Jenny B . Jimenez , BSMT 3A

8/14/2019 Jenny B . Jimenez , BSMT 3A

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Component Processes

vAbsorption entry of a drug from its site ofadministration to the systemic circulationvDistribution process by which a drug enters

the interstitium or tissues from the blood

vMetabolism / Biotransformation processes bywhich a drug is changed: to its active form or toits removable form

v Excretion removal of the drug from the body

Pharmacokinetics

. ,enny B Jimenez BSMT 3A


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Drug

Absorption into Plasma

Distribution toTissuesBound Drug

Free Drug

TissueStorage

Sites ofAction

Drug Metabolism: Liver, Lung,

etc

Drug Excretion: Renal, Biliary,

etc.

Drug Biodisposition


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Solubility -Lip id so lu b ility a b ility to d iffu se

th ro u g h lip id b ila y e rs W a te r solu b ility in a q u e o u s p h a ses :P a rtitio n C o e fficie n t T h e ra tio o f lip id

.so lu b ility to a q u e o u s so lu b ility T h e,h ig h e r th e p a rtitio n co e fficie n t th e

m o re m e m b ra n e solu b le is th e

.substance

Ionization ,D ru g s a re w ea k a cid s o r w ea k b a se s

& can exist in nonionized or ionized,fo rm s in a n e q u ilib riu m d e p e n d in g

& . o n p H p K a T h e H e n d e rso n

H a sse lb a lch e q u a tio n d e te rm in e s th e( p e rce n ta g e o f io n iza tio n io n ize d- ; -w a te r so lu b le n o n io n ize d lip id)so lu b le

Io n iza tio n in cre a se s re n a l cle a ra n ce o fdrugs

Concentration gradient diffusion is down aconcentration radient


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Absorption

vPassive diffusion most commonAqueous diffusion: Ficks Law:

Flux (J) = (C1 C2) x S.A. x P.

coefficient Thickness J = molecules per unit time C1= higher concentration C2 = lower concentration S.A. = surface area available for diffusion P. Coefficient = permeability coefficient /

partition coefficient Thickness = length of the diffusion path


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Absorption

Lipid diffusion: the HendersonHasselbalch equation

log (protonated / unprotonated)

= pKa pH *for acids: pKa = pH + log x

concentration [HA] unionized

concentration [A] *if [A] = [HA], then pKa = pH + log(1); log (1) = 0, so

pKa = pH

*for bases: pKa = pH + log xconcentration [BH+] ionized


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Diffusion

vAqueous diffusionwithin large

aqueouscompartments

across tightjunctionsacross

endotheliumthru pores(MW20,000 -

30,000)molecules tend

to move froman area ofhigher to anarea of lowerconcentration

vLipid diffusionhigher partition

coefficient =easier for a drugto enter lipidphase fromaqueous

charged drugs difficulty indiffusing thru

lipiduncharged lipid-soluble

lower pH relativeto pKa, greaterfraction ofprotonated drug

rotonated


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Special Carriers

vFacilitated diffusion passive (no Eexpended) carrier-mediatedtransport.

saturable;subject to competitive & non-

competitive inhibitionused by peptides, amino acids, glucose

vActive (uses E) carrier-mediatedtransportsaturablesubject to competitive & non-

competitive inhibition


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Endocytosis & Exocytosis

ENDOCYTOSIS

ventry into cells by very large substances(uses E)

ve.g. Iron & vit B12 complexed with theirbinding proteins into intestinal mucosalcellsEXOCYTOSIS

vexpulsion of substances from the cellsinto the ECF (uses E)

ve.g. Neurotransmitters at the synapticjunction


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Ion Trapping

vIon trapping or reabsorption delaysexcretionKidneys:

n e a rly a ll d ru g s a re filte re d a t th eg lo m e ru lu s

-m o st d ru g s in a lip id so lu b le fo rm w illb e re a b so rb e d b y p a ssiv e d iffu sio n

:to in cre a se e x cre tio n ch a n g e u rin a ryp H to fa vo r th e ch a rg e d fo rm o f th e

( )d ru g n o t re a d ily a b sorb e d

weak acids are excreted faster in( )alkaline pH anion form favored weak bases are excreted faster in

( )acidic pH cation form favored

Other sites: body fluids where pH differsfrom blood pH, favoring trapping or

reabsorption stomach contents a ueous humor


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Distribution

vFirst pass effect decreased bioavailabilityof drugs administered orally because ofinitial absorption into the portalcirculation & distribution in the liver

where they may undergo metabolism orexcretion into bilevExtraction Ratio magnitude of the first

pass effect.

ER = cl Liver / q (hepatic blood flow)vSystemic drug bioavailability determinedfrom extent of absorption & ER.

