Pharmacokinetics Flashcards
Clearance
CL = rate of elimination/concentration
CL = Q(Ca-Cv)/Ca = QE
Body’s efficiency of drug removal;
Volume of fluid from which the drug is removed per time
Volume of Distribution
Vd = amount of drug in the body/concentration in blood
Apparent space drug resides in
Elimination Half Life
Rate of drug removal
Bioavailability
Fraction of Drug Absorbed
Dosing Rate
= dose/T
= CL * Css
goal is to maintain steady state concentration
Plasma volume
4L
ECF volume
12L
TBW
40L
elimination constant, Ke
= CL/Vd = 0.7/(t1/2)
One compartment open model
- single IV dose
- assumes entire body is one compartment
- assumes drug is distributed evenly
- assumes open system (excretion)
Two compartment model
- single IV dose
- assumes most of drug is in a particular compartment
- assumes equilibrium between blood and other areas
Multicompartment model
- needs computer assistance
- measures area under curve (AUC)
- more widely used than other models
- CL = dose/AUC
Predicted Css after various dosing schedules:
Css = (F * Dose)/(CL * T)
In a multiple IV bolus, time to steady state:
- is about 5 half lives
- independent of dose or dose interval but dependent on t1/2 (plateau principle)
IV infusion, Css =
infusion rate/total body clearance
Loading dose
- use it when you can’t wait for 5 half lives to achieve Css
- LD = (Css * Vd)/F
- but watch out for dangerously high volumes…
- maintenance dose: Dosing rate = (target Css * CL)/F
What does it mean for a drug to have zero order kinetics?
- Enzymes that metabolize the drug are saturated (are rate limiting) at normal drug levels in the body
- Same amount of drug metabolized regardless of drug level in the body
Zero order kinetics drugs
Ethanol Heparin Phenytoin Aspirin Amobarbital Tetracycline
For zero order kinetics, LD =
(Css * Vd)/F
For zero order kinetics, Css =
(Km * DR) / (Vm - DR)
Km = dose that produces 50% of maximal elimination rate Vm = maximal rate of process
For zero order kinetics, DR =
(Css * (Vm - DR)) / Km
Pharmacokinetics
Concerned with the disposition of the drug in the body
Ways to modify drug absorption
delayed release
rapid release
transdermal
depot preparations
Effect of stomach’s acidic environment on drug absorption
Acidic drugs will be nonionized and absorbed,
basic drugs will be ionized and won’t be absorbed until SI
Drugs that reduce gastric emptying
anticholinergics
narcotics
analgesics
Most rapid drug delivery route
IV
Intrathecal route of delivery
- injection into subarachnoid space
- way to bypass BBB
- good for local effects like spinal anesthesia, or acute CNS infix like meningitis
Topical drug route
- good for lipid soluble drugs that pass easily through epidermis
- fentenyl, nicotine, nitroglycerine, birth control
Factors affecting rate of drug distribution
- cardiac output and regional blood flow
- capillary permeability
- tissue volume
Factors affecting extent of drug distribution
- membrane transport
- permeability
- plasma protein binding
- intracellular binding
Total blood flow is greatest to
brain
kidneys
liver
muscle
Highest perfusion is to
brain
kidneys
liver
heart
Two deviations from typical capillary structure that affect capillary permeability
- kidneys: large spaces between endothelial cells so more extensive drug distribution via filtration
- brain: BBB has tight junctions so polar substances do not readily pass
Drug binding to plasma proteins
- acidic drugs bind to albumin
- basic drugs bind to globulin
- nonspecific and reversible binding
- slight changes in binding of drugs that are mostly bound result in huge clinical effect
Cause of drug accumulation in tissues
- active transport or binding
- reversible and saturable
- dep on: concentration, affinity, binding
Drug reservoirs
- stomach: traps basic drugs (Codeine)
- Albumin: limits availability of free drug (Warfarin)
- Tissues: liver concentrates quinicrine, thyroid concentrates iodine, bone concentrates divalent metal compounds/tetracycline/heavy metals
- Fat: traps lipid soluble drugs, huge variability between patients
Drug redistribution
is a mechanism for drug termination, often b/c differences in blood flow
- example is thiopental (anesthetic) that gets to brain quickly (also equalizing with plasma) but also accumulates in fat
Drug distribution patterns
- remain in vascular system (dextran)
- uniformly distributed in TBW (ethanol)
- concentrated in tissues (iodine, tetracycline)
- non-uniform pattern most drugs
Biotransformation
- chemical modification of xenobiotics by endogenous enzymes
- reactions are enzymatic (follow MM)
Michaelis Menton eqn
V = (Vmax * S)/ (Km + S)
Phase I metabolic reactions
- convert parent drug to inactive drug by adding or unmasking a functional group (-OH, -NH2, -SH)
- if metabolite is polar enough, it can be excreted
- product can be highly reactive and sometimes toxic (free radicals)
- occur mostly in ER
- oxidation, reduction, hydrolysis
Phase 2 metabolic reactions
- covalent addition of amino acids (glucuronic acid, glutathione, acetate, amino acids)
- these covalent modifications are usually inactive and readily excreted (except 6-glucuronide
- occur mostly in cytosol
- glucuronidation, glutathione conjugation, sulfoxidation, acylation
- usually make it more water soluble (except for acylation)
Organ or TIssue sites of biotransformation
- mostly LIVER
- also GI, kidneys, lungs (brain also has metabolic enzymes)
CYPs
- heme containing membrane proteins attached to smooth ER
- involved in Phase I reactions
- broad spectrum, mixed function oxidases
CYPs involved in 50% drug metabolism
CYP3A4 and CYP3A5
CYP reactions
involve a reductase enzyme
- 1 O added to drug, 1 O reduced from water
- NADPH is the energy source, no ATP needed
Drug induction
- when a drug causes an increase in liver enzyme function
- onset (3-12hours), maximal (1-5days), persistance (5-12 days)
Pharmacogenetics
genetic basis for differences in responses to drugs
Pharmacogenomics
application of genomic information toward development of new drugs
Routes of drug excretion
- renal
- liver/intestines
- lungs
- sweat
- saliva
- breast milk
Renal excretion processes
filtration
secretion
reabsorption
What type of molecules are filtered out of the blood in the kidneys?
- molecules of low molecular weight:
ions, glucose, peptides but not proteins
What happens in the proximal tubule of the kidney?
Reabsorption of water
Secretion of weak electrolytes (active process - requires a transporter)
What happens in the distal tubule of the kidney?
Reabsorption of nonionized weak acids/bases
How to determine whether drug is net reabsorbed/secreted or just filtered
Compare clearance to GFR (normal = 120mL/min)
Factors affecting excretion
- Drug MW
- Volatility
- Lipid solubility
- Concentration
- Volume of distribution
- protein binding
- ionization
- excretion mechanism
- rate of metabolism
- blood flow
- disease state
