Pharmacokinetics Flashcards
Study of the mechanisms and quantitative characteristics of drug liberation, drug absorption, distribution, metabolism/biotransformation, and excretion (ADME)
Pharmacokinetics
4 aspects studied by pharmacokinetics
Drug absorption, distribution, metabolism/biotransformation, and excretion (ADME)
passage of drug between site of administration and vascular compartment
Absorption
Enteral routes of administration (4)
Oral, buccal, sublingual, rectal
3 Non-alimentary routes of administration
Pulmonary/inhalation, Parenteral (IV, intraperitoneal, intra-arterial, intraspinal, subcutaneous, intramuscular), topical
Many quick dissolve drugs are not actually sublingual or buccal forms, but simply this
Drug delivery systems that quickly dissolve in the moisture of the mouth
Dissolved drug must be swallowed for absorption
Sublingual and buccal routes of administration are limited to drugs that are _____ soluble and taste good
Lipid soluble
4 factors that affect GI function and can affect oral drug absorption
Drug characteristics
Transit time
Absorptive surface area
Food may interfere with dissolution and absorption
Can you split extended release tablets/capsules/pills?
No
Route of administration that is Usable in unconscious patient, vomiting patient, and in infants
Compliance is major problem
Good absorptive profile
NO first pass effect
Rectal route
Is there first pass effect with rectal route of administration?
No
To be absorbed in the stomach, a drug must be ______
Acidic
Basic drugs likely get absorbed here
In the intestine
If they survive the acidic environment of the stomach
Occurs when portal blood delivers a drug to the liver
The liver biotransforms the drug before it reaches systemic circulation
OR Liver extracts the drug into the bile before it reaches systemic circulation
Net effect: the amount of unchanged drug entering systemic circulation is reduced
May represent a loss of bioavailability
First Pass Effect
Describe the net effect of the First Pass Effect
The amount of unchanged drug entering systemic circulation is reduced
The first pass effect occurs because of this
Portal blood delivers drug to liver where it is biotransformed or extracted into the bile
Oral nitroglycerin is subject to this
First pass effect
Use sublingual route
Oral drug that is subject to first pass effect and uses sublingual route
Nitroglycerin
Primary area of absorption for oral route
Small intestine
Organ with large absorptive surface area
Possible first pass effect
Small intestine
Does the first pass effect occur with the small intestine?
Possible yes
Most absorption in the small intestine occurs here
In first 2 meters
Small intestine is primary area of absorption for this route
Oral route
Organ with limited role in drug absorption; small absorptive surface area, long ‘contact’ time
Dense contents limits access to absorptive surface
Large intestine
The inhalation route has good absorptive capacity here
In alveolar spaces
Route that is closest to ideal for diffusion
High surface area; highly permeable membranes
Many drugs do not reach this space, are not absorbed; Requires gas, aerosol or fine particle
Inhalation route
3 common adverse effects of the inhalation route
Cough, irritation of throat, bronchospasm
What type of drugs are inhalers for asthma and COPD?
Topical drugs (not inhaled drugs)
Only deliver drug to the upper airway structures without necessary entry into blood
Route of administration where systemic absorption is normally minimal
Drug must be non-irritating
Compliance depends on physical characteristics of drug or vehicle
Topical route
Systemic absorption with the topical route is increased with these 4 factors
Increased lipid solubility
Conditions associated with enhanced skin permeability
Application to large surface area
High dosages
Route of administration that uses patch medications
Highly lipophilic drugs only
Generally used for short acting drugs
Slow onset of effect may be a limiting feature
Transdermal delivery
Transdermal deliver requires this type of drugs only
Highly lipophilic drugs only
Patch medications use this type of delivery
Transdermal
Route of administration involving proteins absorbed via lymph
Vehicle, volume, surface area, site of administration, environmental factors all contribute to absorption
Implants or suspensions can be used
Subcutaneous or intramuscular routes
Drugs given via the subcutaneous or intramuscular routes are absorbed via this
Lymph
Route of administration where sterile techniques and materials are obligatory
Rate of administration is important variable
Irreversible as drug is automatically in blood (so not real absorption)
Drug must be water soluble or micro-suspension
Only routes guaranteed to provide 100% bioavailability
Intravenous or intra-arterial routes
Only routes of administration guaranteed to provide 100% bioavailability
Intravenous or intra-arterial routes
Routes of administration where there is no absorption since drug is directly applied to the vascular space
Intravenous or intra-arterial routes
Routes of administration that are irreversible as drug is automatically in blood
Intravenous or intra-arterial routes
Intravenous or intra-arterial routes requires drugs that are this
Water soluble or micro-suspension
Does the first pass effect occur with the intraperitoneal route?
