Pharmacokinetics I Flashcards
What determines passive diffusion
Passive diffusion is determined by the partition coefficient of the drug into oil from water AND its concentration gradient across the membrane
What types of compounds can diffuse readily through the membrane?
Hydrophobic or lipophilic
Weak acid equilibrium
HA ↔ A- + H
HA is not charged and therefore will likely passively diffuse through cell membranes
[HA]/[A-] is determined by:
1) The pH of the environment
2) The pKa of the drug
Henderson-Hasselbach equation:
Log ([protonated]/[unprotonated]) = pKa - pH
Plasma pH:
Stomach pH:
Plasma pH: 7.4
Stomach pH: 1.4
Weak base equilibrium
B + H+ ↔ BH+ The unprotonated (B) form is uncharged and therefore likely to pass through membranes B is predominant when the pH is high
Henderson Hasselbach for bases
Log ([BH+]/[B]) = pKa - pH
Ion Trapping
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
How can morphine (a weak base) be detected in the stomach following intravenous overdose.
Although BH+ dominates in the blood, enough B is present that it will diffuse down its gradient into the stomach. Once there, it is protonated and trapped
Base with pKa of 8.4 in stomach
Log ([BH+]/[B]) = 8.4 - 1.4
Log ([BH+]/[B]) = 7
[BH+]/[B] = 10,000,000/1 (so uncharged to charged is 1/10 million)
Acid with pKa of 4.4 in stomach
Log ([HA]/[A-]) = 4.4-1.4
Log ([HA]/[A-]) = 3
[HA]/[A-] = 1000/1; or 1/0.001
Movement via passive diffusion is:
Bidirectional
Driven by the concentration gradient (movement “down hill” is energetically favored)
Carrier Mediated Transport
Transport of a molecule (solute) across a barrier is mediated by binding of the solute to a protein transporter
Purposes of Carrier Mediated Transport (3)
1) Can move hydrophilic molecules through the bilayer
2) Can move molecules against their concentration gradient
3) Provides specificity
Facilitated diffusion
Carrier mediated
Concentration-gradient driven
No requirement for the input of energy
Active transport
Carrier mediated
Moves solute against its concentration gradient
Therefore, requires energy
P-glycoprotein
An ABC (ATP binding cassette) carrier or pump
- Primarily binds to liphophilic drugs that have entered cells via passive diffusion and mediates their efflux from the cell
- Energy from ATP
- Is encoded by the multi-drug resistance gene
Secondary Active transport
Carrier mediated; move two different solutes in the same (symport) or opposite (antiport) directions
Most often, couple solute movement against its concentration gradient to the movement of sodium or hydrogen with their concentration gradients
Bioavailability (F)
Fraction of the administered dose of drug that reaches the circulation
By definition, an intravenously administered drug would have an F=1
Orally administered drugs are almost never completely bioavailable
First pass effect
Enterohepatic cycling
Drug is metabolized by the liver or excreted back into the intestine through biliary excretion during its “first pass” through the liver
Never reaches the systemic circulation
Bioequivalence between two preparations means:
Same drug
Same route of administration
Same amount of drug enters the circulation
Drug enters the circulation at the same rate
Orally administered drugs
Absorbed from the GI tract
Mostly via passive diffusion
Favors the absorption of unionized drugs
HA form and B form absorbed preferentially
Absorptive surface area of the upper intestine
200m^2 (due to villi)
Relationship between gastric emptying and drug absorption
Increased gastric emptying will increase the rate of drug absorption
Dissolution of solid drug preparation:
Affects the rate of absorption
Is affected by how the drug is formulated
Advantages and Drawbacks to controlled release preparations
Advantages: slower absorption results in decreased frequency of dosing; more uniform concentration of drug in the blood
Drawbacks: Greater variability among patients AND toxicity if all the drug is released at once
Enteric Coatings
Protect the drug from the stomach acid AND the stomach from the drug
Better taste
Do not want the coating to be completely impervious, it will retard or result in variable absorption in the intestine
Other routes of entry
Sublingual:
Buccal:
Under the tongue and Between the gum and cheek
Rectal administration
Useful if patient cannot or won’t swallow
50% less first pass than orally administered agents
Disadvantages: variable absorption; can be incomplete; irritating to the rectal mucosa; uncomfortable
Transdermal administration (and examples)
Through the skin Epidermis is a nearly complete barrier to non-lipophilic substances Permeable to lipophilic drugs Best if hydrated Nicotine, estrogen/progesterone
Parenternal injection
"Without the intestine" Intravenous: no absorption needed Subcutaneous and intramuscular - Injection results in a depot of the drug that is placed either in the dermis or muscle - Drug diffuses to nearby capillaries
Lipophilic drugs: Rate of Absorption
Depends on:
Drug solubility in interstitial fluid
Area of capillary bed in the vicinity
Large hydrophilic drugs
Pass through large, aqueous channels in the capillaries
How do proteins enter the circulation
Enter the circulation slowly via the lymphatic system
Lung absorptive properties
Large capillary bed
Metabolic enzymes that can transform the drug
Filters particulates
Volatile agents can diffuse into the expired air
Lipophilic agents can accumulate; redistribute
Intravenous injection/infusion
Completely bioavailable (F=1)
Achieve immediate action (Anesthetics; emergency treatments)
Drug delivery can be highly controlled
Irritating agents are diluted by the entire blood volume
Advantages of intravenous injection
Control over the dose; adjust based upon patient response
Control over the rate of administration
Disadvantages of IV injection
Route of no return-once the drug is in the circulation, it is very difficult to remove
Needs close monitoring, patent vein, experienced medical staff
Subcutaneous
Into the skin
Drugs must be non-irritating; not painful or damaging to tissue
Can add vasoconstrictors to delay absorption
Intramuscular
Into the muscle
Depends on blood flow to the muscle
Administration to the airway for pulmonary absorption
Used to deliver volatile agents; rapid access to circulation
Drugs to treat airway
Topical application of drugs
Mucous membranes
Eye
Drug eluting stents
Placed into blood vessels, blood flows through and elutes drug
Novel methods of drug delivery
Drug eluting stents
Targeting of drugs using antibodies
Activation of drugs at the site of action
Phases of drug delivery by blood flow
First phase: highly perfused organs receive most of the drug; equilibration is rapid
Second phase: More poorly perfused organs; equilibration is very slow
Capillary permeability of a drug
Endothelial junctions are loose; allow for paracellular movement of most drugs out of the circulation into the tissues
Driving force is hydrostatic pressure
Not in the brain
Drug binding to plasma proteins
Albumin for acidic drugs
alpha 1-acid glycoprotein for basic drugs
Binding law of mass action
Drug + Protein ↔ DrugProtein
[DP] = [Total protein] x [Drug]/(KD + [Drug])
Consequences of Protein binding to Drug
- Protein binding prevents the drug from leaving the circulation
- Drug responses, toxicity , metabolism are all a function of the drug that is free
- At equilibrium is perturbed if:
- Plasma protein concentrations suddenly change
- There are changes in exogenous or endogenous competitors for the binding sites
Extent of protein binding can be affected by disease states that alter plasma binding proteins long term
Liver disease - reduced albumin and reduced protein binding; might need to decrease dose of drug
Immune activation can increase alpha1 acid glycoprotein; might need to increase the dose of drug
Tissues serve as slowly releasing reservoirs
Lipophilic drugs can be stored for long periods in fat
Drugs that bind divalent cations and heavy metals can accumulate in bone
What can lead to the local bone destruction?
Toxins within the bone can result in:
reduced bone blood flow and even slower redistribution of the toxins out of the bone
