RE Chapter 6 Flashcards
True or False? The smaller the molecular size of an agent, the better it crosses the lipid barriers and membranes of tissues.
True.
Pharmacokinetics Definition
The study of changes in the concentration of a drug during the process of absorption, distribution, metabolism, and elimination from the body (what the body does to a drug once the agent has been introduced to the system)
Molecules with molecular weights greater than ____ to ____ do not cross cell membranes.
100 to 200
The transfer of drug depends on what 5 things?
- Molecular Size
- Transporters
- Lipid solubility
- Degree of Ionization
- Protein Binding
Active or passive transport does not require energy and involves transfer of drugs from high to low concentrations
passive
Active or passive transport is generally faster and requires energy.
Active
These drug transporters control passive movement of solutes down their electrochemical gradient.
Solute carrier transporters (SLC)
These drug transporters are active pumps requiring energy derived from ATP.
adenosine triphosphate-binding cassette (ABC) transporters
What is antiport?
The exchange of one molecule for another in a drug transporter
What is symport?
Transport of to molecules together in the same direction
Where are SLCs most important?
blood-brain barrier, GI tract, renal tubules, biliary tract, placenta
The charged (ionized) form of a drug is…(water or lipid soluble?)
water soluble (hydrophillic) - unable to diffuse across cell membranes.
The uncharged (nonionized) form of a drug is…(water or lipid soluble?)
Lipid soluble (lipophillic)
True or False? The higher degree of ionization the less access the drug has across tissues.
True
How are ionized drugs commonly excreted?
Through the RENAL system since they are not absorbed well and may not be metabolized by the liver.
what is the dissociation constant & PH gradient across the membrane?
It determines the degree of ionization of an agent
For basic drugs PKa =pH=
log[(HA+)/(A-)]
For acidic drugs:
pKa=pH=
log[(A-)/(HA+)]
Acids are proton _____(acceptors/donors) and bases are proton ______(acceptors/donors)
Acids - proton donors
Bases - proton acceptors
If a weak acid is placed in a pH below its pKa is the drug ionized or nonionized?
nonionized (so lipid soluble)
if a weak base is placed in an environment below its pKa does it become ionized or nonionized?
ionized (lipid insoluble)
Weak acids:
- pH > pKa - (ionized/equal/nonionized)
- pH = pKa - (ionized/equal/nonionized)
- pH < pKa - (ionized/equal/nonionized)
- Ionized form is predominant
- Equal forms exist
- Nonionized form is predominant
Weak Bases:
- pH > pKa - (ionized/equal/nonionized)
- pH = pKa - (ionized/equal/nonionized)
- pH < pKa - (ionized/equal/nonionized)
- Nonionized predominant
- Nonionized equal to ionized
- Ionized predominant
What are situations when there is reduced plasma proteins?
liver/kidney disease, poor nutrition, the last trimester of pregnancy
What protein favors binding to acidic drugs?
albumin
What proteins favor binding to basic drugs?
alpha1-acid glycoprotein (AAG) & beta-globlulin
What protein binds to cyclosporine?
lipoprotiens
What protein binds to corticosteroids?
transcortin
Degree of protein binding is proportional to _______.
lipid solubility
Drugs with protein binding _____% are conceptualized to have an unexpected intensification of their effect if they are displaced from plasma proteins.
> 90
Drugs with _____% protein binding have so little change in free active fractions that they are not a concern.
<90
When entereally administered acidic drugs are absorbed in the ______ wheras basic drugs are absorbed in the ______
stomach
intestine
What is the definition of presystemic elimination?
the elimination of drug by the GI system before the drug reaches systemic circulation
What are the three mechanisms of presystemic elimination?
- stomach acids hydrolyze the drug
- enzymes in the GI wall deactivate the drug
- liver biotransforms ingested drug before it reaches the effective sites (first pass metabolism)
Which route of administration has the most rapid onset and greatest bioavailability?
Intravenous.
Inhalation also parallels IV administration
Which route of administration has the slowest absorption?
Topical
Name some agents that undergo substantial first-pass elimination
- Aspirin
- glyceryl trinitrate
- Isosorbide dinitrate
- Levodopa
- Lidocane
- Metoprolol
- Morphine
- propanolol
- salbutamol
- verapamil
Which drug routes is the drug rapidly delivered tot he superior vena cava for transport to the effect site?
Sublingual/buccal
Drugs placed in the _____ rectum are absorbed into the portal system via superior hemorrhoidal vein and undergo significant first-pass effect
proximal
Drugs placed in the ______ rectum do not undergo pre-systemic elimination and have a more predictable response.
Distal
What is the definition of bioavailability?
The extent to which a drug reaches its effect site after its introduction into the circulatory system.
What are the main factors that determine the rate of passive diffusion across membranes?
Lipid solubility and concentration gradient.
The central compartment (vessel rich group) consists of what? It represents ____% of body mass and receives _____% of cardiac output.
- heart, lungs, liver, kidneys
- 10%
- 75%
The peripheral compartment (vessel poor group) consists of what? It represents ____% of body mass and receives _____% of cardiac output.
