Pharmacokinetics Flashcards
PHARMACOKINETICS
• “pharmakon” - drugs • “kinesis” - movement • Movement of drugs in the body • Study of the time course of drug absorption, distribution, metabolism and excretion • “what the body does to the drug”
Clinical Pharmacokinetics
Application of pharmacokinetic principles
to the safe and effective therapeutic
management of drugs in an individual
patient
COMPONENT PROCESSES
“ADME”
• Absorption
o Entry of the drug into the plasma
• Distribution
o Into interstitial and intracellular fluids
• Metabolism
o Biotransformation by the liver of other tissues
• Excretion
o drug and metabolites in the urine, feces, bile
OBJECTIVES OF PK
- The prediction of therapeutic doses and suitable dosage regimen
- The adjustment of individual drug dosage forms for optimal efficacy and safety
- The correlation between therapeutic blood concentration of the drug with pharmacologic effects
ABSORPTION
Process by which the unchanged drug proceeds from the
site of administration to the site of measurement (plasma)
FACTORS THAT INFLUENCE ABSORPTION
- Physical State of the drug
- Route of administration
- Blood flow to the absorption site
- Total surface area available for absorption
- Contact time at the absorption surface
- Expression of p-glycoprotein
PHYSICAL STATE
• Solid dosage form, solution, suspension
• Drug in product → Drug in solution → Absorbed drug
• Speed of absorption:
Solution > Suspension > Solid dosage form
ROUTE OF ADMINISTRATION
IV, IM, OR, SUbQ, INH, TOPI
Most common, safest and most economical method of absorbtion
Enteral (oral)
List some limitations of Enteric route
Limited absorbtion
Bioavailabilty
first pass
reaction with other foods
What is sublingual admin
o Placement under the tongue allows a drug to diffuse into the capillary network and enter the systemic circulation directly. (bypassing firstpass effect) o Between the cheek and gum. Advantages: § Ease of administration § Rapid absorption § No first-pass effect
Fick’s law for absorbtion
higher blood flow to the stomach, better absorption
TOTAL SURFACE AREA AVAILABLE FOR ABSORPTION
With a surface rich in brush borders containing
microvilli, the intestine has a surface area about 1000-fold that of the stomach, making the absorption of the drug across the intestine more efficient.
Does Gastric motility effect absorbtion
yes
why is faster motility bad?
less absorption, eg: diarrhea
How is gastric emptying significant?
Less absorption
RECTAL ROUTE
- Irregular and incomplete absorption
- Can cause irritation of the rectal mucosa
- Inconvenient (particularly for pediatric patients)
- 50% of the drug bypass the liver, reducing hepatic first-pass metabolism
Hepatic First-pass Metabolism
When a drug is absorbed from the GI tract, it enters the portal circulation before entering the systemic circulation. If the drug is rapidly metabolized in the liver or gut wall during this initial passage, the amount of unchanged drug entering the systemic circulation is decreased
PARENTERAL ROUTE
• Administration directly into the systemic circulation • Poorly absorbed from the GI tract • Unstable in the GI tract • Unable to take oral medications (ICU and neonate patients) • Rapid onset of action • Highest bioavailability No first pass control over dosing
Types of paraentral route
IV- ->25° § Most common parenteral route § Rapid onset § Maximum degree of control over the amount of drug delivered
IM->90°
§ Aqueous solution = rapidly absorbed
§ Depot preparations = slowly absorption
SubQ- )->45°
§ Absorption via simple diffusion and is slower
than IV
§ Provide constant, slow and sustained effects
Intradermal- 10-15°
. ORAL INHALATIONAL
- Provide rapid delivery of a drug across the large surface area of the mucous membrane of the respiratory tract and pulmonary epithelium.
- Rapid onset of action.
- Effective and convenient for patients with respiratory disorders (e.g. for patients with asthma)
Nasal inhalation
Directly to the nose (Otrovin)
Intrathecal/Intraventricular
Direct to CSF- epidural anasthesia
Topical
local effect of the drug- Fungal creams
Transdermal
transdermal patches
sustained delivery system
Nicotine patch
EXPRESSION OF P-GLYCOPROTEIN
• P-glycoprotein is a transmembrane transporter protein
responsible for transporting various molecules,
including drugs, across cell membranes.
Where is p-gyp found?
All over the body organs
pgyp increases or decreases absorption?
