pharmacokinetics Flashcards
Pharmacokinetics:
the effect of the body on the drug
Transfer of a drug almost always crosses a membrane
Absorption, distribution and excretion of drugs all involve cell membranes
Compounds can diffuse readily thru membranes via passive diffusion
the rate of passive diffusion is determined by the partition coefficient of the drug into oil from water and its concentration gradient across the membrane
Most drugs are in this type of form
weak acids or bases
ligands bind to receptors using the ionic charges
Weak acids exist in an equilibrium:
HA A- + H+
(HA dominates when pH is acidic and theres lots of H)
HA is not charged and will passively diffuse thru cell membranes
how is the ratio of [HA]/[A-]
the pH of the environment , the pKa of the drug
The HH equation:
Log [protonated]/[unprotonated] = pKa- pH
it is the unprotonated that can diffuse and is lipid soluble
what about bases
B + H+ BH +
you can use the HH equation
log [protonated]/[unprotonated] = pka - pH
the unprotonated form is B and uncharged and therefore more likely to pass thru membranes
the protonated form is BH +
ion trapping
acidic drugs accumulate on the side of the membrane thats more basic
basic drugs accumulate on the side thats more acidic
movement via passive diffusion is
bidirectional and driven by the concentration gradient
carrier mediated transport
transport of a molecule across a barrier is mediated by binding of solute to a protein transporter
Serves multiple purposes: can move hydrophilic molecules thru bilayer, can move molecules against their concentration gradient, provides specificity (eg sugars)
facilitated diffusion
carrier mediated, concentration-gradient driven, no requirement for the input of energy
activate transport
carrier mediated, moves solute against its concentration gradient, therefore requires energy
p-glycoprotein
an ABC carrier or pump, ABC (ATP-binding cassette), family of proteins
Primarily binds to lipophilic drugs that have entered cells via passive diffusion and mediates their efflux from the cell
Energy is provided by ATP hydrolysis
Is encoded by the multidrug resistance gene (a gene for which there is genetic polymorphism among humans and is inducible)
Secondary active transport
carrier mediated; move 2 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 down their concentration gradients
Bioavailability (F)
Fraction of the of the administered dose that enters the circulation
IV=1
orally administered drugs are almost never completely bioavailable (incomplete absorption, first pass effect)
Bioequivalence
Same drug, same route of administration, drug enters the circulation at the same rate
used to compare formulations (generic)
orally administered drugs
absorbed into the circulation from the GI tract, mostly via passive diffusion (passive absorption)- favors absorption of unionized drugs
Characteristics of the absorptive regions of the GI tract
Stomach- very acidic (pH 1-2) lined with thick mucus, small surface area, limited absorption (even of weak acids)
Upper intestine- pH is about 7 very large absorptive surface area (200 m2)
The vast majority of drug absorption from the GI tract occurs in the upper intestine, even if the drug is ionized at the pH of this environment becuase equilibrium is not reached with moving blood
gastric emptying impact on drug absorption
increased gastric emptying will increase the rate of drug absorption
dissolution of solid drug prep on drug prep
will affect the rate of absorption, its affected by how the drug is formulated (coatings, particle sizes for example)
controlled release prep, usually accomplished by coating the active drug with hard to dissolve agents, results in slow, uniform drug dissolution and absorption
pros: slower absorption results in decreased freq of dosing, more uniform conc of drug in the blood
cons: greater variability among pts 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, but the coating ant be completely impervious bc itll retard/variable absorption in the intestine
other ways of giving drugs
sublingia, buccal
blood drains into the superior vena cava (avoids the liver for the 1st pass)
small surface area, so drug needs to be lipophillic (readily pass through membranes)
rectal admin: 50% less 1st pass, can be variable absoprtion, can be incomplete irritating to rectal mucosa, uncomfortable
Transdermal administration
thru skin, epidermis is nearly complete barrier to non-lipophillic substance, but its permeable to lipophillic drugs, best if skin is hydrated
Parenteral injection
without intestine IV SubQ (drug cant be irritating, painful, damaging, can add vasoconstrictors to delay absorption) and IM- drug diffuses to nearby capillary where it enters the blood stream
drugs distribute to lungs before the liver
lung is metabolically active, with a large capillary bed, has metabolic enzymes, filters particles and volitile agents can diffuse into expired air, lipophilic agents can accumulate, redistribute
IV injection/infusion
completely bioavailable (F=1) achieve immediate action, drug delivery can be highly controlled dose and rate of delivery can be rapidly adjusted
anesthetic, ER treatments, irritating agents are diluted byt he entire blood volume
pros: control, adjust based upon pt response, control over the rate of admin, bolus or slow diffusion
cons: route of no return, needs close monitring, patent vein, experienced med staff
lipophilic vs large hydrophobic vs protein admin
lipophilic drugs: rate of absorption depends on drug solubility in IF area of capillary ben in the vicinity
Large hydrophilic drugs (insulin): pass thru large aqueous channels in the capillaries
Proteins: enter the circulation slowly via the lymphatic system (eg Ag in immunization)
administration to the airway for pulmonary absorption
used to deliver volatile agents, rapid access to the circulation (general anesthetics) drugs to treat the airway
topical application of drugs
Mucous membranes: best for lipophilic drugs
Eye: requires absorption thru the cornea, can get systemic effects if drugs gets into the general circulation via the nasolacrimal canal, can delay absorption and reduce systemic effects with formulations, inserts
Extent of and rate of drug delivery depend on
- Blood flow (1st phase, highly perfused organs recieve most drug, equilibration is rapid; second phase, more poorly perfused organs, equilibration is very slow)
