CPPS 304: pharmacokinetics III

what type of reactions are phase II reactions

conjugation reactionss

in phase II reactions what groups are added to the exposed functional group (from phase I) of drugs

glucuronic acid, sulfate, glutathione, glycine or acetate

-works to make the drugs more polar

what is the most common phase II reaction

glucuronidation

the conjugated drug is then..

highly polar and mostly inactive

-conjugated drug is then easily excreted

where are the enzymes for phase II reactions mostly located

in the cell cytoplasm

what two factors affect phase II biotransformation

genetic variations in phase II enzymes and drug response

genetic variations in phase II

50% of americans and 60-70% of europeans have reduced expression of N-acetyl transferase (NAT)

-these ppl are slow acetylators

what does 'slow-acetylors' description of those with variations in N-acetyl transferase (NAT) mean

they slow down the metabolism of drugs, such as isoniazid (antituberculosis drug- increased concentration of isoniazid can precipitate peripheral neuropathy)

enterohepatic circulation

allows for recycling of compounds

-called the drug recycling route

enterohepatic circulation:

compounds absorbed from the gastrointestinal tract enter the portal circulation, go to the liver and undergo phase I/II metabolism

enterohepatic circulation- where do some of the metabolized compounds enter

the bile and reach the gastrointestinal tract for elimination

enterohepatic circulation- however, what do enzymes present in the gut microbiome (microflora) do

deconjugate some of these compounds, which then enter the circulation again

what is an example of the clinical relevance of deconjugation

oral contraceptives can fail when antibiotics are taken

-phase II conjugation of estrogen occurs in liver and the metabolite is excreted via bile to the intestine

oral contraceptive example; what then happens to the compound once in the intestine

the microflora in the intestine deconjugate estrogen and then it is reabsorbed back (enterohepatic circulation)

why is it not a big deal that estrogen is normaly absorbed back

because its already known and the dose is adjusted accordingly

oral contraceptive example, when an antibiotic is taken what happens

the microflora is depleted and deconjugation reaction does NOT occur

-hence no reabsorption happens which results in low concentration of estrogen and oral contraceptive failure

what major factors affect drug metabolism

-activity of enzymes

-liver function

-tissue distribution of drugs

-gut microbiome

factors affectin drug metabolism: activity of enzymes

specifically the activity of enzymes that contribute to phase I and phase II biotransformation reactions

factors affect drug metabolism: liver function

liver significantly contributes to the metabolism of drugs and influence their plasma levels

THEREFORE; liver function...

which is impaired in disease states is important to consider while deciding the dose of drugs

factors affect drug metabolism: tissue distribution of drugs

a highly lipophilic drug may accumulate in fat, and this can delay metabolism

what factors affect drug elimation

-polarity of drug

-the kinetics of drug metabolism

-liver and kidney functions

-pH of the blood and urine (ion trapping)

-plasma protein binding

what is the MAJOR factor effecting drug elimination

liver and kidney functions

how does plasma protein binding affect drug elimination

slows it down because if the drug is in plasma -> not distributed

what are most drugs eliminated by

first-order kinetics

first order kinetics

a constant fraction of drug is eliminated per unit time

-i.e the amount of drug eliminated per unit time will depend on the initial plasma concentration

first order kinetics- so the higher the [plasma]....

the greater the amount eliminated per unit time, however, the fraction of total drug eliminated per unit time remains the same

first order kinetics; in effect, the blood concentration...

of drug declines over time in an exponential manner

why is first order kinetics possible for most drugs

because at their therapeutic dose range, their metabolic enzymes are not saturated

-i.e there is sufficient enzyme available for metabolizing the drug

first order rate of elimination -

constant fraction of drug is eliminated per unit time

zero order elimination

generally the metabolic mechanism of drugs is saturated only at very high concentrations

-at doses that are not commonly used for therapeutic purposes

zero order elimination: the metabolism of very few drugs becomes what

saturated at concentrations within the therapeutic range

-e.g phenytoin (they undergo zero-order kinetics)

in zero order kinetics a constant...

amount of drug is eliminated per unit time (ex: Xmg/h) because this is the maximum rate of elimination when the mechanism is saturated

zero-order kinetics, hence a slight increase in dose can do what

significantly increase the plasma concentration of drug

what are the critical steps associated with renal elimination of drugs

glomerular filtration, active secretion and passive reabsorption

renal elimination of drugs: glomerular filtration

free drugs (not bound to proteins) pass through capillaries as part of glomerular filtrate

renal elimination of drugs: glomerular filtration - what is the normal glomerular filtration rate (GFR)

