Pharmacokinetics Flashcards
Cell Membrane Polarity
Charged heads (hydrophilic) Uncharged tails (lipophilic)
Types of compounds that diffuse passively through membrane
Lipophilic (uncharged)
Determinants of passive diffusion
Partition coefficent
Concentration gradient
Form of weak acid that diffuses
HA
Form of weak base that diffuses
B
Definition of pKa
pH where ratio of unprotonated to protonated is equal
Henderson-Hasselbach equation
log([protonated]/[unprotonated]) = pKa - pH
Ion trapping of drugs
Acidic drugs accumulate on the side of the membrane that is more basic
Basic drugs accumulate on the side of the membrane that is more acidic
Characteristics of passive diffusion
Bidirectional
Driven by concentration gradient
Definition of carrier mediated transport
Molecule across a barrier is mediated by the binding of solute to protein transporter
Purposes of carrier mediated transport
Hydrophilic molecule movements
Molecules against gradient
Providing specificity
Characteristics of facilitated diffusion
Carrier mediated
Concentration gradient driven
Not active energy
Example: Glucose transport
Characteristics of active transport
Carrier mediated
Moves solute against its concentration gradient
Active energy
What is p-glycoprotein?
ATP binding cassette (ABC) carrier or pump
Binds to lipophilic drugs to promote their efflux (removal) from cell
Energy from ATP hydrolysis
Encoded by multidrug resistance gene
Characteristics of secondary active transport
Carrier mediated
Multiple solutes in same (symport) or opposite (antiport) directions
Requires moving one solute down its gradient to drive the movement of the other against its concentration gradient
Most often driving solute for secondary active transport
Sodium or hydrogen
Name of symport and antiport proteins
Symport: Co-transporter
Antiport: Exchangers
Definition of bioavailability
F - Fraction of the administered dose of drug that reaches circulation
What is an F = 1 defined to be?
IV delivery
Bioavailability of oral drugs
F < 1
Incomplete absorption, first pass effect
Definition of first pass effect
Orally administered drugs are metabolized by liver or excreted into intestine via biliary excretion (enterohepatic circulation)
Results in not reaching systemic circulation
Propranolol’s bioavailability
Loss during first pass
Causes it to have low potency
Therapeutic considerations of first pass effect
More for older, established drugs
Newer drugs are designed with this in mind so structure minimizes the effect
Definition of bioequivalence
Same drug
Same route of administration
Same amount of drug enters the circulation
Drug enters the circulation at same rate
Standard for comparing formulations (generics)
Absorption of orally administered drugs
Passive diffusion in GI tract Unionized form (No not the auto workers)
Characteristics of Stomach Absorption
Very acidic, thick mucous, small surface area
Limited absorption of even weak acids
Characteristics of Upper Intestine Absorption
pH of about 7
Large absorptive surface area (200 sq meters)
Moving blood prevents formation of an equilibrium (Le Chatelier all day to the blood)
Gastric emptying impact on drug absorption
Increased emptying increases the rate of absorption
Effect of dissolution of a solid drug
Affect the rate of absorption
Coatings, particle sizes need to be considered
How to achieve controlled release solid drug?
Hard-to-dissolve agents for slow uniform dissolution and absorption
Advantages of controlled release solid drug
Slower absorption results in decreased frequency of dosing, more uniform concentration of drug in the blood
Disadvantages of controlled release solid drug
Greater variability among patients (Grapefruit and dat Cytochrome P450 action)
Greater toxicity if incorrectly absorbed (Chewing the pill)
Purpose of enteric coatings
Protect the drug from the stomach acid and stomach from drug (e.g. aspirin)
Better taste
Sublingual delivery definition
Under the tongue (e.g. nitroglycerin for angina)
Rapid absorption
Buccal delivery definition
Beneath gum and cheek
Characteristics of sublingual/buccal delivery
Blood drains into the sup. vena cava
Avoids liver for first pass
Small surface area so drug is lipophilic
Rectal administration advantages
Useful if patient cannot or won’t swallow (unconscious, vomiting, pediatric, etc.)
