Absorption and Distribution Flashcards
What is pharmacokinetics?
3
intended to get the drug to the site of action so it may exert its effect (i.e., pharmacodynamics) and then remove the drug from the body
How the body affects the drug
Movement of drug through the body
Intended to get the drug to the site of action so it may exert its effect
What are the stages of PK?
Liberation Absorption Distribution Metabolism Excretion
What is liberation?
the release of the drug from its dosage (administered) form
What is absorption?
the movement of drug from the site of administration to the blood circulation
What is distribution?
the process by which drug diffuses or is transferred from intravascular space to extravascular space (body tissues)
What is metabolism?
the chemical conversion of drugs into compounds which are easier to eliminate
What is excretion and through what pathways (3)?
the elimination of unchanged drug or metabolite from the body
via renal, biliary, or pulmonary processes
Where does absorption mainly occur?
3
GI tract
Skin
Lungs
Where does distribution and metabolism mainly occur?
4
Blood
Lymph
(liver and kidney)
How does elimination mainly occur?
3
Feces
Urine
Expired air
What are the various types of liberation?
3
Immediate
delyaed
Extended
Describe immediate release drugs
the medicine is formulated to release the medicinal drug without delay
Describe delayed release drugs
the medicine is formulated to release medicinal drug sometime after it is taken
Describe extended release drugs
the medicine is formulated to make the drug available over an extended period
Why does extended release have an advantage over the other types?
2
allowing a reduction in dosing frequency compared with immediate or delayed-release medicines. So you only have to take it once a day instead of multiple.
Lasts longer
Describe the enteral route
-how can it be administered?
Drug is placed directly into the gastrointestinal (GI) tract
-orally or via gastric feeding tube
Advantages of enteral (orally) route of administration?
5
Simple Inexpensive Convenient Painless No infection risk
Disadvantages of enteral (orally) route?
6
- Drug exposed to harsh GI environment
- First pass metabolism
- Requires GI absorption
- Slow delivery to site of pharmacologic action
- Gastric mucosa irritation
- Unpleasant taste
Describe the enteral (rectal) route?
Drug is placed directly into the GI tract
Rectally
Advantages of the enteral (rectal) route?
6
- First pass metabolism partially avoided (if low)
- Unconscious patients and children
- Use in nauseous or vomiting patients
- Use in patients with poor GI absorption
- Easy to stop exposure
- Good for drugs affecting bowel (i.e. laxatives)
Disadvantages of the enteral (rectal) route?
3
- Variable absorption (not very reliable/you never know how much is actually absorbed)
- Invasion of privacy
- Irritating drugs contraindicated
What is the first pass effect (metabolism)?
Term used for the hepatic metabolism of a pharmacological agent when it is absorbed from the gut and delivered to the liver via the portal circulation.
What does a high first pass effect result in?
A smaller amount of the agent or drug reaching the systemic circulation when the agent is admistered orally
What is the extraction ratio?
Magnitude of the first pass hepatic effect
What is the equation for the extraction ratio
ER= CL liver/Q
CL liver = drug clearance through the liver
Q= hepatic blood flow
How do you determine systemic drug bioavailability (F)?
from the extent of absorption (f) and the extraction ratio (ER):
F = fraction absorbed (1 - ER)
Quantity of drug reaching systemic circulation / quantity of drug administered
What is the area under the curve represent?
Area Under the Curve (AUC) = total amount of drug reaching circulation
Parenteral VS Enteral?
IV goes straight to the body
Oral drugs go straight to the liver and are metabolized extensively before they go to the body
What are the types of parenteral routes of administration?
4
Intravascular (IV, IA)
Intrathecal (IT)
Intramuscular (IM)
Subcutaneous (SQ or SubQ)
What phase is bypassed in an IV route?
absorption phase
What is an IV routes bioavailability?
100%
Advantages of IV route?
3
- Precise and accurate dosing
- Almost immediate onset of action
- Large quantities may be given, fairly pain free
Disadvantages of IV routes?
5
- Greater risk of adverse effects
- High concentration attained rapidly
- Requires aseptic technique
- Risk of embolism
- OOPs factor
What is the intrathecal (IT) route?
placing a drug directly into the cerebrospinal fluid
Advantages of IT route?
bypasses the blood brain barrier
Disadvantages of the IT route?
3
Infection
Highly skilled personnel required
Aseptic technigue required
What is the IM intramuscular route of administration?
drug injected into skeletal muscle
Advantages of IM route?
2
- Very rapid absorption of drugs in aqueous solution
2. Repository and slow release preparations
Disadvantages of IM route?
3
- Pain at injection sites (for certain drugs)
- Increased risk of intramuscular hemorrhage
- Can affect lab tests (creatine kinase)
What is the subcutaneous (SQ or SubQ) route of administration?
Drugs injected into the tissue right below the skin
Advantages of the subcutaneous route?
Slow and constant absorption
Disadvantages of the Subcutaneous route?
- Absorption is limited by blood flow, affected if circulatory problems exist
- Concurrent administration of vasoconstrictor will slow absorption
- Small volumes (2-3 mL)
What are examples of the mucous membrane route?
