Exam 1 Pharmacokinetics Flashcards
Lecture 3
List the steps of the life of a drug in the body
- Route of administration
- Absorption
- Distribution
- Metabolism (changed so can be extracted)
- Excretion
What are the 3 routes of administration?
- Enteral
- Parenteral
- Topical (type of parenteral)
____ uses the gastrointestinal tract for ingestion
Enteral
What route avoids the GI tract?
Parenteral
Topical is also a ____ route
Parenteral
Topical drugs can be applied to:
Skin or mucous membranes
Once a drug enters the body via enteral route, what happens?
- Absorbed from stomach/intestine
- Goes to the liver (first pass effect)
- Distributed to the rest of the body
What is the first pass effect?
Most blood supplying the GI tract travels to the liver before going to the rest of the body (portal system), often inactivating drugs
What organ is metabolic (change) machine?
Liver
What is the pathway a drug takes in the enteral route?
- Goes to lumen of GI tract
- Enters hepatic portal system (capillaries –> hepatic portal vein)
- Liver (metabolizes drugs)
- General circulation
Special points of the enteral route
- Sublingual
- Rectal
What point in the enteral route has rapid absorption of certain drugs?
Sublingual
True or false: Sublingual route still has first-pass drug metabolism in the liver
False - avoids first pass
Is rectal route systemic?
Yes
____ is useful for when pt has nausea/vomiting
Rectal route
Enteral route special point
True or false: rectal has relatively little first-pass metabolism
True
Examples of parenteral routes
- Subcutaneous injection
- Intramuscular injection
- Intravenous injection
- Transdermal
- Implantation
- Intrathecal injection (into CSF/spinal cord)
- Intra-articular injection (arthritis)
- Inhalation
- Topical
All forms of injections (IM, SQ, IV)
Topical administration can be given through a ____
Transdermal patch (Scopolamine for motion sickness)
In a transdermal patch, dose is ____ to the area of the patch
Proportional
Distribution of transdermal patch depends on what?
Blood flow
Inhalation involves:
Gases or solid/liquid particulate aerosols
What is used for an acute allergic reaction?
Epinephrine aerosol
The more layers between the site of administration and the bloodstream, the ___ the rate
Slower
Rank order of routes from slowest to fast - IM, SQ, oral
Oral < SQ < IM
Rank order of membrane systems from slowest to fast
Muscle, GI, skin
GI < skin < muscle
What route will result in the quickest absorption?
IV injection
Most oral administered drugs are absorbed in the ____
Small intestine
What factors affect speed of absorption in the enteral route?
- Surface area
- Drug-food interactions
- Dosage form
- Drug inactivation
Small intestine has what structures that greatly increase effective surface area?
Folds, villi, microvilli
The bigger the surface, the ____ drug gets across
More
A glass of water on an empty stomach enters the small intestine ____. Half of water in ____ and all liquid removed from stomach in ____
Rapidly; 15 min; 1 hour
A mixed meal of solids and liquids begins to enter the duodenum in about ____ and requires up to ____ to leave stomach completely
30 min; 4 hours
How should most drugs be taken?
In absence of food but with a full glass of water (exception is drug with high lipid solubility, such as fat soluble vitamins)
Dosage form
Solution vs tablet: concentration of aspirin in plasma after 30 min can be ___ for ____ as for ____
2x for solution as for tablet
Other factors affect speed:
What are enteric coated tablets?
Film over tablet that is insoluble under acidic conditions of the stomach, but breaks down in alkaline small intestine
Other factors affect speed: Dosage form
What is sustained release?
Porous matrix or spheres of drug with different coatings that dissolve at different rates
Other factors affect speed: Drug inactivation
Examples of drug inactivation
- Gastric acid breaks down drugs
- Enzymatic activity (hydrolysis by pancreatic and intestinal peptidases)
- Enteric bacterial enzymes
- Drugs chelate with divalent cations, or form insoluble salts (tetracycline with Ca2+ in dairy products)
What is absorption?
Passage of a drug from the site of administration into the bloodstream
All drugs have to:
Cross membranes, reach its site of action, and eventually elimination
How do things get across the membrane?
Passive transport or active transport
Passive transport is diffusion of ____ soluble substances through:
Lipid; Protein channels and facilitated transport
Active transport is transport against ____ through ____
Gradients; active, co-transport, counter transport
Absorption is favorable when:
A drug is lipid soluble
Oral Ingestion: Influence of pH
The ___ of the surrounding medium affects the degree of ____, and therefore drug absorption
pH; Ionization
True or false: H+ concentrations of stomach and small intestine are very similar
False - very different, therefore very different patterns of drug absorption
Aspirin is a ____ acid
Weak
Codeine is a weak ____
Base
Where do acidic drugs favor absorption?
Stomach (where pH is low)
Where are basic drugs absorbed?
