Exam 1: Pharmacokinetics Flashcards
Pharmacokinetics
The absorption, distribution, metabolism, and excretion of a drug.
(What the body does to a drug)
Pharmacodynamics
The pharmacologic effect and clinical response of a given drug.
(What a drug dose to the body)
A drug can cross a cell membrane via…
carrier-mediated transport
or
passive diffusion
Carrier-mediated transport exhibits…
selectivity & saturability
Can also be inhibited by other compounds.
Predominant mechanism for absorption and distribution of drugs is via…
passive diffusion
Most drugs are…
weak acids or bases
The charged form of a drug is…
impermeant
The uncharged form of a drug is…
permeant
Balance between charged and uncharged forms depends on…
pH and pK of the compound
Henderson-Hasselbach
Equation
A weak acid is better absorbed at ___ in the ___.
acidic pH’s
stomach
A weak base is better absorbed at ___ in the ___.
basic pH’s
intestine
Aspirin Absorption
- Acidic pH of stomach ⇒ uncharged permeant form predominants
- [HA] = 1
- Rapidly equilibrates across membranes of stomach
- In plasma, most converted to charged impermeant form (A-)
- Traps ASA in the plasma
Other Factors Affecting
Absorption
- Solubility in aqueous solution
- Dissolution rate (if solid)
- Surface area of absorption site
- Rate of blood flow
Bioavailability
The fraction of an administered dose that reaches systemic circulation in an unchanged form.
- Reflects the efficiency of delivery
- Accounts for metabolism and/or excretion before drug reaches general circulation
- IV drug administration = 100% bioavailability
First-Pass Effect
The portion of a drug that is metabolized by the liver via portal system before it can reach systemic circulation.
Significantly affects bioavailability of drugs given PO.
Enteral Routes
Utilizes the GI tract:
- Oral
- Rectal
- Sublingual
- Buccal
Oral Route
- Most common
- Most economical and convenient
- Disadvantages
- GI irritation
- Potential for first pass metabolism
Rectal Route
- Delivered via suppository
- Used for patients who are vomiting or unable to swallow pills
Sublingual Route
- Absorbed via head/neck venous drainage
- Avoids first-pass metabolism
Buccal Route
- Dose placed in the cheek
- Absorption similar to sublingual
Parenteral Routes
Avoids the GI tract:
- Intravenous
- Subcutaneous
- Intramuscular
- Topical/transdermal
- Pulmonary
- Intrathecal
IV route
- Max bioavailability
- Continuous infusion ⇒ constant drug level
- Potential for irritation of vascular walls
- Inc. risk of blood-borne infections
- Difficult to reverse once given
Subcutaneous Route
- Less painful than IV
- Self-admin possible
- Circulation at injection site important for delivery
Intramuscular Route
- Site can serve as depot for slow delivery of drug
- Not all of the drug absorbed instantly so get slow release
- Depends on blood flow
- Ex. exercising or anxiety ⇒ inc. blood flow ⇒ inc. delivery
- Large volumes often feasible
- Self-admin possible
Topical/Transdermal Route
- Absorption depends on lipid solubility of drug or vehicle
- Can be irritants
- Can get slow absorption
Pulmonary Route
- Technically a topical application
- Usually see local affect with little systemic absorption
- Ex. bronchodilators
- With anesthesia, can finely control depth of anesthesia
Intrathecal Route
- Admin of drug to CSF
- Used to produce slelective spinal blockade
Routes of Administration
Summary
Distribution
The movement of a drug from systemic circulation to other tissues.
Elimination
The process of removing a drug from the systemic circulation by excretion or metabolism.
Single Compartment Model
Body acts as a single compartment.
ka ⇒ rate of absorption
ke ⇒ rate of elimination
Assume instantaneous delivery and distribution ⇒ ka = ∞
Elimination Rate
Proportional to drug concentration:
ke = elimination rate constant
Given in concentration per unit time e.g. (mg/ml)/hr
Drug Time Course
Follows a single exponential time course.
C0 ⇒ concentration at t = 0
Half-life
( t½ )
Time it takes for the concentration at any one time to get to 50% of that value.
Volume of Distribution
( Vd )
The volume needed to account for the amount of a drug that reaches the plasma for a given amount of drug introduced.
Commonly normalized to body weight ⇒ l/kg
Causes of High Vd
Drugs that accumulate in the tissue or fat have unrealistic Vd because majority is not in the plasma.
Total body water =
0.6 L/kg
Extracellular water =
0.2 L/kg
Blood =
0.08 L/kg
Plasma =
0.04 L/kg
Fat =
0.2-0.35 L/kg
Bone =
0.07 L/kg
Body Compartment
Volumes
Clearance
(CL)
Relates the rate of elimination to the plasma concentration.
Units of amount of drug per unit time e.g. mg/hr
CL, Vd, and T½
Relationship
Non-instantaneous Delivery
Absorption slow enough to measure.
ka ≠ ∞
ke can still be determined from the late decay phase.
Cannot extrapolate t=0 to get C0.
Vd Definition
(Non-intantaneous delivery)
AUC ⇒ area under the concentration-time curve
(For single exponential decay, AUC = ke/C0)
Constant Infusion
Dose needed to maintain a steady-stant concentration (Css).
Deliver rate = Elimination rate
ka = ke
Generally, it takes ___ to reach steady state concentration.
