Pharmacokinetics Flashcards
what is liberation
when the active ingredient of the drug is released from the solution
where are the 3 sites a free drug might migrate to
- theraputic site of action (good)
- tissue resevoirs
- unwanted site of action
what are the processes that the body uses to modify and transport a drug
absorption
distribution
metabolism
excretion
transport of a drug across cell membranes is affected by…
- size and structural features of the drug
- degree of ionization
- relative lipid solubility of ionized/non-ionized forms
- affinity and binding to serum and tissue proteins
types of transport across membranes for drugs
passive transport (major)
carrier-mediated transport - active and facilitated
characteristics of passive transport of drugs
- happens across amphipathic lipids in membranes which are permeable to water
- bulk flow of water carries small water soluble substances
- limitted to unbound drugs
what are 2 subtypes of passive transport
passive diffusion
paracellular passage
what is passive diffusion of a drug
- large lipophilic drugs pass through membranes
- limitted to unboudnd drug
what is paracellular passage of a drug
- happens through intercellular gaps
- transfer in the capillary endothelium is limited only by bloodflow
- “tight” intercellular junctions limit paracellular flow (e.g. in the CNS)
passive flux across membranes is driven by…
- drug concentration gradient (C1-C2)
- solubility of drug (lipid-water partition coefficient)
- surface area of membrane
- membrane thickness
what is the passive flux of a drug proportional to
directly: (C1-C2) x area x partition coefficient
inversely: membrane thickness
how does the ionized or unionized form of a drug affect its transport
- unionized species are more lipid soluble - diffuse more readily
- ionized species are less lipid soluble - harder to diffuse
what does the pKa of a drug determine
pKa = the pH at which 50% of drug is ionized and 50% is unionized
- pKa influenced the transmembrane distribution of a weak electrolyte
what is ion trapping
- the drug accumulates on the side of the membrane where ionization is highest
- basic drugs accumulate in acidic solutions and visa versa
- the pH on either side of the membrane determines the degree of ionization
ionization of weak acids and bases
weak acid: unprotonated = ionized acid
weak base: protonated = ionized base
why might carrier-mediated transport be needed for drugs
- molecules are too large for passive diffusion
- molecules not lipid-soluble for passive diffusion
- carriers ae saturable, selective and inhibitable
active transporters vs. facilitated transporters
active: move molecules against their concentration and chemical gradient, requires ATP for energy
facilitated: more large/lipid insoluble molecules down their electrochemical gradient
what is drug absorption
following administration drugs are absorbed into the systemic circulation to get to target site
which routes of drug administration do NOT require absorption
- intravenous (IV)
- intrathecal (CSF and epidural)
- topical
what must happen in absorption before the drug enters circulation
dissolution of the active drug - active ingredient released
the rate of drug absorption affects…
onset, duration and intensity of action
if the absorption phase for a drug is longer what happens to its duration of action
it also becomes longer
what affects the rate of absorption from site of drug administration
physiochemical factors
physiologic factors
drug formulation
how do physiologic factors affect the rate of absorption
- a large concentration gradient between the site of drug administration and surrounding tissue drives uptake of drug into the circulation
- regional or local blood flow has greatest effect on maintaining large concentration gradient favouring drug absorption
how does drug formulation affect the rate of absorption
- includes active drug and inactive chemicals that comprise the product ready for administration
why would modifications be made to the active pharmaceutical ingredient to delay the release of the API for absorption
- more convenient
- short elimination half life
- prolong the dissolution phase
- prevent erratic absorption or “dose-dumping”
types of drug formulations and the reasons for them
- enteric coated formulations: protect the drug from destruction by gastric juices
- long acting insulins: slows dissolution via the addition of proteins
- controlled release formulations: slowly release a constant amount of the drug
what is bioavailability
the fraction (%) of administered dose that reaches the systemic circulation unchanged