50% less first pass than orally administered agents
Rectal administration disadvantages
Variable absorption, can be incomplete, irritating to rectal mucosa, uncomfortable
Transdermal administration definition
Through the skin
Characteristics of transdermal
Epidermis is impermeable to hydrophilic, but permeable to lipophilic
Best if hydrated
Examples are nicotine, estrogen/progesterone
Definition of parenteral injection
Without the intestine
Include IV, subcut, and intramuscular
Mechanism of subcutaneous and intramuscular delivery
Injection results in a depot of drug in dermis or muscle
Drug diffuses to nearby capillaries
Rate of absorption of lipophilic drugs via injection
Depends on drug solubility in interstitial fluid
Area of capillary bed in vicinity
Mechanism of absorption of large hydrophilic drugs via injection
Pass through large, aqueous channels in the capilaries
Example insulin
Mechanism of absorption of proteins via injection
Enter via the lymphatic system
Example: Antigens in vaccination
Where do the parenterally drugs distribute to first?
The Lungs
Characteristics of lung during drug absorption
Metabolically active organ, large capillary bed
Filters particulates
Volatile agents can diffuse into the expired air (breathilizer test)
Lipophilic agents can accumulate; redistribute
Characteristics of IV injection
Completely bioavailable (F = 1)
Achieve immediate action; drug delivery can be highly controlled
Dose and rate of delivery can be rapidly adjusted
Anesthetics; emergency treatments
Irritating agents are diluted by the entire blood volume
Advantages of IV injections
Control over dosage
Control over rate of administration (Bolus. slow infusion)
Disadvantages
Route of no return, hard to remove once in circulation
Need close monitoring, experienced staff
Subcutaneous control of absorption
Add vasoconstrictors to delay absorption
Variability of intramuscular absorption
Blood flow based on muscle demand
Airway administration purposes
Volatile agents; rapid access to the circulation
Treatment of the airway (targeted delivery in brachoconstriction)
Topical targets for drugs
Mucous membranes
Eye
Definition of drug eluting stents
Placing a scaffold into the artery (stent) with drugs bound onto the stent for controlled release
Example: Anticoagulants post balloon angioplasty
Drug delivery targeting of cells via ________
Antibodies
Possible treatment for tumor cells
Prodrug delivery
Inactive drugs that are activated by enzymes at target site
Example; Heroin in the brain
Blood flow phases of drug delivery
First phase: Highly perfused organs receive most of the drug; equilibration is rapid
Second phase: More poorly perfused organs; equilibration is very slow
Role of capillary permeability of drug delivery
Endothelial junctions are loose so paracellular delivery (except in brain) - Driven by hydrostatic pressures
Lipids can transfer transceullularly
Role of plasma proteins in drug delivery
Drug binding to plasma proteins (low affinity, easily reversible)
Follows mass action
Specific proteins for acidic and basic drugs
Albumin - Acidic (Has positive charge sites)
Alpha-1-Acid-Glycoprotein - Basic (Has negative charge sites)
Equation for drug binding
[DP] = [Total protein]*[Drug]/(Kd+[Drug])
[DP] remains constant if drug is repeatedly delivered ([Drug] = constant)
Method of disease altering protein binding
Alters concentration of plasma binding proteins long term
Liver disease effect on protein binding
Reduced albumin and reduced binding
Need to decrease the dose of drug
Immune activation effect on protein binding
Increase α-1-acid glycoprotein
Need to increase drug dosage
Examples of tissue reservoirs for drugs
Fat - Lipophilic drugs for long periods
Bone - Divalent cations (tetracycline) and heavy metals
Definition of redistribution
Mechanism of termination of action of a drug
Redistribution from active site (tissue) to inactive site
Examples of redistribution
Highly lipid soluble drugs
Drugs acting on a highly perfused organ (brain or heart)
Drugs administered by IV or inhalation (general anesthetics)
Issues of drug distribution into CNS
Has to overcome tight capillary endothelial cell junctions (blood-brain barrier) and tight epithelial cell junctions (blood-CSF barrier)
Drugs able to enter the brain
Unionized, not protein, bound, and highly lipophilic
Substrates for carriers (e.g. Levo-dopa)
Brain efflux mechanisms
P-glycoprotein (lipophilic drugs; inducible)
Organic anion transporting polypeptide (OATP; negatively charged molecules)
Why does loperamide (an opioid) not have any CNS effects?
