PK/PD and ADMET

PK vs PD

PK - effect of host on drug
PD - effect of drug on pathogen

interplay between what factors PH and PD

Host - abx: PK, toxicodynamics
abx - pathogen: resistance, PD
pathogen - host: immune response, infectious disease

why is PK/PD important? (2)

to make sure the abx do work at the location where it is supposed to - avoid relapses, avoid resistance development
can help to give the best dosing regimen - ie the factors that can be influenced by the clinician

diff types of administration (5)

inhaled, oral, intramuscular, topical, intravenous

General principles of PK descr (4)

AUC - area under curve, function of how high the [] of the drug gets and how fast it gets removed
Cmax - highest [] of the drug in blood
t1/2 (half life) - time at which drug has lost half of its max []
Cmin - lowest [] of drug in blood

what is this a graph of

pharmacokinetics

what is AUC a result of

ADME

ADMET long

absorption, distribution, metabolism, excretion, toxicity

Absorption descr (+ 3 qs w/ it)

process where compounds enter the blood flow from the administration side - what is the [] of drugs in blood plasma? Is Cmax diff for different administration routes (oral vs IV)? Some drugs not well absorbed by gastrointestinal tract so should adjust accordingly

Metabolism descr

chemical breakdown of compounds in metabolites

oral vs IV absorption

Oral - slow rise, slow fall
IV - quick rise, Cmax larger but T1/2 smaller

which is which?

green - IV
blue - oral

4 major compartments of the body

blood, extracellular fluid, intracellular fluid, fat

Distribution descr

drug associates w/ binding moleculea (eg proteins like albumin)- sequesters drug in compartments, increases storage capacity; equilibrium between bound and unbound drugs

what do unbound drugs do

can move into new compartment - maintains equilibrium

what is balance of drugs in body determined by + descr

Kc - equilibrium constant, dependent on permeability of barriers (cell membrane) and binding capacity

what case is this?

drug evenly distributed - uncommon

label bottom 3

1 - drug confined to circulation (very large drug molecules)
2 - drug excluded by cell membranes (very polar drug molecules)
3 - drug enriched in fat (lipophilic drugs)

Metabolism descr

most often in the liver but also in lungs or gut
fact the metabolized by liver important for PK - orally given drugs metabolized by liver before they reach systemic circulation - influences PK (first pass metabolism)

metabolis in liver more detail

first step - by Cyp 450- oxidases - can lead to drug inactivation or activation
(other phase I enzymes like esterases, hydrolases and dehydrogenases also possible)
then phase II conjugating enzymes eg GST

result modifications of metabolism phase I

drug becomes water soluble, drug can be modified by other enzymes (phase 2)

eg of drug metabolism

phenytoin - first highly lipophilic then after phase I slightly soluble in water and after phase 2 very soluble in water

3 ways of excretion

liver (into bile), kindeys, sweat/tears/milk

excretion via the kidney (3)

filtration - only free drug filtered, # determined by renal blood flow/glomerular filtration rate/plasma protein binding
secretion - saturable mechanisms for organic anions and organic cations, overlapping substrate specificity, important excretion mechanism for highly protein bound drugs
reabsorption - lipophilic drugs, modulated by urine pH & drug pKa

therepeutic index

between therapeutic effect and toxic effect

important things for PD

Cmax/MIC - how high peak [] is above the MIC, for drugs that kill better at high [] (eg aminoglycosides)
AUC/MIC - total drug exposure relative to MIC - eg for vancomycin and fluoroquinolones, also account for post antibiotic effect - suppresion after AB is removed
time ~ conc > MIC - how long drug [] is above the MIC - eg for time dependent drugs like beta lactams - continuous infusion

safety index

TI = TD50/ED50

what can you tell with PD

what is the effect of the drug on the microbe, crucial relationship w/ MIC, other factors?

are all abx [] dependent

no! eg ticarcillin is not

persistence effect

post abx effect - eg ticeracillin has direct regrowth w/ similar kinetics after dilution BUT
ciprofloxacin - delayed outgrowth after dilution

3 patterns of antimicrobial activity

PD property: []-dependent killing, prologued persistence - AUC24/MC, Cmax/MIC - goal is maximize drug []
time dependent killing, minimal persistence - T>MIC - goal is maximize duration of drug exposure
time dependent killing, moderate to prologued persistence - AUC24/MIC - goal is maximize amount of drug

what does this show

diff strategies required based on the drug and its properties

time dependent killing - eg and what application best

beta lactams - continuous application best for therapy (if MIC is known)

special conditions - location of infection (4)

bladder
lung - penetration problematic, inhalation of drugs can be advantageous
meninges
granulomas

2 abx w/ unusual PK - how used to our advantage

eg nitrofurantoin - v quickly cleared by your kidneys - 20 min half life - used for UTIs
rifaximin - derivative of rifampicin, oral abx which cannot be absorbed - used for e coli (travelers diarrhea)

special conditions - special patients (5)

disturbed blood circulation eg diabetic food, disturbed renal function, obese patients, children, pregnant women

PK/PD conclusions (3)

PK characteristics (ADME) important for [] of drug in tissue
PD - 3 diff types of behavior for diff abx
diff types request diff strategies of administration