120 mL/min/1.73m^2

renal elimination of drugs: active secretion

carrier mediated transport of molecules to nephric lumen occurs in the proximal tubule

-drug molecules compete for the transporters in this region

renal elimination of drugs: active secretion - example

probenecid competes with penicillin for the transporter resulting in increased half-life of penicillin

renal elimination of drugs: passive reabsorption

drugs, if uncharged, may diffuse out of the nephric lumen, back into the systemic circulation

renal elimination of drugs- steps; 1

free drug enters glomerular filtrate

renal elimination of drugs- steps; 2

active secretion of drugs with transporters occurring in proximal tubule

renal elimination of drugs- steps; 3

passive reabsorption of lipid-soluble, un-ionized drug, which has been concentrated so that the intra-luminal concentration is greater than that in the perivascular space

what is clearance

the volume of blood (ml or L) from which drug is irreversibly removed (cleared) per unit time (min or h)

what is the whole body clearance (WBC) of a drug

the sum of clearance of drug from all organs (e.g liver, kidney, lungs, etc)

-need to look at everything as drugs can excrete through sweat

what are clearance values useful to do

calculate the maintenance dose of a drug

-i.e the dose that allows to maintain a steady-state concentration of drug in the plasma

when does steady state occur

when rate of administration (drug input) equals rate of elimination (drug exit), resulting in a constant plasma concentration of drug for a prolonged time

what is half-life

the time required to reduce the concentration of drug by 50% in the blood (plasma)

half life and its clinical significance

if a fixed dose of a drug is given repeatedly at fixed intervals, it takes about 5 half-lives to achieve ~97% of steady-state concentration in the plasma

example of half-life and significance

if the half-life of a drug is 20hrs then it will achieve ~97% steady state concentration after 100hrs

why is only 97% steady state acceptable

it still gets the therapeutic benefit and increases is a minimal difference

what does half-life apply to

drugs that follow first order elimination kinetics

half life and complete drug elimination time

in general, it takes about 5 half-lives for about 97% of a drug to be effectively eliminated from the body (when drug administration is stopped)

what can an increase in Vd cause

an increase in the half-life of drug

-an exceptionally large Vd indicates considerable sequestration of drug in some tissues (example; fat)

any factor that increases clearance...

may decrease the half-life of drug

t (1/2) =

(0.693 x Vd)/Cl

define the above terms

-t (1/2)= half life

-Vd= volume of distribution

-Cl= clearance

where did 0.693 come from in the half life equation

its the natural log rhythm of 2 from the first order kinetics equation

clinical conditions affecting half-life

kidney and liver diseases impair clearance and increase half-life (dose adjustment required)

clinical conditions affecting half-life: what can IMPAIR clearance and INCREASE half-life

diseases (cardiogenic shock, heart failure, or hemorrhage) that affect blood flow to liver and kidney impair clearance and increase half-life

clinical conditions affecting half-life: what can decrease the half-life

increased metabolic activity (enzyme induction)

clearance

is a critical parameter for determining the maintenance dose of drugs

CLp =

rate of elimination of drug from plasma (ug/min)/plasma drug concentration (ug/mL)

define the term CLp

plasma clearance

what are additional methods to calculate clearance

clearance can be calculated from half-life and can also be calculated from dose and AUC

what is the equation to use if calculating CL from dose and AUC (area under the curve)

CL = dose/AUC

maintenance dose

a dosing regimen for a drug indicates its route of administration, dose strength and dosing interval

what is the goal of the maintenance dose

to achieve therapeutic concentration of drug (and maintain the concentration using maintenance doses if long term treatment is desired)

how can the maintenance dose rate (mg/h) be determined by

knowing the target plasma concentration (Cp), clearance (CL) and bioavailability (F)

maintenance dose (mg/h)=

(target Cp (mg/L) x clearance (L/h)/ F

doing rate =

target Cp x clearance (for IV since F=1 for IV)

when is a loading dose sometimes required

to rapidly achieve the desired plasma concentration (example; serious infections or arrhythmias)

loading dose: in such emergent cases why is a loading dose administered

to rapidly achieve the desired plasma concentration, followed by maintenance dose to maintain the steady state

how can the loading dose be determined

by knowing the target plasma concentration (Cp), volume of distribution (Vd) and bioavailability (F)

loading dose =

(target Cp x Vd)/F

IV: loading dose =

target Cp x Vd (for IV, since F=1 for IV)