Decreases
Types of Absorbption
Passive
Facilitated
Active
Endocytosis/exocytosis
Passive transport
o Concentration gradient across a membrane
o High concentration to low concentration
o Not saturable
o Shows low structural specificity
Facilitated Diffusion
o Specialized transmembrane carrier proteins that facilitate the passage of large molecules
o This transmembrane carrier protein will
have conformational changes once the drug binds to them allowing the drug pass-through
the concentration gradient.
o Across a concentration gradient
o Does not require energy
o Can be saturated
o Inhibited by compounds that compete for the carrier
AT
o Involves specific proteins that span the
membrane
o Energy-dependent, driven by the hydrolysis of ATP
o Against concentration gradient
o Saturable
o Selective and may be competitively inhibited by other cotransported substances
Bioavailabity (F)
Fraction of unchanged drug reaching the systemic circulation following administration by any route
Bioavailabity of IV
100% no FPM
bioavailabilty of Oral
<100%
DETERMINATION OF BIOAVAILABILITY
• Comparing plasma levels of a drug after particular route of administration with levels achieved by IV route
AUC Oral/AUC IV plasma conc.
What is Area Under the Curve?
• By plotting the plasma concentrations of the drug versus time, the area under the curve (AUC) can be
measured.
• So AUC now represent the rate as well as the extent of absorption.
Absolute Bioavailability
Comparison of the bioavailability after an
extravascular administration to IV
administration, which by definition, has 100% F
Relative Bioavailability
o Determined if there are no IV data
o Determined by comparing different dosage forms, different routes of administration, or different conditions
The formula for Absolute F
AUC(Oral)/AUC(IV) * Dose (IV)/ Dose (oral)
Relative F formula
AUC (A)/AUC(B) * Dose (B)/Dose (A)
F of IV
100%, most rapid
F of IM
75 to <100, large volumes, but painful
F of SC
75 to <100, smaller than IM, slower than IM or IV
F of PO
5 to <100, most convenient but FPM
F of PR
30 to <100, less FPM than oral
F of Transdermal
80 to <100, usually slow, no FPM, long duration of action
FACTORS THAT INFLUENCE BIOAVAILABILITY
First-pass hepatic metabolism
Solubility of the drug
Too Hydrophilic = poorly absorbed, cannot cross lipid bilayer
o Too Lipophilic = poorly absorbed, insoluble in aqueous body fluids
Chemical instability
o Some drugs are unstable in the pH of the gastric contents
§ Pen G
o Destroyed in the GI tract by degradative
enzyme
§ Insulin
Nature of drug formulation
Particle size, salt form, polymorphism,
enteric coating, presence of excipients = can influence the ease of dissolution and
therefore, alter the rate of absorption
BIOEQUIVALENCE
• Drug products are considered to be pharmaceutical equivalents if they contain the same active ingredients and are identical in strength or
concentration, dosage form, and route of
administration
Two pharmaceutically equivalent drug products are
considered to be bioequivalent when the rates and
extents of bioavailability of the active ingredient in the
two products are not significantly different under
suitable and identical test conditions.
Drugs that may require tighter limits on the permissible difference in Bioavailability
Drugs with a narrow margin of safety o Drugs with known serious dose-related toxicity o Drugs with a steep dose-response curve o Drugs showing non-linear pharmacokinetics within therapeutic dosage range
Low Oral Bioavailability may be due to:
o Poor absorption
o Poorly formulated dosage form that fails to disintegrate and dissolve in GIT fluids
o Interaction between drugs in the GIT
o Metabolism of drugs in the GIT
o Hepatic extraction ú Competing reactions
DISTRIBUTION
• Process by which a drug reversibly leaves the bloodstream and enters the interstitium (extracellular
fluid) and the tissue
Blood FLow on Rate of D
§ Rate of blood flow to tissue capillaries varies widely § Brain, Liver, Kidneys greater blood flow than the skeletal muscles (receive most of the drug) § Adipose tissue, skin and viscera lower rates of blood flow (slower distribution)
Capillary Permeability on RoD
More permeable the capillaries are the greater transfer/ diffusion of the drug from the blood into interstitium
Binding to plasma proteins on RoD
§ Reversible binding to plasma proteins sequesters drugs in a nondiffusible form and slows their transfer out of the vascular compartment § Albumin- major carrier of acidic drugs § Α1-acid glycoprotein- basic drugs § The greater the plasma protein binding capacity of the drug the lesser unloading/transfer of drug from systemic circulation into the interstitium
Binding to tissue proteins on RoD
Binding to tissue proteins
o many drugs accumulate in the
tissue at a higher concentration than those in the extracellular fluids and blood
o Binding to lipids, proteins, nucleic acids
Lipophilicity on RoD
Lipophilic drugs readily move across
most biologic membranes à dissolve
in the lipid membranes and
penetrate the entire cell surface
Volume of Distribution
dose (mg)/mg/L
we administer 1000mg paracetamol after an two
hour we extracted the blood and determined that plasma concentration of the paracetamol was 50mg/L. Compute for
the Vd.
