assumed to be **instantaneously** and **homogenously mixed** in the compartment
ONE-COMPARTMENT MODEL
44
# **ONE COMPARTMENT MODEL | KEY PK PARAMETERS**
* **fraction** of the drug **eliminated** oer unit time
ELIMINATION RATE CONSTANT (k)
45
# **ONE COMPARTMENT MODEL | KEY PK PARAMETERS**
* a theoretical volume that relates the **amount of drug in the body** to the **plasma concentration**
APPARENT VOLUME OF DISTRIBUTION
46
# **ONE COMPARTMENT MODEL | KEY PK PARAMETERS**
APPARENT VD:
* **VD** DOES NOT correspond to an actual ____ hence it is **apparent**
anatomical space
47
# **ONE COMPARTMENT MODEL | KEY PK PARAMETERS**
APPARENT VD:
* VD indicates the ____ into tissues
extent of drug distribution
48
# **ONE COMPARTMENT MODEL | KEY PK PARAMETERS**
APPARENT VD:
* **0.14 L/kg**
* **SMALL**, **highly bound** to plasma proteins -> mostly **stays** in the **blood**
WARFARIN
49
# **ONE COMPARTMENT MODEL | KEY PK PARAMETERS**
APPARENT VD:
* **7 L/kg**
* **VERY LARGE**
* binds **extensively** to muscle tissues
DIGOXIN
50
# **ONE COMPARTMENT MODEL | KEY PK PARAMETERS**
APPARENT VD:
* **HIGH** plasma protein binding
SMALLER VD
51
# **ONE COMPARTMENT MODEL | KEY PK PARAMETERS**
APPARENT VD:
* **HIGH** fat solubility (lipophilicity)
LARGER VD
52
# **ONE COMPARTMENT MODEL | KEY PK PARAMETERS**
APPARENT VD:
* **LARGE** organs
INCREASE VD
53
# **ONE COMPARTMENT MODEL | KEY PK PARAMETERS**
APPARENT VD:
* **edema**
LARGER VD
54
# **ONE COMPARTMENT MODEL | KEY PK PARAMETERS**
* volume of **plasma CLEARED** of drug per unit time
* tells **how efficiently** the body **removes drug**
* **KIDNEYS** (renal); **LIVER** (hepatic)
CLEARANCE
55
# **ONE COMPARTMENT MODEL | METHODS OF DETERMINING ELIMINATION**
* **DIRECT** method
PLASMA CONCENTRATION -- TIME DATA
56
# **ONE COMPARTMENT MODEL | METHODS OF DETERMINING ELIMINATION**
* useful when **plasma sampling is DIFFICULT**
* **Rate** method
* **Sigma-minus** method
* requires **complete urine collection**, **unaffected by metabolites**, **frequent sampling**
URINARY EXCRETION DATA
57
# **ONE COMPARTMENT MODEL | METHODS OF DETERMINING ELIMINATION**
METHODS IN **URINARY EXCRETION DATA**
RATE method
SIGMA-MINUS method
58
# **ONE COMPARTMENT MODEL**
* drug enters **directly** into the bloodstream
* **NO** absorption
* **RAPID** distribution -> equilibrium is **instantly** obtained
* **Decline** in plasma concentration DEPENDS only on **metabolism** and **excretion**
* useful in **EMERGENCY situations** and **investigational drugs**
* **HIGH RISK** for ADRs, **precipitation** of poorly soluble drugs, **direct exposure** of organs
IV BOLUS
59
# **ONE COMPARTMENT MODEL**
IV BOLUS:
* penicillin formulation that is given **IM** because it can be FATAL if given IV
Pen G Benzathine (Bicillin)
60
# **ONE COMPARTMENT MODEL**
provides **quick data** but is **rarely** preferred route
IV BOLUS
61
# **ONE COMPARTMENT MODEL**
safer, steadier plasma levels
IV infusion
62
# **ONE COMPARTMENT MODEL**
* at time **zero**, **NO** drug is in circulation
* drug **must be absorbed**
* **Elimination** occurs **SIMULTANEOUSLY** with **absorption**
* NOT ALL drugs are absorbed
EXTRAVASCULAR
63
# **ONE COMPARTMENT MODEL**
EXTRAVASCULAR:
* rate at which drug is **eliminated**
ELIMINATION RATE CONSTANT (Kel, K)
64
# **ONE COMPARTMENT MODEL**
EXTRAVASCULAR:
* rate at which drug **enters circulation**
ABSORPTION RATE CONSTANT (Ka)
65
# **ONE COMPARTMENT MODEL**
EXTRAVASCULAR:
* **HIGHER** Ka -> ____ absorption
FASTER
66
# **ONE COMPARTMENT MODEL**
EXTRAVASCULAR:
* for MOST drugs, **absorption** after ORAL administration is usually **nearly complete** by ____
1-2 hours
67
# **ONE COMPARTMENT MODEL**
EXTRAVASCULAR:
* A ____ slope indicates that the **natural log** of concentration **DECLINES** with **INCREASING TIME**
NEGATIVE
68
# **ONE COMPARTMENT MODEL**
EXTRAVASCULAR:
* a ____ slope indicates a **FASTER** rate of elimination