what is the “first pass effect”
- happens following oral administration of drugs
- liver metabolizing enzymes inactivate the drug before their job is done and can enter systemic circulation
bioavailability can be reduced of affected by…
- precipitation of drug at injection site
- drug interaction with the GI tract
- physiochemical property of the drug
- “first pass” elimination of the drug
what are the broad routes of administration for drugs
enteral: oral, oral transmucosal, rectal
parenteral: subcutaneous injection (SC), intramuscular injection (IM), intravenous injection (IV), topical, transdermal
advantages of oral drug administration
- most convenient
- most economical
- safer than injection
- minimal infection risk
- induce vomitting to potentially remove drug (in case of overdose)
disadvantages of oral drug administration
- absorption may be erratic
- enteric coating can resist gastric juices
- patient complience problems
- not for unconscious patients
- emesis and GI irritation possible
- first pass effect possible
characteristics of oral transmucosal drug administration: sublingual
- under tounge
- absorption from the oral mucosa
- potentially by-pass “first pass effect” by venous drainage
- highly lipophilic drugs
characteristics of oral transmucosal drug administration: buccal
- between cheek and gum
- absorbed from the mucosa
characteristics of rectal drug administration
- ~50% of the drug bypasses “first pass” effect
- absorption can be erratic and incomplete
- potential for irritation
- less nausea
- used in patients with GI motility disorders
characteristics of Parenteral drug administration route
- injectable drugs are most common form
- drug availability is more rapid and predictable over oral
- by passes “first pass effect”
subcutaneous injection of drug advantages
- suitable for solid pellets (e.g. contraceptives)
- suitable for insoluble suspensions
- easier to administer than IV
subcutaneous injection of drug disadvantages
- absorption slower than IM route
- not suitable for large volumes
- pain and necrosis possible
- technical skills needed for some injections
- drug is irretrievable
intramuscular injection of drug advantages
- absorption is rapid for drugs in aqueous solution
- safe, easier than IV
intramuscular injection of drug disadvantages
- local pain and swelling with irritating solutions
intravenous injection of drug advantages
- route of choice for emergency drug administration
- large volumes can be given
- bioavailability is complete
- most rapid onset of actions
- irritating solutions can be given this route
intravenous injection of drug disadvantages
- must inject slowly
- not for oily suspensions
- adverse reactions can occur due to higher blood levels
topical route of drug administration
- drug applied to eye, skin, and mucus membranes
- advantage = drug delivered locally, high conc.
- disadvantage = may be absorbed systemically
transdermal route of drug administration
- drug applied to skin then absorbed into systemic circulation
- advantage = absorption enhanced, controlled release, bypasses “first pass”
- disadvantage = delay onset of action
unless the drug is given via IV, what is required to establish adequate blood drug levels
absorption of the drug
what is drug distribution
- how a drug reaches its target site in adequate concentrations
- achieved primarily thru systemic circulation with minor contribution from lymphatics
once in systemic circulation, a drug can…
- remain in vascular space
- distribute to enter interstitial fluid
- further distribute to enter intracellular fluid
distribution of a drug is affected by…
- physiochemical properties (size, lipid solubility and ionization)
- anatomy and physiology of the patient
- non-target binding of drug
how does anatomy and physiology of the patient affect drug distribution
- depends on the proportion of systemic blood received by specific organs and tissues
- vessel-rich tissues receive greatest cardiac output and distribution of blood
- distribution to less well-perfused tissues is slower but accounts for most of the extravascular drug
which organs have the greatest capacity for drug distribution
adipose and muscle
how does non-target binding affect drug distribution
- drugs that bind plasma proteins cannot diffuse from vascular space to tissues
- many drugs accumulate in tissues at levels higher than blood or interstitial fluid - can prolong drug action
what is the volume of distribution for a drug
- the extent to which a drug partitions between blood and tissue compartments
- Vd = amount of drug in body / plasma drug conc.