1000/50 = 20L
why is Vd important
• VD is useful in estimating the plasma concentration when
a known amount of drug is in the body or conversely, in
estimating the dose required to achieve a given plasma
concentration.
does Vd correspond to Real Volume?
Rarely
First order Kinetics
1st-Order (Linear Kinetics)
§ Amount of drug metabolized per unit time is proportional to the plasma the concentration of the drug
§ Fraction of drug removed by
metabolism is constant
§ Concentration falls exponentially and the fraction remaining at a
given time is independent of the
initial concentration
Zero-Order (Nonlinear Kinetics)
§ Constant amount of drug is
metabolized per unit time
§ Mechanism for elimination becomes saturated
§ Clearance become variable
§ The rate of drug transfer or loss is constant and independent of
the concentration of a drug
Phase 1 metab
• Convert lipophilic drugs into more polar molecules
by introducing or unmasking a polar functional group
such as –OH or –NH2
Phase 1 examples
Oxy, Red, Hydrolysis
phase 1 catalysed by
Cyt p450
account for 50% of the metabolism of drugs
CYP1A2, CYP3A4, CYP2C
cyt p450 reactions
aromatic oxidation aliphatic hydroxylation epoxidation oxidative dealkylation, deamination Dehalogenation Oxidation Reduction Desulphuration
Non CYP
Hydrolysis Reduction Oxidation Flav monooxygenase MAO Alcohol, Aldehyde dehydrogenases
PHASE II
Consists of conjugation reactions
• Many Phase I metabolites are still too lipophilic to be excreted.
• A subsequent conjugation reaction with an endogenous substrate, such as glucuronic acid, sulfuric acid, acetic acid, or amino acid, results in
polar, usually more water-soluble compounds that are often therapeutically inactive.
• The highly polar drug conjugates are then excreted
by the kidneys or in bile.
Elimination
• Drugs must be sufficiently polar to be eliminated from the body.
• Most important route is elimination through the
kidneys into the urine.
RENAL ELIMINATION
o If drug is highly protein bound you expect the glomerular filtration of that drug to be much
lower
Active (proximal)
Secretion primarily occurs in the proximal tubules by two energy-requiring active transport systems: One for anions and one
for cations
Passive (Distal) tubular reabsorption
o As a drug moves toward the distal convoluted tubule, its concentration increases and exceeds that of the perivascular space. o The drug, if uncharged, may diffuse out of the nephric lumen, back into the systemic circulation § Acidification = weak bases § Alkalinization = weak acids
how to eliminate weak basic drugs?
acidify the urine
CLEARANCE BY OTHER ROUTES
- Intestines, bile, lungs, breast milk, feces
* Clearance = factor that predicts the rate of elimination in relation to the drug concentration
CLEARANCE
Dose/AUC
how to calculate First order elimination?
0.693/t-half
Clearance is…
Vd x Ke Vd x (0.693/t-half)
TOTAL BODY CLEARANCE
Is the sum of all clearances from the drug metabolizing an drug-eliminating organs
What is the major organ of elimination
Kidneys
HALF-LIFE
The time required to change the amount of drug in the body by one-half during elimination (or
during a constant infusion)
t-half = 0.693*Vd/CL
When is steady state acheived?
4-5 half lives
Loading dose
Rapid plasma concentration to reach steady state.
Vd*Cp
Maintenance Dose (IV)
TCp x CL
Maintenace Dose (oral)
TCpxCL/F (bioavailability)
Given the following drugs, which is the most
extensively sequestered in the tissues:
a. Drug U: Vd= 1L, Plasma protein binding= 90%
b. Drug S: Vd= 5L, Plasma protein binding= 80%
c. Drug T: Vd= 30L, Plasma protein binding= 10%
d. Drug V: Vd= 22L, Plasma protein binding= 25%
c.