6
inhalation, sublingual, nasal, vaginal, ocular, urinary
Advantages of the mucous membranes route?
4
- Avoids first-pass metabolism
- Direct delivery to affected tissue
- Rapid onset of action due to rapid access to circulation
- Large surface area
- High blood flow - Simple, convenient, low infection risk
Disadvantages of Mucous membrane route?
Few drugs available to administer in this route
Describe the topical or transdermal route of administration
Highly lipophilic drugs can passively diffuse across the skin
Advantages of the transdermal route?
6
- 100% bioavailability
- Sustained, therapeutic plasma levels
- Less peaks/valleys - Avoids continuous infusion technique difficulties
- Low side effect incidence (smaller doses)
- Generally good patient compliance
Disadvanatges of the transdermal route?
4
- Skin irritation
2. Molecular weight
Which of the following routes would undergo the largest degree of first-pass metabolism?
Oral
What are the two definitions for absorption?
Process by which a drug enters the bloodstream without being chemically altered
OR
Movement of a drug from its site of application into the blood or lymphatic system
Name the factors that affect drug absorption
6
Administration route Rate of dissolution of tablet(if oral) Drug formulation Physical factors Diffusion Transport
What are the physical factors that affect drug absorption?
6
Blood flow Surface area Contact time GI motility Gastric emptying time Food
What kind of circulation recieves 25% of cardiac output?
Sphlanic circulation
How can GI motility affect drug absorption?
fasting or interdigestive state promote propulsion of food from the upper GI
Describe how gastric emptying time can affect drug absorption
high fat meals, cold beverages, and anticholinergic drugs can delay gastric emptying time
What does Fick’s law describe?
passive movement of molecules down its concentration gradient.
What is the equation for Fick’s law?
Flux (J) (molecules per unit time) = (C1 - C2) · (Area ·Permeability coefficient) / Thickness
Diffusion Flux (F) = (C1-C2) x (Area x permeability)/ membrane thickness
What do C1 and C2 respresent?
C1 is the higher concentration and C2 is the lower concentration
What is the area in Ficks Law state?
Area across which diffusion occurs
What is the permeability coefficient?
drug mobility in the diffusion path for lipid diffusion
What does a partition coefficient reflect?
reflects how easily the drug enters the lipid phase from the aqueous medium.
What does thickness mean in Fick’s Law?
Length of the diffusion path
What is rate of transport across membranes dependent on?
6
Molecular size Lipophilicity Charge Degree of ionization Blood flow Protein binding
What types of molecules passively diffuse the most rapidly?
4
- Small
- Hydrophobic/
lipophilic - Non-polar
- Non-ionized
What is the pKa of a drug?
pKa = the pH at which 50% of the drug is ionized
What are most drugs considered in regards to pH?
weak acids or weak bases
How do weak bases interact with hydrogen?
accept hydrogen
How to weak acids interact with hydrogen?
donate hydrogen
Non-ionized or protonated molecules can do what more readily?
diffuse across the cell membrane easier because they are lipid soluable
When the pH = pKa what is going on with the drug?
The drug is being absorbed and eliminated equally
If the pH
-uncharged (non-ionized) form dominates
Weak acids exposed to low pH diffuse across cell membrane, but weak bases do not
If the pH > pKa what is going on with the drug?
3
-charged (ionized) form dominates
Weak acids exposed to high pH (ionized) will not diffuse across cell membrane
If a weak acid goes into the stomach what will happen?
The stomach is highly acidic. The drug molecule will remain unchanged and diffuse freely from GI into the blood stream
What happens with the weak acid moved into the blood stream?
It was changed to an ioized form (charged form) and cannot diffuse back into the GI tract trapping it in the blood stream
If the intestine environment is basic what kind of drug will remain unchanged?
weak bases (non-ionized)
In the stomach (pH of 1), will aspirin (pKa = 3.5) have low or high absorption?
High
What is the extent of ionization of drug molecules is influenced by?
pKa of the drug and the pH of the surrounding fluid
When do drug molecules tend to be ionized?
when in a pH-opposite fluid (basic drugs are ionized and retained in acidic fluid)
How do non-ionized drug molecules move across biological membranes?
passive diffusion
What are the three ways ionized molecules can pass the cell membrane?
active transport mechanisms, facilitated diffusions, or endo/exocytosis`
What is distribution?
Movement of drug to and from the blood and various tissues of the body
-fat, muscle, and brain tissue
What factors affect distribution?
6
Blood flow to the tissue Size of the organ Solubility of the drug Capillary permeability Binding Volume of distribution
How will tissues with high blood flow recieve drugs?
examples?3
recieve a significant amount in a short period of time
viscera, brain, muscle
Organs with low perfusion will recieve drugs how?
examples?
2
receive drugs more slowly
fat and bone
How does size affect organ distribution?
Very large organs (e.g., skeletal muscle) can take up large quantities of drug if allowed to reach steady state
How would you treat an aspirin overdose?
- Alkalanize the urine (IV sodium bicarbonate)
- Increasing urine pH to just 6.3 doubles extent of ionization in urine, thereby trapping more of the drug there > elimination
If you overdose on aspirin where does the majority go and why?
moves to the blood because its more acidic there
What is the blood brain barrier made of and what can enter it?