Small intestine (where pH is higher)
The absorption of aspirin is further promoted by:
Ion trapping within the plasma
The low pH of the stomach favors ____ of codeine
Gastric retention
____ behaves similarly to codeine
Local anesthetic
Bioavailability refers to:
- Extent of absorption of intact drug
- the fraction of an extravascularly administered dose (generally oral) that reaches the systemic circulation in an unchanged form
What do bioavailability studies provide?
- Useful information on the specific dosage and dosage regimen for non-intravenous routes of administration
- Information regarding the performance of a formulation
If 100 mg of a drug is administered orally and 70 mg of the drug is absorbed unchanged, what is the bioavailability?
70% (0.7)
What is the bioavailability for a IV dose administered directly into systemic circulation?
100%
____ is when a formulation is interchangeable if it contains the same dose of the same chemical entity, generally int he same dosage form and they exhibit the same rate and extent of absorption
Bioequivalence
What is bioequivalence documentation useful for?
- Evaluate different formulations (tablet vs capsule)
- Compare generic vs branded drug
What is drug distribution?
How a drug, once absorbed, gets to tissues and fluids of the body
Total body H2O (42 L) is found where?
Inside cells and outside cells
How much water is found inside cells?
28 L
How much water is found outside cells?
14 L
Where specifically is water found outside cells?
- Between cells and the water in blood (3L of plasma)
- Interstitial fluid (10L)
- Transcellular fluid (1L)
What is transcellular fluid?
Specialized fluids separated from plasma by epithelium (synovial, intraocular, cerebrospinal)
____ is the apparent and hypothetical volume in which a drug is dispersed
Volume of distribution (equilibrium concept)
Volume of distribution formula
Dose (mg)/Plasma concentration (mg/mL)
Your patient takes 3 tablets of 200 mg ibuprofen. Plasma concentration is measured as 0.043 mg/mL. Calculate Vd and likely location of the ibuprofen?
13.9 L; Extracellular fluid
True or false: drugs may be hidden from measurement
True
Drugs can “hide” if they:
- Dissolve well in fat and are stored there
- Bound to PROTEINS in the blood
True or false: Vd is an actual volume
False - theoretical volume (used to estimate where a drug is in the body)
Vd example: drug that is high molecular weight binds to ____
Plasma proteins (heparin –> 3 liters –> plasma)
Vd example: drug that is low molecular weight and is hydrophilic
Amoxicillin –> 4 to 14 liters –> extracellular fluid
Vd example
For a drug that diffuses to intracellular fluid, Vd would equal:
Total body water (ethanol is 34 to 41 liters)
If a drug binds strongly to tissues, what happens to Vd?
Would be higher than total body water (fentanyl is 280 L)
Drug distribution depends on?
Blood flow
To where is blood flow large?
- Heart
- Liver
- Kidneys
- Brain
The brain is guarded by tightly bound cells in the ____ (blood brain barrier)
Capillary walls
What to drugs have to be in order to pass the blood brain barrier?
- Small, lipid soluble or actively pumped in
- Not bound to protein
Why is plasma protein binding important when considering drug absorption?
- If a drug is bound it cannot exert an effect
- individual variability in protein binding can affect concentration of free drug leading to insufficient therapy or overdose
What is alpha1-acid glycoprotein?
Plasma protein that binds basic/cationic drugs
What is the most predominant protein in plasma?
Albumin
Albumin has ____ ionized functional groups per molecules, which allows it to ____
200; bind many different substances concurrently
True or false: drugs differ slightly in affinity for plasma proteins
False - drastically
Hepatic uptake and glomerular filtration involve only:
Free drug
During ____, one drug displaces another from plasma proteins
Drug interactions
The anticoagulant, Coumadin, is highly bound to plasma proteins (only 0.2% is free in the blood). Your classmate administers an analgesic drug that displaces the bound Coumadin from plasma proteins because it too binds there. What happens to the concentration of Coumadin in the plasma?
Increases
Transfer of drugs into saliva can be thought of as a form of ____ because the drug regains access to the systemic circulation after saliva is swallowed
Redistribution
Can drugs gaining access to the oral environment from the systemic circulation affect microorganisms or tissue surfaces within the mouth?
Yes (antibiotic or antifungal)
____ can provide a noninvasive measure of the free plasma concentration of drugs
Salivary drug concentrations
Drug metabolism is also known as:
Biotransformation; change
Drug metabolism changes drug from ____ to ____
The form in which it was administered to a more water soluble (hydrophilic) form (to pee it out better)
The majority of drugs are metabolized by enzymes in the ____
Some drugs are metabolized in what other organs?
Liver; kidney, plasma, intestine, lungs
Some drugs ____ or ____ enzymes that metabolize drugs
Some drugs inhibit or compete for ____
Induce or activate; enzymes
80% of all drugs are ____ before metabolism and ____ after metabolism
Active; inactive
Valacyclovir is ____ before metabolism and ____ after metabolism
Inactive (prodrug); Active
Tylenol is ____ before metabolism and ____ after metabolism
Active; toxic metabolite
Aspirin is ____ before metabolism and ____ after metabolism
Active; Active
How many phases of metabolism are there?
2
What happens during Phase I metabolism?