STEEPER
69
* the body consists of **TWO interconnected compartments**; ***Peripheral*** and ***Central***
* drug can **REVERSIBLY DISTRIBUTE** between the compartments
* DISTRIBUTION between compartments in **NOT INSTANTANEOUS**
* there is an **initial distribution phase** followed by a **slower elimination phase**
TWO-COMPARTMENT MODEL
70
# **TWO COMPARTMENT OPEN MODEL**
plasma + **HIGHLY** perfused tissues
* heart, lungs, liver, kidneys
CENTRAL compartment
71
# **TWO COMPARTMENT OPEN MODEL**
**LESS** well-perfused tissues
* muscle, fat, skin
PERIPHERAL COMPARTMENT
72
this model is especillay important for **LIPOPHILIC DRUGS**, drugs with **SLOW TISSUE PENETRATION**, or drugs with **COMPLEX DISTRIBUTION PATTERNS**
TWO-COMPARTMENT OPEN MODEL
73
# **TWO COMPARTMENT OPEN MODEL**
drug can **ENTER** the ____
CENTRAL compartment
74
# **TWO COMPARTMENT OPEN MODEL**
drug can be **eliminated ONLY** from the ____
CENTRAL compartment
75
# **TWO COMPARTMENT OPEN MODEL | KEY PK PARAMETERS**
RATE CONSTANTS:
* transfer rate constant from **central → peripheral**
k12
76
# **TWO COMPARTMENT OPEN MODEL | KEY PK PARAMETERS**
RATE CONSTANTS:
* transfer rate constant from **peripheral → central**
k21
77
# **TWO COMPARTMENT OPEN MODEL | KEY PK PARAMETERS**
RATE CONSTANTS:
* **elimination rate constant** from **CENTRAL** compartment
k10
78
# **TWO COMPARTMENT OPEN MODEL | KEY PK PARAMETERS**
VOLUME OF DISTRIBUTION:
* the **INITIAL volume** in which drug **appears immediately** after administration
CENTRAL VOLUME OF DISTRIBUTION (VC)
79
# **TWO COMPARTMENT OPEN MODEL | KEY PK PARAMETERS**
VOLUME OF DISTRIBUTION:
* represents distribution when **equilibrium** between central and peripheral is **reached**
VOLUME OF DISTRIBUTION DURING ELIMINATION PHASE (Vβ)
80
# **TWO COMPARTMENT OPEN MODEL | KEY PK PARAMETERS**
VOLUME OF DISTRIBUTION:
* **theoretical volume** after **INFINITE TIME** when distribution is **complete**
STEADY STATE VOLUME OF DISTRIBUTION (Vss)
81
# **TWO COMPARTMENT OPEN MODEL | KEY PK PARAMETERS**
Elimination occrus from the **central compartment only**
CLEARANCE
82
# **TWO COMPARTMENT OPEN MODEL**
* drug ENTERS **central** compartment, then DISTRIBUTES to **peripheral**
* plasma curve has two phases; **distribution phase**, **elimination phase**
IV BOLUS
83
# **TWO COMPARTMENT OPEN MODEL**
IV BOLUS | PLASMA CURVE:
* **STEEP FALL** as drug **leaves** blood to tissues
DISTRIBUTION PHASE (a-phase)
84
# **TWO COMPARTMENT OPEN MODEL**
IV BOLUS | PLASMA CURVE:
* **SLOWER DECLINE**, influenced by metabolism, excretion, and redistribution
ELIMINATION PHASE (β-phase)
85
# **TWO COMPARTMENT OPEN MODEL**
* drug ENTERS **GI Tract**
* drug is ABSORBED into **central** compartment
* drug DISTRIBUTES between **central** and **preipheral** compartments
* **elimination** occurs from the **central** compartment
EXTRAVASCULAR
86
# **TWO COMPARTMENT OPEN MODEL**
EXTRAVASCULAR:
* **ascending curve**
absorption phase (Ka)
87
# **TWO COMPARTMENT OPEN MODEL | CLINICAL APPLICATIONS**
drugs with **EXTENSIVE TISSUE BINDING**
Digoxin
Chloroquine
88
# **TWO COMPARTMENT OPEN MODEL | CLINICAL APPLICATIONS**
drugs with **SLOW TISSUE PENETRATION**
Aminoglycosides
anesthetics
89
# **TWO COMPARTMENT OPEN MODEL | CLINICAL APPLICATIONS**
**HIGHLY LIPOPHILIC** drugs
Thiopental
90
# **TWO COMPARTMENT OPEN MODEL | CLINICAL APPLICATIONS**
for ____ drug
NARROW THERAPEUTIC INDEX
91
# **TWO COMPARTMENT OPEN MODEL | CLINICAL APPLICATIONS**
* **RAPID onset** because of brain distribution but **SHORT duration** due to redistribution into fat
* after IV bolus, patient is **unconscious** within **seconds** but **consciousness return within minutes**
THIOPENTAL
92
# **TWO COMPARTMENT OPEN MODEL | CLINICAL APPLICATIONS**
* CENTRAL VD is **small**, but **Vss** is **large** -> drug accumulates in muscle tissues
DIGOXIN
93