- Capillary permeability: endothelial junctions are loose, allows for paracellular movement, with hydrostatic pressure pushing out the drug (not in brain BBB), lipids diffuse more easily, for weak acids/bases pH will influence distribution (but usually not much bc ph is the same as blood in most compartments)
- Drug binding to plasma proteins (albumin for acidic drugs, alpha1 acid glycoproteins for basic drugs)**
binding is low affinity and easily reversible and binding follows laws of mass action ( [DP] = [Protein tot][ drug]/ (Kd + [drug]) ) for most drugs given repeatedly, [drug] is relatively constant so [DP] is also constant
protein binding
- protein binding prevents from leaving the circulation
- Drug responses, toxicity, metabolism are all a function of the drug that is free (not protein bound)
- at equilibrium amount of free drug is constant, so protein binding is not that important to effect
- Equilibrium is perturbed transiently if (plasma protein concentrations suddenly change, there are changes in exogenous or endogenous competitors for the binding sites, but these changes usually transient and important for drugs that have a narrow therapeutic window
Extent of protein binding can be affected by disease states that alter plasma binding proteins long term (liver disease ie reduced albumin and reduced protein binding, it could be necessary to decrease the dose of drug) (immune activation- Chrons or arthritis, can increase alpha1- acid glycoprotein it could be necessary to increase the dose of drug
Tissues accumulate drugs
tissues can accumulate drugs and serve as slowly releasing resevoirs, Lipophilic drugs can be stored for long periods in the fat THC reintoxication syndrome, drugs that bind to heavy metals
Redistribution
a mechanism for the termination of action of a drug, due to its redistribution from the tissue or site of action to tissues in which it is inactive
Can be a factor for: highly lipid soluble drugs, drugs acting on high blood flow organ, drugs administered by IV injection or inhalation
Drug distribution in brain: able to get in via unionized, not protein bound and highly lipophilic, substrates AA or sugar carriers (brain can be opposed via P-glycoprotein, lipophilic drugs inducible, and organic anion transporting polypeptide OATP
Fetal plasma is acidic so holds on to basic drugs
Renal excretion of a drug
glomerular filtration: unbound drug enters the tubular lumen, if its the only process involved in the renal excretion of a drug, its rate of elimination will be the same as the glomerular filtration rate.
active tubular secretion: proximal tubule, drug is moved into tubular lumen, regardless of conc. gradient via energy pumps- P-glycoproteins (multi drug resistance results in excretion rate thats greater than the GFR)
Passive tubular REAB- proximal and distal tubules, passive diffusion of unionized drugs, follows the concentration gradient (lumen-> blood as the urine becomes conc as water is REAB), for acid its REAB as HA, excreted as A- form, alkalinization of the urine promotes excretion
biliary and fecal excretion
canalicular membrane of hepatocytes expresses ABC transporters, these function to move drugs into bile. Together with REAB of drug into plasma from intestine contributes to interohepatic recycling
lag time, rate of absorption, extent of absorption, theraputic window
lag time: time to peak plasma concentration
Rate of absorption:
Extent of absorption: is concerned with the area under the curve
Therapeutic window: minimum toxic concentration to minimum effective concentration
The effectiveness of the drug is measured by the concentration of the drug in the circulation, but drugs that are in other compartments are measured by the volume of distribution
how to calculate the volume of the solvent that a drug is placed in
total amount of a solute is known, its concentration is known
Then you remove an aliquot and get the concentration
amount of drug/concentration of aliquout = volume of container= volume of distribution
amount of drug in the body/ plasma concentration using the total plasma concentration (bound and unbound) can also use blood or serum concentration
volume of distribution
immediately after administration (time zero, Co), the entire drug dose is in the body, but not all in circulation (even if IV) at a later time the drug has been eliminated so we dont know the amount. but you can calculate at Co by extrapolation of the elimination phase (linear portion where hypothetically 0 elimination has occured)
Vd= D/Co (D=dose), assumption that concentration of drug is the same throughout the body is the same as the plasma
if drug stays completely in plasma: Vd is small 2.8 liters for 70kg body
if drug moves with water: Vd=total body volume (70 l = 70 kg)
if Vd is larger than body then drug is sequestered in a non plasma compartment
D= Vd * Co if you want to calculate a dose for initial plasma concentration (with a known Vd)
to factor in bioavailability : D= Vd * Co/ F
F determines the area under the curve, and the does not alter the the kinetics of elimination
Clearance of the drug from the body
clearance = rate of elimination / concentration
unit of clearance: volume/time
Clearance is additive if a drug is eliminated by multiple routes, if the processes involved in the clearance of a drug are not saturated, then clearances is constant (this is the typical behavior at therapeutic concentration
most drugs are cleared in a 1st order decay process
Slope of clearance= -k el/2.3
T1/2 = .69/ kel constant for a 1st order process, as most drugs are eliminated by this process
Phases for drugs given IV
alpha phase: distribution
beta phase: elimination, slope = -Kel/2.3
clearance for saturated elimination processes
clearance is not a constant because rate of elimination cannot increase with increasing concentration
Rate of elimination = Vmax * C / (Km +C )
When C is very large compared to Km , rate of elimination is equal to Vmax and independent of concentration
zero order kinetics
aka capacity limited, dose dependent, MM elimination
As concentration increases, clearance decreases, Kel decreases, t1/2 increases
Half life and clearance are not constants (ethanol, aspirin, phenytoin)
1st order kinetics
clearance is defined by elimination rate constant and Vd
Cl= Kel * Vd
And T 1/2 = .69/kel
t1/2 = .69* Vd/CL
repeated dosing of drugs cleared by 1st order kinetics
Drugs will accumulate until the amount added into the body and the amount eliminated are equal. At that point the concentration of the drug in the plasma reaches a steady state
Dose/dosing interval = Cl *Css /F
to reach Css takes 4-5 half lives when same dose is given
maintanence dose = Css * CL * DI / F