Converts parent drug to a more polar metabolite by introducing or unmasking a functional group (-OH, -COOH, -NH2, -SH) via oxidation, reduction, or hydrolysis
Phase I metabolism usually results in:
Loss of pharmacological activity
Sometimes, phase I metabolism results in ____ than the parent drug
Equally or more active
Where does phase I metabolism occur primarily?
Liver
Where are Cytochrome P450 (CYP) enzymes found?
Liver
____ is a superfamily of enzymes with very broad substrate activity
Cytochrome P450 (CYP) enzymes
CYP enzymes are responsible for ____ of drug metabolism
75%
There are ____ CYP enzymes but only ____ play significant roles in drug metabolism
57; a few (mainly CYP3A4)
Phase II metabolism involves:
- Conjugation reactions
- Reaction in which a covalent linkage is formed between the parent drug or Phase I metabolite and an endogenous substrate such as glucuronic acid, sulfate, acetate, or an amino acid
After phase II metabolism, the drug becomes ____ so it is rapidly excreted in urine and feces
Highly polar
Phase II metabolism products are usually ____. What is an exception?
Inactive; Morphine 6-glucuronide (still active)
Where does Phase II metabolism occur?
Liver and kidney (other organs sometimes involved)
Major enzymes with phase I metabolism are ____
Major enzymes with phase II metabolism are ____
CYP; transferases
A useful drug may inhibit the metabolism of many other drugs by:
- Inactivating various CYP 450 enzymes: these drugs or their metabolites bond strongly with specific sites on CYP enzymes
- The affected CYP enzymes are responsible for inactivation of other therapeutic agents, resulting in drug interactions)
Double negative
What can inhibit certain classes of CYP enzymes?
- Macrolide antibiotics
- Azole antifungals
- Gingko biloba
- Grapefruit juice
Drugs and environmental toxins can stimulate what?
CYP mediated metabolism, including their own biotransformation
How do drugs and environmental toxins stimulate CYP mediated metabolism?
Usually by activation of receptors/transcription factors that are responsible for the expression of the CYP genes
What is pharmacokinetic tolerance?
A loss of therapeutic effect due to induction of enzymes
Example of pharmacokinetic tolerance
In an epileptic patient taking phenytoin, this induces ____ responsible for ____. Patient will develop ____
CYP enzyme; Vitamin D oxidation; rickets (low vitamin D)
Where is blood filtered and urine made?
Kidney
Kidney can only excrete ____
Water soluble substances
Most drugs excreted have been ____
Modified (in the liver)
The more ____, the more easily excreted
Polar (occurs in the liver)
True or false: the kidney is also a site of biotransformation
True
Some drugs have ____ kidney elimination
100%
Clearance describes _____
- the efficiency of irreversible elimination of a drug from the body
- rate/speed at which a drug is eliminated
Volume of blood cleared of drug per unit time is referred to as ____
Clearance
Clearance can be ____ or ____
Specific (organ, process) or whole body
What is total body clearance?
Sum of total of all the different clearances (renal clearance + hepatic clearance + clearance from other organs)
What is the formula for elimination rate?
Clearance x Plasma drug concentration
Elimination rate is equal to?
Maintenance dose rate
What is maintenance dose formula?
Clearance x Css (steady state concentration of drug mg/L)
Every drug has a ____ and we want to be in it
Therapeutic range (we use maintenance dosing to do this)
What is zero order kinetics?
A process that occurs at a constant amount per unit time independent of how much is present
What is first order kinetics?
A process that occurs at a constant fractional rate per unit of time
____ generally exhibit first-order kinetics because they generally rely on processes that are first-order in character
Absorption, distribution, and elimination of drugs
During first order kinetics, as drug load increases:
The amount of drug eliminated per unit time increases
In first order kinetics, what is half life useful in?
Determining the rate of drug disappearance and the concentration of drug remaining after a given period of time
____ is the amount of time required to rid the body of half (50%) of the initial concentration of the drug
Half life
What is the half life formula?
(0.693 x Vd)/CL
What happens to half life if Vd goes up?
Half life increases
What happens to half life if CL goes down (liver disease)
Half life increases
Half life is a combination of:
Vd and CL
It takes ___ half lives to rid the body of any drug
5 (3% at 5th half life)
Why do we care about half life?
- Duration of action after a single dose
- Dosing frequency required to avoid large fluctuations
- Time required to reach steady state
Half life of penicillin (hours)
0.5
Half life of clindamycin (hours)
3
Half life of acetaminophen (hours)
3
Half life of lidocaine (hours)
1.8
Half life of procaine (hours)
0.01
Half life of diazepam (hours)
45
Fluctuations are proportional to:
Dosage interval and half life
More frequent dosing means:
Less fluctuations
Longer half life means:
Less fluctuations
Steady state is generally reached at:
4 half lives (independent of dosage and drug)
____ is the time from interval administration to therapeutic effect
Onset
____ is the length of time drug produces therapeutic effect
Duration
____ is reached when absorption rate = elimination rate
Peak