what is drug elimination and the 2 processes it consists of
- the process of clearing drugs from the body
- excretion: drugs are cleared unchanged
- biotransformation: drugs are converted to metabolites then cleared
biotransformation (metabolism) and excretion are 2 differnt processes BUT reach the same end point of…
reducing circulating levels of active drug
what is drug clearance
- gives an indication of efficiency of elimination of drug from the body
- total systemic clearance involves elimination of drug via all routes
- clearance = (metabolism + excretion) / plasma conc. of drug
what is the extraction ratio
- the extent to which an organ contributes to drug clearance
- extraction = (drug in - drug out) / drug in
rate of drug metabolism and excretion by an organ is limited by…
the rate of bloodflow to the organ
what is the most important excratory mechanism/organ
the kidney
what are minor excretory mechanisms
- sweat saliva and tears
- breast milk
- lungs
- intestinal tract
biliary tract excretion of drugs
- eliminates drugs via feces
- reabsorption of excreted drug is possible in SI
renal excretion of drugs - basics
- free drug and metabolites are freely filtered at glomerulus
- active drug secretion in PCT adds the drug to urine
- reabsorption of drug back into blood from urine happens at DCT for the non ionized form of the drug
lipid soluble vs water soluble drugs in renal excretion
lipid: can readily diffuse from urine back into tubules and blood
water: remain in urine (ion trapped)
what is drug metabolism/biotransformation
the change in chemical structure of an absorbed drug
what is the main metabolizing organ
the liver
drug metabolism in the liver
- orally administered drugs are taken to the liver via the portal system
- can be metabolized before reaching systemic circulation - “first pass effect”
- reduces bioavailability or drug at target site
why is drug metabolism important
- makes drugs more excitable and inactivates them
- makes lipid-soluble drugs water soluble so they can be more readily excreted in urine and bile
some drugs are activated by metabolism instead of inactivated…
- administered as “prodrugs”
- designed to improve bioavailability
- decrease GI toxicity and prolong elimination
which cellular compartments is biotransformation catalyzed in
major: smooth ER, cytoplasm
minor: mitochondria, membranes, lysosomes
other than the liver where can metabolism occur
lungs, GI tract, skin, kidneys, blood plasma, brain
- GI tract can also contribute to the first pass effect
how are drugs metabolized
- in 1or 2 phases
- phase I: drugs are converted to more polar (hydrophilic) metabolites
- phase II: a substance from the diet is attached to the functional group derived from phase I
phase I metabolism reactions
- aka oxidation/reduction/hydrolysis rxns
- drugs are converted to more polar metabolites
- they are then either excreted or go onto phase II
phase II metabolism reactions
- aka conjugation rxns
- a substance from the diet is attached to the functional group derived from phase I rxns
- creates a more polar/excretable product
- some drugs skip phase I and go right to phase II
characteristics of phase I reactions
- introduce or unmask functional groups
- involves one or more cytochrome P-450 enzymes in the smooth ER
- CYP2C, CYP2D and CYP3A are the subfamilies
types of phase I reactions
- oxidation: most common rxn, loss of e- from drug
- reduction
- hydrolysis
what are common hydrophilic conjugate moiety’s that can be added to a drug in a phase II rxn
glucuronic acid
sulfate
glutathione
acetylene groups
characteristics of phase II reactions
- couple drug (or phase I metabolite) with substances from diet to produce conjugate
- conjugates are more polar, inactive and readily excretable
- conjugates require the to have O, N or S as acceptors of a hydrophilic group
types of phase II reactions
- glucuronic acid conjugation
- sulphate conjugation
- acetylation
- glutathione conjugation
characteristics of the phase II reaction - Glucuronic acid conjugation
- includes conjugation of morphine, acetaminophen, salicylic acid and chloramphenicol
- glucuronidases in gut bacteria can hydrolyze the conjugate off, free the drug and it can be reabsorbed
- causes enterohepatic recirculation to prolong the drug elimination half life
- individuals deficient in glucuronide synthesis are slow to metabolize certain drugs
when can a drug go through phase I reaction but bypass a phase II reaction and go right to excretion
when the drug is polar (hydrophilic) enough after the phase I reaction
what key characteristic change is observed in a drug from absorption to excretion
the drug goes from lipophilic to hydrophilic