- muscle, fat, bone
- 90%
- 25%
What is the equation for volume of distribution?
volume of distribution = dose of drug / plasma concentration of drug
In a 70 kg patient what is the volume for: plasma compartment? interstitial compartment? extracellular compartment? intracellular fluid?
plasma: 4 liters
interstitial: 10 liters
extracellular: 14 liters (plasma + intersitital)
intracellular: 28 liters
What is total body water volume for a 70 kg patient?
42 liters (plasma + interstitial + ICF)
What is the typical volume of distribution for a 70 kg patient?
42L/70kg = 0.6L/kg
Drugs with a high volume of distribution are considered to be ______(lipid/water soluble) and drugs with a low volume of distribution are considered to be ______(lipid/water soluble)
large Vd (>0.6L/kg): lipid soluble small Vd(<0.4L/kg): water soluble
What does the alpha phase of the plasma concentration curve represent?
The distribution phase, the initial dispersal of drug into the tissue compartments from the central compartment.
What does the beta phase of the plasma concentration curve represent?
Elimination phase, elimination of the drug from the circulation
What phase of the plasma concentration curve is used to determine elimination half-life of drugs?
beta phase
What is a biexponential decay curve?
When two components of decay exist such as in the plasma concentration curve. The first slope describes distribution and the second describes elimination.
What is the goal of metabolism?
To change lipid soluble agents into more water soluble forms so the kidneys can eliminate them from the body.
What is first order kinetics?
Drugs leave the body at a constant rate or percentage over time. The half-life is constant. Dose is independent of clearance.
What is zero order kinetics?
Even at therapeutic doses drugs exceed the body’s ability to excrete or metabolize them, the enzymes that eliminate them are saturated.
What are phase I reactions?
Oxidation, reduction, and hydrolysis
What is oxidation?
Oxygen is introduced to the molecule, loss of electrons.
What is reduction?
Involves the gain of electrons. Insufficient oxygen is present to compete for electrons so enzymes transfer electrons directly to substrate.
What enzymes catalyze oxidation and reduction?
Cytochrome P-450
What is hydrolysis?
Addition of water to an ester or amide to break the bond and form two smaller molecules.
Addition of water to an ester leads to…
acid and alcohol
Addition of amides leads to…
acid and amine
What are some pseudocholinesterase catalyzed drugs that undergo hydrolysis?
Succinylcholine, cocaine, procaine, chloroprocaine, tetracaine, neostigmine, edrophonium.
What are some non-esterase dependent drugs that undergo hydrolysis?
remifentanil, atracurium, cisatracurium, esmolol, aspirin, clevidipine, MOC-etomidate.
Why are phase II reactions also known as synthetic reactions?
The body synthesizes a new compound by donating a functional group.
Conjugation always leads to a more _____(polar/non-polar) compound, that is ______(ionized/non-ionized) therefore more easily extractible via glomerular filtration.
polar
Ionized
During a phase II reaction a conjugate from the phase I reaction joins a _____, ______, or ________ group to form an ester or amide bond.
OH, COOH, or NH
Why is cytochrome P450 also called mixed-function oxidase system?
It includes both oxidation and reduction and has low substrate specificity
What is enzyme induction?
Stimulation of enzymes over a period of time increases the activity and can more quickly break down agents.
What is enzyme inhibition?
Exposure to certain drugs and chemicals leads to accumulation of the agent, increases plasma levels, and may lead to toxicity.
What is the elimination half-life (t1/2)?
The time necessary for the plasma content of a drug to drop half of its prevailing concentration after a rapid bolus injection
How many half lives must pass before the drug is considered fully eliminated and termination of action usually occurs?
4
After 4 half lives what % of drug is eliminated and what % remains in the body?
93.75 % is eliminated and 6.25% remains in the body.
What is zero-order elimination?
A constant amount (not percentage) is eliminated over time.
What is the Michaelis-Menton model?
Dose dependent and follows zero order at high doses and first order once drug levels have fallen.
What is the context-sensitive half-time?
The time too halving of the blood concentration after termination of drug administration by an infusion designed to maintain a constant concentration. Does not mean recovery from anesthetic though.
What is the equation for clearance?
Clearance = Q x E
Q= blood flow E= extraction ratio
Drugs that have an extraction ratio of _____ or greater rely heavily on perfusion of the liver to be cleared.
0.7
What does perfusion-dependent elimination mean?
Hepatic blood flow outweighs enzymatic activity in clearing drugs from the body. A decrease in hepatic blood flow decreases rate of clearance.
Drugs with an extraction ratio of _____ rely very little on hepatic perfusion, this is known as _________ elimination.
0.3
capacity-dependent
What are examples of high hepatic clearance drugs?
verapamil, morphine, & lidocaine
What are examples of low hepatic clearance drugs?
diazepam & theophylline.
______(lipid / water) soluble drugs are easily excreted by the kidneys, whereas ________(lipid / water) soluble drugs are reabsorbed by the kidneys into circulation.
water
lipid
Are weak acids better excreted in alkaline or acidic urine?
alkaline
weak bases are better excreted in acidic urine.