OATP
Factors for placental transfer of drug
Lipophilicity, unionized drug, protein binding for passive
Fetal plasma is more acidic than maternal; trapping of basic drugs
Carriers are present
Renal excretion processes
Glomerular filtration - Unbound drug enters the tubular lumen
Active tubular secretion (Proximal tubule)
Passive tubular reabsorption (proximal and distal tubules)
Methods of active tubular secretion
Moved into tubular lumen via pumps
P-glycoprotein; multi-drug resistance protein type 2 (MDRP-2, an ABC transporter)
Results in excretion rate that is greater than GFR
Clinical importance of passive tubular reabsorption
Treating overdoses or poisonings (altering pH of urine) to hasten excretion
Methods of biliary and fecal excretion
Canalicular membrane of hepatocytes ABC transporters to move drugs into bile
Carriers on enterocytes to move drugs from circulation into intestinal lumen
Role in enterohepatic recycling
Other Routes of Excretion
Sweat, saliva, tears, hair, skin (useful for drug detection)
Milk (Lipophilic drugs enter easily)
Slightly acidic compared to blood; trapping of weak bases
Definition of rate of absorption
Peak height/Time to peak = Cmax/tmax
Definition of lag time
Time to peak = tmax
Definition of extent of absorption
Area under concentration curve
Definition of therapeutic window
Amount of time where drug concentration is between minimum effective concentration and minimum toxic concentration
Definition of volume of distribution
Amount of volume in the body that contains the drug
Equation of volume of distribution (Vd)
Amount of drug in the body = Vd * [Drug]
Vd = D/C0; D is the dosage
Definition of C0
Concentration of drug at time zero
Determined by extrapolating the elimination phase
Definition of accumulation phase/elimination phase
Accumulation - Drug plasma curve pre-peak
Elimination - Drug plasma curve post-peak (linear in log-range)
Assumption for determining Vd
Concentration of drug throughout body is the same as its concentration in plasma/serum (likely incorrect)
Notable Vd values
Small - Entirely in plasma (2.8 L/70kg person)
Total body volume - Moves like water (about 70 L)
Very large - Drug is being sequestered in non-plasma
How is Vd given in dosing tables?
Usually as a rate dependent on patient body weight (Liters/kg)
Drug dosage equation with bioavailability factored in
D = Vd * C0/F
What does bioavailability change in a drug response curve?
Cmax and area under curve are directly proportional to F
Rate of accumulations and elimination are unfaffected
Definition of clearance of drug
CL = rate of elimination/concentration (Volume/time)
CLs are additive if multiple routes
CL_total = CL_renal + CL_liver
When is clearance constant?
If clearance processes are not saturated.
Common at therapeutic concentraions
What order process are drugs cleared through?
First order-decay
Log-linear
Slope of drug clearance in a log10 curve
-k_el/2.3
Half-life of drug
T1/2 = 0.69/k_el
Time needed to reduce the amount of drug by one half
Constant for a first order process
Definitions of IV phases
Alpha Phase - Distribution: From circulation to tissues instead of accumulation phase for oral
Beta Phase - Elimination: Same concepts as oral drug elimination phase
Zero-order kinetics
Saturated elimination processes (via Michaelis-Menten kinetics)
Clearance is not a constant
Effect on CL, k_el, T1/2 with increasing concentration in zero-order kinetics
CL decreases
k_el decreases
half-life increases
Drugs that show zero-order kinetics
Ethanol, aspirin, phenytoin
Therapeutic concern for zero-order kinetics
Drugs accumulate due to lack of elimination
Relationship between CL and T1/2
CL = k_el * Vd
T1/2 = 0.69/k_el
Therefore: T1/2 = 0.69 * Vd/CL
Effect of repeat dosing on first-order kinetics
Body reaches steady state where amount added and the amount eliminated are equal
Equation of steady state concentration of drug
F*Dose/dosing interval = CL * Css
Rate in = Rate out
What is a desirable value for Css?
Somewhere in the therapeutic window
Definition of maintenance dose
Dose that keeps the Css
How long does it take for a maintenance dose to reach Css?
4-5 half-lives
How to reach Css more quickly?
Loading dose - Large dose which is used to reach Co
4 Important Equations
Henderson-Hasselbach
Loading dose
Half-life/clearance relationship
Maintenance dose
Effect of decreased renal function on drug response
Elimination rate and clearance decrease
Half-life increases
New higher steady state if same dosage maintained
Effect of decreased dose interval (assuming accompanied decrease in dosage)
Narrows concentration window while keeps the same Css (same concept for controlled release)
Useful if therapeutic window is narrow