Yes
Route that is similar to oral without the problems associated with the stomach or intestine
First pass effect
Intraperitoneal
Route of administration where Drug is placed inside meninges
Requires high degree of training and skill
Little margin for error permitted
Ensues access to CNS with all inherent risks
NOT the same as an epidural
Intrathecal route
Drugs given via the intrathecal route are placed here
Inside meninges
4 drug characteristics that favor crossing membranes
Uncharged
Nonpolar
Low molecular weight
High lipid solubility
Drug permeation process that is not saturable; most drugs use this to move along concentration gradient
Paracellular transport
Diffusion is most important limiting factor
Passive
Drug permeation process that is saturable, can be facilitated or active transport (moves substance against gradient)
Special carriers
Drug permeation process that used for proteins and very large molecules
Endocytosis/exocytosis
Number used to predict the membrane permeability of a drug at different pH values
Negative log of a drug’s dissociation constant (pKa)
Henderson-Hasselbalch can be used to predict this
How much drug crosses membrane
Used to predict the portion of a drug that will permeate a membrane in a given pH environment based on the drug pKa
Henderson-Hasselbalch
Degree of ionization for weak acids are greater at ______ pH
Higher
Degree of ionization for weak acids are lesser at ______ pH
Lower
Degree of ionization for weak bases are greater at ______ pH
Lower
Degree of ionization for weak bases are lesser at ______ pH
Higher
Is the pKa for a drug constant?
Yes
Will a weak acid be ionized when solvent pH is less than its pKa?
Unionized
(acid - acid)
Will a weak acid be ionized when solvent pH is more than its pKa?
Ionized
(base - acid)
Will a weak base be ionized when solvent pH is less than its pKa?
Ionized
(acid - base)
Will a weak base be ionized when solvent pH is more than its pKa?
Unionized
(base - base)
If pH < pKa, solvent is _____ relative to drug
Acidic
If pH > pKa, solvent is _____ relative to drug
Basic
Weak acids are ionized in ______ solvents
Basic
Weak acids are unionized in ______ solvents
Acid
Weak bases are ionized in ______ solvents
Acidic
Weak bases are unionized in ______ solvents
Basic
10 ^ ([pH - pKa]) predicts this
Ratio of drug ionized to unionized
ATP-driven efflux transporter expressed in intestine and other tissues
‘Pumps’ drugs back into the intestinal lumen or out of cells and into blood
Substrates include anti-cancer drugs, immunosuppressive drugs and some drugs used to treat heart failure
Reduces absorption
P-glycoprotein (Pgp)
P-glycoprotein does this
Pumps drugs back into intestinal lumen or out of cells and into blood
Reduces absorption
P-glycoprotein expression is increased by this
TB antibiotic rifampicin
Leads to reduced drug absorption
TB antibiotic rifampicin has this affect on P-glycoprotein
Induces expression, leads to reduced drug absorption
TB antibiotic rifampicin has this affect on drug absorption
Reduces due to increased expression of P-glycoprotein
P-glycoprotein is inhibited by this drug, thus increasing drug absorption
Verapamil
Fraction of total drug administered that is transferred to blood (how much drug eventually gets into circulation)
Bioavailability (F)
Bioavailability (F) of IV route
100%
Oral route has bioavailability F<100% due to this
First pass metabolism by liver and incomplete absorption into systemic blood
Effect that removes drug before systemic circulation
First pass metabolism
This can be reduced by formation of insoluble complexes in GI
Bioavailability
Equation to convert dosage when changing drug formulation
Dose1 x F1 = Dose2 x F2
How many nanograms in a microgram?
