Pharmacokinetics Flashcards by Stacey Hansen

Study of the mechanisms and quantitative characteristics of drug liberation, drug absorption, distribution, metabolism/biotransformation, and excretion (ADME)

Pharmacokinetics

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4 aspects studied by pharmacokinetics

Drug absorption, distribution, metabolism/biotransformation, and excretion (ADME)

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passage of drug between site of administration and vascular compartment

Absorption

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Enteral routes of administration (4)

Oral, buccal, sublingual, rectal

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3 Non-alimentary routes of administration

Pulmonary/inhalation, Parenteral (IV, intraperitoneal, intra-arterial, intraspinal, subcutaneous, intramuscular), topical

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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

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Sublingual and buccal routes of administration are limited to drugs that are _____ soluble and taste good

Lipid soluble

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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

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Can you split extended release tablets/capsules/pills?

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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

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Is there first pass effect with rectal route of administration?

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To be absorbed in the stomach, a drug must be ______

Acidic

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Basic drugs likely get absorbed here

In the intestine
If they survive the acidic environment of the stomach

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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

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Describe the net effect of the First Pass Effect

The amount of unchanged drug entering systemic circulation is reduced

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The first pass effect occurs because of this

Portal blood delivers drug to liver where it is biotransformed or extracted into the bile

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Oral nitroglycerin is subject to this

First pass effect
Use sublingual route

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Oral drug that is subject to first pass effect and uses sublingual route

Nitroglycerin

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Primary area of absorption for oral route

Small intestine

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Organ with large absorptive surface area
Possible first pass effect

Small intestine

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Does the first pass effect occur with the small intestine?

Possible yes

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Most absorption in the small intestine occurs here

In first 2 meters

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Small intestine is primary area of absorption for this route

Oral route

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Organ with limited role in drug absorption; small absorptive surface area, long ‘contact’ time
Dense contents limits access to absorptive surface

Large intestine

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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

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)