4-5 half lives
Two Compartment Model
Central compartment ⇒ plasma
Peripheral compartment ⇒ tissues that are in rapid equilibrium with the plasma
It takes time for a drug to be evenly distributed throughout the body.
Drug concentration falls more rapidly during distribution phase than during elimination phase.
Two-Exponential Decay
Model
Half-life of a drug is determined from the slow phase.
Vd and CL can also be determined.
Multiple Dosage Regimen
Need to maintain a therapeutic level:
- Constant infusion
-
Infrequent large doses
- Goes above toxic levels
- Dips below therapeutic levels
-
Frequent small doses
- Takes time to reach therapeutic levels
- Steady state concentration stays between toxic and therapeutic levels ⇒ ‘safe zone’
Biotransformation
Active, lipophiic molecules ⇒ less active, polar molecules
Two broad categories:
Phase I reactions
Phase II reactions
Phase I Reactions
Parent drug ⇒ more polar metabolite via introduction/unmasking of a polar functional group
(-OH, -NH2, -SH)
- ↑ polarity ⇒ ↑ water solubility
-
∆ pharmacological activity
- Usually means reduction or loss of activity
- Some are inactive drugs converted to active metabolites ⇒ prodrugs
- Some are non-toxic compounds ⇒ toxic compounds
Enalapril
Enalapril ⇒ Enalaprilat
(inactive “prodrug” ⇒ active)
By de-esterification.
Parathion / Malathion
- Used as a pesticide
- Converted to toxic intermediates via phase I reactions by desulfuration
- Birds & mammals able to convert these to non-toxic substances via phase IL reactions
- Insects are not
Phase II Reactions
Phase I reaction ⇒ add polar group
Phase II reaction ⇒ conjugate to endogenous polar substrates
- Glucuronic acid
- Sulfuric acid
- Acetic acid
- Glycine
Produces highly polar compounds w/ high water solubility ⇒ increases excretion
Almost all conjugated products are inactive.
Metabolism Sites
Liver is 1° site of biotransformation
Most phase I reactions catalyzed by SER enzymes ⇒ microsomes
Microsomal Enzymes
Two play key roles in phase I reactions:
Cytochrome p450 (“CYP”) ⇒ oxidases
NADPH-cytochrome P450 reductase
CYP
Induction
Repeated administration of some substances ⇒ inc. levels of CYP isoform that metabolizes compound
Results in acceleration of metabolism of all substrates for that isoform
Ex. Barbiturates ↑ [CYP2C9] ⇒ ↑ warfarin metabolism
CYP
Inhibition
Some substrates can inhibit CYPs via:
-
Competitive inhibition
- Ex. Erythromycin & Terfenadine both metabolized by CYP3A4
-
Covalent modification of enyme
- Usually attacks heme moiety
Two major routes of drug excretion are…
renal & biliary
Renal Excretion
Major site of excretion.
3 transport mechanisms involved:
-
Glomerular filtration
- Factors that ∆ GFR ⇒ ∆ CL
- % bound to plasma proteins ⇒ ∆ CL
-
Active tubular secretion
- Non-selective organic cation/anion transporters can move some compounds
-
Passive tubular absorption
- H2O reabsorption ⇒ ↑ [Drug]
- Only uncharged drugs can be reabsorbed
- pH of urine ∆ CL
Biliary Excretion
- Must undergo conjugation in the liver first
- Products frequently excreted into biliary tract ⇒ bowel
- May be excreted
- Bowel flora can cleave off conjugate
- Drug may be reabsorbed if lipid-soluble ⇒ enterohepatic recirculation
Pharmacogenetics
Genetic differences ⇒ ∆ rate of drug metabolism
- ∆ expression levels of enzyme
- ∆ enzymatic activity
Isoniazid
-
Slow acetylators
- ↓ [enzyme]
- ↑ plasma levels of drug
- AR trait seen in 50% of blacks and whites in US & Europheans living @ high altitude
-
Fast acetylators
- Usually Asians and Inuits
CYP2D6
Pharmacogenetics
- CYP2D6 metabolizes many medications
- Flecanide, Metoprolol, Fluoxetine, Imipramine
- Genetic polymorphisms
- Gene duplication ⇒ ultrarapid metabolizers
- Null nutation ⇒ poor metabolizers
- Exam ratio of debrisoquin : 4-hydroxydrisoquin in urine
- Determine activity of CYP2D6
- Ratio < 0.1 ⇒ ultrarapid
- Ratio > 10 ⇒ poor
- Compound is inert in the body
- Determine activity of CYP2D6
Thiopurine Methyltransferase (TPMT)
Pharmacogenetics
- TPMT metabolizes thiopurine drugs
- Patients w/ low or absent TPMT activity @ inc. risk for drug induced bone marrow toxicity
- Test for abnormal TPMT*3A allele before treatment
Influence of Disease
-
Liver function
- Hepatitis
- Cirrhosis
-
Hepatic blood flow
- Affects “flow-limited” metabolism drugs most
- Metabolism so fast that it is limited by rate of delivery to liver
- Ex. Amitriptyline & imiprimine
- Affects “flow-limited” metabolism drugs most
Influence of Age
Generally, very old and very young more sensitive to drugs.
Can be due to many factors:
- Renal clearance
- Body fat content
- End-organ responsiveness
- Drug metabolism
- Reduced rate of hepatic metabolism ⇒ most significant determinant