1 ug = 1000 ng
Blood flow to a tissue/region determines the rate of drug delivery and can contribute to termination of drug action
Distribution
Key concept of distribution
A mathematically definable space to which drug may enter and exit
Compartments
3 possible compartments involved in drug distribution
Plasma, interstitial fluid, and cells
Changes in this compartment will be directly reflective of changes in connected areas
Plasma
Describe the one compartment model of distribution
Plasma is in equilibrium with interstitial areas and is accessible
Changes in plasma will be directly reflective of changes in connected areas
Plasma is surrogate for other compartments
Equation for volume; used to understand drug distribution throughout a compartment
Volume = Dose / Plasma Concentration
hypothetical volume in which a dose (D) of drug would have to be placed in to obtain the measured plasma concentration (Cp)
Volume of distribution (Vd)
Vd = D / Plasma concentration = (mg/kg) / (mg/L) = L/kg
Vd of 3-5 indicates a drug is likely distributed in this
Plasma water
Vd of 5-10 indicates a drug is likely distributed in this
Blood volume
Vd of 10-20 indicates a drug is likely distributed in this
Interstitial space
Vd of 22-42 indicates a drug is likely distributed in this
Total body water
Vd of >70 indicates a drug is likely distributed in this
Tissue bound (or even accumulating)
Vd is inversely related to this
Drug concentration for a given dose
Large Vd are associated with low drug plasma concentration and imply high ______ solubility
High lipid solubility (low water solubility)
Small Vd are associated with high drug plasma concentration and imply high ______ solubility
High water solubility (low lipid solubility)
Does large or small Vd have longer durations of action?
Large
Does large or small Vd have shorter durations of action?
Small
Does large Vd indicate long or short durations of action?
Long
Does small Vd indicate long or short durations of action?
Short
Describes how much drug must be given at one time to achieve effective blood levels
Used to achieve a desired blood level (concentration at steady state) quickly and reliably
Loading dose = Vd x TC/F
TC = target concentration
Equation for loading dose
Loading dose = Vd x TC/F
(TC = target concentation; F = bioavailability)
What is loading dose used for?
Used to achieve a desired blood level (concentration at steady state) quickly and reliably
Only _____ drug is active drug
Free drug
Protein binding typically parallels increased _______
Lipid solubility
This typically parallels increased lipid solubility
Protein binding
Are drugs with large or small Vd often highly protein bound?
Large
Most common acceptor protein in the body; 50% serum protein
Albumin
Common acceptor protein binding cardiovascular and centrally acting drugs
Alpha1-acid glycoprotein
3 drug acceptor proteins
Albumin
Lipoprotein
Alpha1-acid glycoprotein
Process of enzymatic biotransformation of a drug into another compound (a metabolite)
Generally regarded as a function of the liver, though GI tract, kidney and placenta have capacity
Usually results in drug conversion to a more polar form more likely to be renally excreted
Not always an inactivation process, as the metabolite may be the active form of the drug.
Metabolism/biotransformation
Metabolism usually results in drug conversion to a more ______ form that is more likely to be renally excreted
Polar
Type of drugs that have little or no activity until biotransformed
Prodrugs
Two primary biotransformation pathways
Phase I reactions (oxidation, reduction, hydrolysis)
Phase II reactions (conjugation, acetylation, methylation)
3 types of reactions involved in phase I reactions of biotransformation
Oxidation, reduction, hydrolysis
3 types of reactions involved in phase II reactions of biotransformation
Conjugation, acetylation, methylation
Most common phase I reaction
Oxidation
Most important oxidation system of phase I reactions of biotransformation
Cytochrome P450 oxidative system (CYP, mixed function oxidase (MFO), monooxygenase, microsomal enzyme system)
Phase I or II reactions of biotransformation:
Destructive pathways as primary compound is forever changed
Often diminished in elderly patients
Phase I
Cytochrome P450 oxidative system is involved in Phase I or II reactions of biotransformation?
Phase I
Are these reactions Phase I or II of biotransformation:
Oxidation, reduction, hydrolysis
Phase I
Are these reactions Phase I or II of biotransformation:
Conjugation, acetylation, methylation
Phase II
Intracellular location of cytochrome P450 oxidative system
Endoplasmic reticulum
Predominant CYP isoform; amount and importance, accounts for a lot of first pass effect
High interaction potential
Few genetic polymorphisms
CYP 3A4/5
CYP 3A4/5 is induced by
Smoke and some vegetables
CYP 3A4/5 is inhibited by
Some antibiotics (quinolone and macrolides) and grapefruit
Partial irreversible inhibitor of CYP 3A4
Grapefruit
CYP 3A4/5 is especially important for these drugs
Orally administered drugs biotransformed by intestinal wall CYP3A4 enzymes
E.g. lovastatin (Mevacor)
Recovery half-life of CYP 3A4/5
About one day
Does CYP 3A4/5 have genetic polymorphisms?