what are the 4 key parameters that govern drug disposition and dosage regimens
- Bioavailability (%F)
- Volume of distribution (Vd)
- Clearance
- Elimination half-life (t1/2)
what is elimination half life
- the time required for blood drug concentrations to decrease by 50%
- does not depend of dose or blood-drug concentration
what happens to the elimination half life when twice the amount of the same drug is administered
the half life is the same becasue it is still the same drug (just a different dose)
when is a drug essentially eliminated from the blood
after 4-5 half lives
how can prolonged efficacy of a drug be achieved
by administering musltiple small doses of drug maintaining drug concentration above MEC for desired effects - but below MEC for adverse effects
what happens when prolonging duration of action above the MEC for desired effects
it may produce peak concentrations that lead to adverse effects
difference in accumulation when a drug is administered every 6 1/2 lives vs every 1/2 life
every 6: drugs will no accumulate with repeated dosing because half life is short
every time: drug accumulation is greater, then steady state is reached after ~5 half lives (drug input = drug diminished)
what is meant by “elimination half life is a hybrid constant”
- it is dependent on other independent parameters (volume distribution and clearance
- factors that affect Vd and CL will affetc half life
- increased Vd = increased half life
- increased clearance = decreased half life
dosing regimens consider the following guidelines…
- dose of drug given
- route of administration
- frequency of administration
- duration of therapy
types of drug dosing
- theraputic dosing: drug accumulation but takes a few doses to get to the theraputic range
- theraputic dosing with loadig dose: gets to the theraputic range faster, then have drug accumulation
- toxic dosing: dosing level too high and begins to cause adverse effects
- subtheraputic dosing: dosing too small so stays at the threshold of theraputic range
loading dose
- used to achieve target theraputic levels quickly, usually only given as forst dose
- considers Vd
maintenence dose
- given to maintain drug levels in the target theraputic range
- considers clearance
physiologic, disease and drug factors can influence blood-drug levels and PK which leads to…
effects on elimination half life through changes in Vd and CL
factors affecting half-life: effects on volume distribution examples
- aging: decreased 1/2 life
- obesity: increased 1/2 life
- pathologic fluid: increased 1/2 life
factors affecting half-life: effects on clearance examples
- cytochrome P450 induction: decreased 1/2 life
- cytochrome P450 inhibition: increased 1/2 life
- cardiac failure: increased 1/2 life
- hepatic failure: increased 1/2 life
- renal failure: increased 1/2 life
what factors can cause an increase in drug half-life
- obesity
- pathologic fluid
- cytochrome P450 inhibition
- cardiac failure
- hepatic failure
- renal failure
what factors can cause a decrease in drug half-life
- aging
- cytochrome P450 induction
how do drug-drug interactions affect PK
- cause changes in the magnitude or duration of a pharmacological effect
- due to increased number of drugs given or incresed duration of use
how do pharmaceutical interactions affect PKs
- occurs before the drug is absorbed
- usually when combined in the same syringe or IV fluids
- can occur in GI tract lumen
- affects total dose available for absorption if given orally or for injection if given by IV
exapmles of how alterations result in physiochemical properties by interactions with the affected drug
- drug-drug interactions cause drug incompatabilities
- drug-environment interactions affects how they need to be stored in order to remain functional
- drug-diet interactions
types of pharmicokinetic interactions (things drugs can react with at each step)
- absorption interactions: stomach pH, GI motility, enzymes
- distribution interactions: plasma protein binding, changes in tissue blood flow
- metabolsim interactions: enzymes (CYP450), inhibition and induction
- excretion interactions: urine pH, tubular secretion, renal blood flow
drug interaction factor: induction of P450 enzymes
- produces increased expression of enzyme
- concequences include incresed metabolsim
- takes time to be realized clinically
- reduced elimination half life (need increased dosing)
- decreases blood drug levels
drug interaction factor: inhibition of P450 enzymes
- enzyme is directly inhibited by the affecting drug
- onset of inhibition effects on other co-administered drugs PKs
- increases elimination half life (need decreased dosage)