- Astrocytic sheath
- Endothelium cells are more tightly joined
- Slow the diffusion of water-soluble drugs - Most non-ionized, lipid-soluble drugs readily enter the brain
What does it mean when a drug has a low plasma protein binding affinity?
- Effectively restricted to the vasculature
- Only unbound drug is able to diffuse across membranes
- Low volume of distribution
- Potential of drug-drug interactions due to competing for binding sites
Ex. warfarin
What is the volume of drug (Vd) distribution?
Represents the fluid volume that would be required to contain the total amount of absorbed drug in the body at a uniform concentration equivalent to that in the plasma at steady-state
Bioavailabilty in laymens terms?
If i gave a certain amount of drugby mouth, how much of that drug ends upgetting into the systemic circulation
Distribution is was?
The dispersion of a drug throughout your body
Where is it starting and where is it going?
Ex. from your vascular space to your extravascular space
Equation for volume of distribution?
total mass absorbed/ concentration of drug in the plasma
If you give not that much drug (10mg) but the plasma concentration is really high then what is your Vd?
low volume of distribution
If the drug give the same 10mg of a different drug but the plasma concentration is really low then what does that mean about your Vd?
High volume of distribution
What compartments can drugs distribute in?
3
plasma
interstitial fluid
intracellular fluid
Vd is a proportionality constant defined as?
Amount of drug in the body/plasma concentration
If drug likes to stay in the plasma we say it has a what kind of distribution?
low Vd
If a drug likes to stay in the extravascular compartments we say it has what kind of distribution?
high Vd
What factors affect the volume of distribution?
3 drug related factors and 4 patient related factors
- Drug pKa
- Extent of drug-plasma protein binding
- Partition coefficient of the drug in fat (lipid solubility)
- Vd may be affected by:
- patient’s gender
- patient’s age
- patient’s disease
- patient’s body composition (muscle mass, body fat, etc)
If a drug as a high volume of distribution then what kind of dose do we need to give to reach our desired plasma concentration?
a high dose
If a drug as a low volume of distribution then what kind of dose do we need to give to reach our desired plasma concentration?
a low dose
What is the four compartment model of drug distribution?
- Blood- initally high but falls rapidly
- VRG- first to accumulate drug but its tissue uptake is variable
- Muscle- less perfused than vessel rich group but is a larger compartment
- Fat- much of the drug has already been metabolized and excreted by the time it gets to the fat but its the best holder of drug
What is the order of capacity to accumulate drug for each compartment?
- Fat, 2. Muscle, 3. VRG, …. Bone, ligament and cartilage.
If fat has the highest capacity to accumulate a drug, why is it’s peak lower than that of muscle for a single dose?
Because the body is already eliminating the drug and it takes time for the drug to accumulate into fat.
Examples of drugs with high Vd for a 70 mg person?
Amiodarone = 4620 L (66 L/kg) Amitryptiline = 1050 L (15 L/kg) Azithromycin = 2170 L (31 L/kg)
What do we need to keep in mind about apparent volume of distribution?
Not a physical volume but an extrapolated volume based on the concentration of drug in plasma.
A drug with a high Vd or that os taken up in large quantities by body tissue will be how present in the circulation?
largely removed from the circulation
Explain saturation of tissue levels and how that affects the efficacy of the drug?
Tissues must be saturated before plasma levels can increase sufficiently to affect the target organ. (there is no more places in the tissue for the drug to go so it has to stay in the plasma)
What kind of drugs would require a loading dose?
For drugs of equal potency, a drug with a high Vd typically requires a higher initial dose to establish therapeutic plasma levels (“loading dose”)
So does the Vd (L/kg) give us a good estimate of?
how well the drug is distributed
Vd values less than or equal to 0.071 L/kg indicate what about the drug?
That it is mainly in the circulatory system
Vd values greater than or equal to 0.071 L/kg indicate what about the drug?
That the drug has gotten into specific tissue
How are drug distribution and drug elimination related?
2
- Distribution is typically quicker than elimination
2. Drug distribution is affected by elimination
Dosing decisions should be based on what?
2
Route
Desired tissue
The following factors affect drug distribution except: Blood flow to the tissue Solubility of the drug Capillary permeability Binding Volume of distribution All the above
All of the above
If all of these were low how what kind of distribution would you have? Blood flow to the tissue Solubility of the drug Capillary permeability Binding Volume of distribution
low Blood flow to the tissue= low Vd Solubility of the drug= low Vd Capillary permeability= low Vd Binding affinity= Low Vd Volume of distribution= Low Vd
If a drug is really big/molecular weight is high then what kind of volume of distribution will it have?
low Vd
If a drug likes to bind to plasma proteins it has what kind of Vd?
low
If a drug likes to bind to extracellualr proteins it has what kind of Vd?
high
If the drug is lipophilic it will have what kind of Vd?
high Vd
If the drug is hydrophilic (really charged/ionized) it will have what kind of Vd?
low Vd
If there is low albumin what will be the Vd?
low Vd?