No; few
Grapefruit is a partial irreversible inhibitor of this
CYP 3A4
CYP that is especially important for orally administered drugs biotransformed by intestinal wall
E.g. lovastain (Mevacor)
CYP 3A4
CYP with high interaction potential
Induced by many drugs (anticonvulsants, warfarin)
Clinically important genetic polymorphisms have different metabolizing capacity than more common genotypes (some are poor metabolizers, reducing first pass metabolism and patient exposure to drugs)
CYP 2C8/9/10
Drugs that induce CYP 2C8/9/10
Anticonvulsants and warfarin
Does CYP 2C8/9/10 have genetic polymorphisms?
Yes!
Clinically important genetic polymorphisms in CYP2C9 and CYP2C19 have different metabolizing capacity than more common genotypes
Some are poor metabolizers, reducing first pass metabolism and patient exposure to drugs
Does CYP 3A4/5 have high or low interaction potential?
High
Does CYP 2C8/9/10 have high or low interaction potential?
High
Second most predominant CYP isoform
Highest number of genetic polymorphisms
Deficiencies are common; hyper metabolizers are noted
Several inhibitors noted including many cardiovascular and psychoactive drugs
CYP 2D6
Does CYP 2D6 have genetic polymorphisms?
Yes! Highest number of genetic polymorphisms
7% Caucasians are deficient
1-3% African Americans and Asians are deficient
Hyper metabolizers (multiple copies of CYP 2D6 gene) are noted
Percentage of caucasians that are deficient in CYP 2D6
7%
Percentage of African Americans and Asians are deficient in CYP 2D6
1-3%
30% of cytochrome P450 interactions involve this CYP
CYP 2D6
Hyper metabolizers (multiple copies of the CYP gene) are noted for this CYP
CYP 2D6
Inhibitors of CYP 2D6
Cardiovascular and pyschoactive drugs
Drugs that inhibit CYP450 activity are often this mechanism-based
Covalent “suicide” inhibitors
5 drugs that induce CYP expression
Anticonvulsants
Rifampin (anti TB)
Chronic alcohol
Glucocorticoids
Phenobarbital
Induction of CYP involves increased this
Heme protein synthesis
Induction of an increase in CYP450 expression results from this
Elevated CYP450 mRNA production
Deficiency of heme synthesis pathways and during CYP induction toxic levels of heme proteins may accumulate
Porphyria
Porphyria is this
Deficiency of heme synthesis pathways
During CYP induction toxic levels of heme proteins may accumulate
Phase I or II reactions of biotransformation:
Synthetic pathways as primary compound is chemically added; attaches a polar group to the drug by transferase enzymes
Final result generally very polar compared to parent compound, more likely to make product excretable (renally or in bile) than phase 1 process
Phase II
Final result of phase II reactions is generally ________ compared to parent compound, and more likely to be excreted (renal or bile) than phase I process
Very polar
Kidneys can’t easily eliminate _________ drugs, so these drugs need to be made more hydrophilic by phase I and II reactions
Lipophilic (membrane permeable)
Is conjugated drug usually active or inactive?
Inactive
Following Phase I reactions, drug is most often _______
Inactivated
6 factors that affect drug biotransformation
Enzyme induction
Genetics
Age
Nutrition
Disease (hepatitis, cirrhosis)
Other drugs
Does increased activity or cytochrome P450 system enhance or reduce metabolism of substrates?
Enhance
Drugs removed faster, inadequate dose, subtherapeutic levels
Levels of drug biotransformation in newborn
Limited
Levels of drug biotransformation in adolescence
Unstable and often high
Levels of drug biotransformation in puberty
Relatively high
Levels of drug biotransformation in great age
Diminished
Nutrition reduces biotransformation in these 3 conditions
Protein deficiency
Diets deficient in essential fatty acids
Excessive intake of glucose, sucrose, or fructose
2 diseases that affect drug biotransformation
Hepatitis, cirrhosis
Two primary mechanisms for clearing drugs and their metabolites from the body:
Hepatic and biliary clearance
Renal clearance
Renal drug clearance mechanisms are the same as for endogenous substances and include these 3 mechanisms:
Glomerular filtration
Tubular secretion (active process)
Tubular reabsorption (may be active or passive, mostly passive diffusion)
Is tubular secretion an active or passive process?