# **TWO COMPARTMENT OPEN MODEL | CLINICAL APPLICATIONS**
IMPLICATIONS FOR DOSING:
* **LOADING DOSES** must consider ____ (not just VC)
Vss
94
# **TWO COMPARTMENT OPEN MODEL**
* administration of a drug **directly** into the bloodstream at a **CONSTANT RATE** over a period of time
* provides a **GRADUAL** and **CONTROLLED** delivery
* **ELIMINATION** follows **first-order kinetics**
* **WELL-STIRRED model**
* STEADY STATE is **eventually reached**
* used when:
* **steady plasma concentrations** are needed
* **avoiding toxic peaks** or **sub-therapeutic troughs**
* **continuous therapeutic action** is required
INTRAVENOUS INFUSION
95
# **TWO COMPARTMENT OPEN MODEL**
INTRAVENOUS INFUSION:
* **Input** is what order
zero-order
96
# **TWO COMPARTMENT OPEN MODEL**
INTRAVENOUS INFUSION:
* **elimination** is what order
first order
97
# **TWO COMPARTMENT OPEN MODEL**
INTRAVENOUS INFUSION:
* drug **distributes** ____ within each compartment
INSTANTANEOUSLY
98
# **TWO COMPARTMENT OPEN MODEL | IV INFUSION KEY PK PARAMETERS**
* **input rate** in mg/h or mg/min
RATE OF INFUSION
99
# **TWO COMPARTMENT OPEN MODEL | IV INFUSION KEY PK PARAMETERS**
* volume of **plasma cleared** per unit time
* determines **steady-state concentration**
CLEARANCE
100
# **TWO COMPARTMENT OPEN MODEL | IV INFUSION KEY PK PARAMETERS**
* **plateau concentration** achieved when **input = output**
STEADY STATE CONCENTRATION (Css)
101
# **TWO COMPARTMENT OPEN MODEL | IV INFUSION KEY PK PARAMETERS**
* **INDEPENDENT** of infusion rate
* DEPENDS only on **drug HALF-LIFE**
* Css is reached after 4-5 half-lives
TIME TO REACH STEADY STATE
102
# **TWO COMPARTMENT OPEN MODEL | IV INFUSION KEY PK PARAMETERS**
* used when **immediate Css** is desired
LOADING DOSE
103
# **TWO COMPARTMENT OPEN MODEL | IV INFUSION CLINICAL APPLICATIONS**
anesthesia maintenance
PROPOFOL infusion
104
# **TWO COMPARTMENT OPEN MODEL | IV INFUSION CLINICAL APPLICATIONS**
avoids nephrotoxicity
VANCOMYCIN infusion
105
# **TWO COMPARTMENT OPEN MODEL | IV INFUSION CLINICAL APPLICATIONS**
continuous cardiovascular support
DOPAMINE infusion
106
# **TWO COMPARTMENT OPEN MODEL | IV INFUSION CLINICAL APPLICATIONS**
rate **TOO HIGH** =
toxicity
107
# **TWO COMPARTMENT OPEN MODEL | IV INFUSION CLINICAL APPLICATIONS**
rate **TOO LOW** =
therapeutic failure
108
# **TWO COMPARTMENT OPEN MODEL | IV INFUSION CLINICAL APPLICATIONS**
____ may be necessary
LOADING DOSE
109
# **TWO COMPARTMENT OPEN MODEL | IV INFUSION CLINICAL APPLICATIONS**
INFUSION REACTIONS
phlebitis
extravasation
110
# **APPROACHES TO STUDYING ABDORPTION**
* BASIS: uses **clinical plasma concentration data** after drug administration
* METHOD: **SIMPLIFIED** model (first-order absorption)
* STRENGTHS: **Practical**, **directly reflects** clinical outcomes
* LIMITATIONS: **DOES NOT** explain why absorption occurs the way it does -- only describes it
TOP-DOWN APPROACH
111
# **APPROACHES TO STUDYING ABDORPTION**
* **Physiologically Based Pharmacokinetic Model (PBK)**
* BASIS: **Mechanistic**, starts from **in VITRO** drug data + physiological parameters
* MODEL: body divideed into **physiological compartments** (stomach, duodenum, jejunum, ileum, colon)
* APPLICATIONS: **Predicts absorption** in **SPECIAL POPULATIONS** (children, elderly, liver disease, gastric bypass)
BOTTOM-UP APPROACH
112
# **APPROACHES TO STUDYING ABDORPTION**
* represents the **GI TRACT** as **NINE sequential compartments**
* Each compartment has:
* **Rate in / Rate out** = **movement** of drug or fluid
* **Secretions** = gastric into stomach, bile/pancreatic into duodenum
* **Fluid absorption** = duodenum → jejunum → ileum → colon
* **site-specific** absorption profiles
* **amount absorbed** in each GI region
* **overall plasma concentration-time curve**
ABSORPTION TRANSIT MODEL
BIOPHARM & PHARMACOKINETICS
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