Drug T has the highest volume of distribution. Plasma protein binding is only 10%. The highly
protein-bound drug will remain inside the circulation for a longer period of time so there will be
less unloading at the tissues
Which of the following describes first pass effect?
a. metabolism of drug given orally before
reaching the circulation
b. redistribution of the drug from the site of action
to other tissues
c. inactivation of the drug in the stomach due to
gastric acid
d. absorption of the drug in the duodenum
A
Given the apparent volume of distribution of a drug, the total drug in the body at any time after administration may be determined by the measurement of the drugs: a. Bioavailability b. Concentration in the plasma c. Half-life d. Clearance
b. Conc in Plasma
If a drug is given at a dosage interval equal to the half-life of the drug, how many doses are required to reach 90% of the steady state concentration?
4
5. The bioavailability of a new investigational drug was studied. Below are the date from the study:
mg AUC (mcg/mL
Oral Tablet 200 100
Oral solution 200 80
IV bolus injection 50 40
What is the absolute bioavailability of the drug from the solution? a. 150% b. 80% c. 50% d. 100%
c.
Absolute bioavailability compares the AUC of oral preparation to the IV preparation
AUC(Oral)/AUC(IV) * Dose (IV)/ Dose (oral)
80/40 * 50/200 X 100 =
This will provide the best measure of the extent of absorption:
a. AUC
b. Blood concentration-time curve
c. Cmax
d. Tmax
A
AUC tells the rate and extent of
absorption.
Drug A has reached its target concentration of
300mg/mL. After 30days, the drug concentration was 75mg/mL. Assuming that the drug follows first-order kinetics, when will the drug decline to one-half of the target concentration?
a. 15 days
b. 45days
c. 60days
d. 10days
a
15 days
Plasma protein binding will prolong the renal
clearance of a drug that is excreted primarily by:
a. filtration and secretion
b. filtration and reabsorption
c. glomerular filtration
d. tubular secretion
c.
GF
A single bolus injection of 500mg of drug X is given to an adult with a weight of 50kg. If Vd is 0.1L/kg, elimination half-life is 1.5hrs, and is eliminated by first order kinetics, the plasma concentration is
a. 100mg/L
b. 25mg/L
c. 0.01mg/L
d. 2.5mg/L
a
100mg/L
Cp = dose/Vd
500/0.1 * 50kg
A single bolus injection of 500mg of drug X is given to an adult with a weight of 50kg. If Vd is 0.1L/kg, the elimination half-life is 1.5hrs and is eliminated by first order kinetics.
The fraction of drug X eliminated 6hours after the
dose is given is
a. 12.5%
b. 94%
c. 97%
d. 6%
94%
- Drug A Has a Vd= 1.5L/Kg. To achieve a plasma
concentration of 10mg/L, the amount of drug in the body should be:
a. 15 mg
b. 6.67 mg
c. 46.67 mg
d. 0.15 g
A.
15mg
1.5 * 10 = 15mg
dose= Vd X Cp
F Vd t-1/2 A 88 67 2 B 100 38 98 C 26 270 3.9 D 100 9.1 14 Which drug most likely has significant first-pass effect?
Drug C, because it has the lowest oral bioavailability. Only 26% of the orally administered drug reached the systemic circulation
F Vd t-1/2 A 88 67 2 B 100 38 98 C 26 270 3.9 D 100 9.1 14 Which drug most likely has the highest degree of plasma protein binding?
Drug D, because of lowest Vd. The higher the plasma protein binding capacity of the drug the
lower the volume of distribution
F Vd t-1/2
A 88 67 2
B 100 38 98
C 26 270 3.9
D 100 9.1 14
If plasma concentration is the same in all drugs,
which will require the highest loading dose?
Which drug most likely has the highest clearance
(assuming 1st order kinetics)?
Drug C, because bioavailability of drug C is very low so you need a higher loading dose is to
achieve desired target
Drug A, because of shortest half-life
Compute for the Loading dose of Phenobarbital
needed for a 5year old male patient with a known case of seizure disorder.
• Wt= 15kg
• Desired Plasma Conc=15mg/L
• VD of Pb= 0.5L/kg
Ld = Cp * Vd
Vd= 0.5 * 15 = 7.5 L
Ld = 7.5 * 15
Compute for the maintenance dose of Phenobarbital
needed for a 5year old male patient with a known case of seizure disorder.
• Wt= 15kg
• Desired Plasma Conc=15mg/L
• VD of Pb= 0.5L/kg
if the drug is to be given every 12hours with an oral bioavailability of 100% and t 1⁄2 of 98hours.
Md = Cp * Cl * Time int)/F
Clearance= Vd * Ke
7.5 * 0.693/98 = 0.0525L/hr
Md = 15 X 0.0525 X 12/1 = 9.45mg/12 hours to maintain 50mg/L