Active
Is tubular reabsorption an active or passive process?
May be active or passive
Mostly passive diffusion
Only a small fraction of drug is cleared by this in each pass through the kidneys
Glomerular filtration
Drugs bound to plasma protein are too large to be cleared by this
Glomerular filtration
Route of elimination that is available to volatiles, diffusion is primary mechanisms
Have relatively high level of biotransformation potential
Pulmonary elimination
Many drugs are subject to a pulmonary “first pass” effect because of this
Lungs have a relatively high level of biotransformation potential
Following process such as conjugation with __________, a drug is excreted by the liver cells into the bile and then delivered to the small intestine
Glucuronic acid
Type of excretion important for some molecules that are anionic, cationic, or non-ionized molecules containing polar or lipophilic groups
Biliary excretion
When deciding on starting doses for a drug eliminated by renal processes, the patient’s renal function should be assessed by this level
Creatinine clearance (CrCl)
Normal creatinine clearance (CrCl) range
70-160 mg/min
Creatinine clearance (CrCl) range that indicates a minor dosage adjustment is needed
30-60 mg/min
Creatinine clearance (CrCl) range that indicates moderate dosage adjustment is needed
15-30 mg/min
Creatinine clearance (CrCl) range that indicates a major dosage adjustment is needed
Below 15 mg/min
_________ has an impact on the magnitude and duration of responses to drugs
Pharmacokinetics
Equation for clearance
Cl = rate of drug elimination / plasma drug concentration
Is clearance specific for route of elimination?
NO
If multiple routes of elimination exist, the clearance rate is additive
Time required for drug serum concentration to decline by one half after absorption and distribution are complete
Half life (T 1/2)
Do rapidly eliminated drugs (large clearance values) have short or long half lives?
Short
Do slowly eliminated drugs (small clearance values) have short or long half lives?
Long
Equation for half life
T 1/2 = 0.7 / Ke
(Ke = elimination constant for that drug)
Relation between clearance and half life
Clearance is inversely related to half life
Two primary mathematical models of elimination
Zero (aka linear) and first (aka nonlinear) order kinetics
Mathematical modeling of elimination:
Amount per unit time
Rate is constant and independent of drug
Typical of biological processes that are saturated
Unusual
Dependent on starting drug concentration
Half-life is not constant, but each subsequent half-life is half of the preceding one
Zero order kinetics (aka linear or saturation kinetics)
Mathematical modeling of elimination:
Fractions per unit time
Rate is diminishing and always in proportion to the amount of drug in the body
Typical
Half-life is constant regardless of drug concentration
First order kinetics (aka nonlinear kinetics)
Mathematical modeling of elimination:
Amount per unit time
Zero order kinetics
Mathematical modeling of elimination:
Fractions per unit time
First order kinetics
First order kinetics are linearized when using this
Semi-log Y-axis
Mathematical modeling of elimination:
Half-life is dependent on starting drug concentration
Zero order kinetics
Mathematical modeling of elimination:
Half-life is constant regardless of drug concentration
First order kinetics
Zero order kinetics involve _______ per unit time
Amount
First order kinetics involve _______ per unit time
Fractions
Mathematical modeling of elimination:
Rate is constant and independent of drug
Zero order kinetics
Mathematical modeling of elimination:
Rate is diminishing and always in proportion to the amount of drug in the body
First order kinetics
Pattern of half-life in zero order kinetics
Dependent on starting drug concentration
Each subsequent half-life is half of the preceding one
Pattern of half-life in first order kinetics
Constant regardless of drug concentration
Loading and maintenance doses must be corrected for _________ less than 1.0
Bioavailabilities (F)
Loading and maintenance doses must be corrected for bioavailabilities (F) less than this
1.0
Once a steady state has been achieved, this can be used to sustain it over time
Maintenance dose
For maintenance dose, use this as the dosing interval
Drug’s half life
Maximal blood level is _____ the drug serum concentration achieved with the first dose
Twice
Minimal blood level is _______ the drug serum concentration achieved with the first dose
Equal
Loading dose is ______ the maintenance dose
Twice
Loading dose is twice this
Maintenance dose
Refers to the condition where overall drug intake is in dynamic equilibrium with its elimination, and is generally achieved within five half-lives (for first order kinetics)
Steady state concentration (Css)
Equation for steady state concentration (Css)
Css = Rate in (infusion rate) / Rate out (elimination/clearance)