F = f x (1 ER)

v


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Distribution

vVolume of Distribution ratiobetween the amount of drug in thebody (dose given) & the

concentration of the drug in bloodplasma. Vd = drug in body / drug inblood

Factors influencing Vd:drug pKa (permeation)extent of drug-plasma protein bindinglipid solubility (partition coefficient)

patient age, gender, disease states,


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Drug Plasma ProteinBinding

vMost drugs are bound to some extent toplasma proteins Albumin, Lipoproteins,alpha 1 acid glycoprotein

vExtent of protein binding parallels druglipid solubility

vBinding of drug to Albumin is often non-selective,

vAcidophilic drugs bind to Albumin,

basophilic drugs bind to Globulinsvdrugs with similar chemical/physicalproperties may compete for the samebinding sites

vVolume of distribution is inverselyproportional to protein binding


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Distribution

vNon-ionized (hydrophobic) drugs crossbiomembranes easily

vBinding to plasma proteins accelerates

absorption into plasma but slowsdiffusion into tissues

vUnbound / free drug crossesbiomembranes

vCompetition between drugs may lead todisplacement of a previously bound drug r l v ls o

r un oun ru tt r str ut on

v str ut on o urs mor w


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Distribution

vSpecial barriers to distribution:placentablood-brain barrier

vMany disease states alter distribution:

Edematous states cirrhosis, heart failure,nephrotic syndrome prolong distribution& delay Clearance

Obesity allows for greater accumulation oflipophilic agents within fat cells,increasing distribution & prolonging half-life

Pregnancy increases intravascular volume,thus increasing distribution

hypoAlbuminemia allows drugs thatnormally bind to it to have increased

bioavailability


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Blood Brain Barrier (BBB): Only lipid-soluble compounds get through

the BBB. Four components to the blood-brain barrier:

T ig h t Ju n ctio n s in b ra in ca p illa rie s G lia l ce ll o o t p ro ce sse swrap around

th e ca p illa rie s ------>Lo w C S F p ro te in co n ce n tra tio n n o

o n co tic p re ssu re fo r re a b so rb in g p ro te in.ou t o f th e p la sm a

E n d o th e lia l ce lls in th e b ra in co n ta in

, ,e n zym e s th a t m e ta b o lize n e u tra lize.m a n y d ru g s b e fo re th e y a cce ss th e C S F

M A O a n d C O M T a re fo u n d in b ra in.e n d o th e lia l ce lls T h e y m e ta b o lize

D o p a m in e before itreaches the, -C S F th u s w e m u st g ive L D O PA in


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Exceptions to the BBB. Certain parts of thebrain are not protected by the BBB:

,P itu ita ry M e d ia n E m in e n ce S u p ra v e n tricu la r a re a s P a rts of h yp o th a la m u s

Meningitis: It opens up the blood brain

barrier due to edema. Thus Penicillin-G canbe used to treat meningitis (caused byNeisseria meningitides), despite the factthat it doesn't normally cross the BBB.Penicillin-G is also actively pumped back

out of the brain once it has crossed the BBB.Sites of Concentration: can affect the Vd

Fat, Bone, any Tissue, Transcellular sites: drugconcentrates in Fat / Bone / non-Plasmalocations low ron ntr t on o ru n


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Metabolism

Biotransformation of drugs (usually in the Liver;also in the Lungs, Skin, Kidney, GIT)) to morepolar, hydrophilic, biologically inactive molecules;required for elimination from the body.

vPhase I reactions alteration of the parent drug

by exposing a functional group; active drugtransformed by phase I reactions usually losepharmacologic activity, while inactive prodrugsare converted to biologically active metabolites

vPhase II reactions parent drug undergoesconjugation reactions (to make them moresoluble) that form covalent linkages with afunctional group: glucuronic acid, acetyl coA,sulfate, glutathione, amino acids, acetate, S-adenosyl-methionine


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Metabolism

Phase Iv reaction products may be directly excreted in

urine or react with endogenous compounds toform water-soluble conjugates

vmixed function oxidase system (cytochrome

P450 enzymecomplex: Cyt P450 enzyme,Cyt P450 reductase) requires NADPH (notATP) as E source, & molecular O2; [drugmetabolizing enzymes are located in hepaticmicrosomes: lipophilic, endoplasmic reticulummembranes (SER)]

v Phase I enzymes perform multiple types ofreactions:

OXIDATIVEREACTIONS REDUCTIVEREACTIONS HYDROLYTICREACTIONS

v


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CYTOCHROME-P450 COMPLEX:There are multiple isotypes.

CYT-P450-2,CYT-P450-3A are responsible for themetabolism of most drugs.

CYT-P450-3A4 metabolizes many drugs in the GIT,decreasing the bioavailabilityof many orallyabsorbed drugs.

INDUCERS of CYT-P450 COMPLEX: Drugs thatincrease the production or degradation of Cyt-P450 enzymes.

Phenobarbital, Phenytoin, Carbamazepine induceCYT-P450-3A4

Phenobarbital, Phenytoin also induce CYT-P450-2B1

Polycyclic Aromatics (PAH): Induce CYT-P450-1A1 Glucocorticoids induce CYT-P450-3A4 Chronic Alcoholism, Isoniazid induce CYT-P450-

2E1. important! this drug activates some


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INHIBITORS of CYT-P450 COMPLEX Inhibit production: Ethanol suppresses many

of the CYT-P450 enzymes, explaining someof the drug-interactions of acute alcoholuse.

Noncompetitive inhibition:Chloramphenicolis metabolized by Cyt P450 to an alkylating

metabolite that inactivates Cyt P450 Competitive inhibition: Erythromycin inhibits

CYT-P450-3A4. Terfenadine (Seldane) ismetabolized by CYT-P450-3A4, so the toxicunmetabolized form builds up in thepresence of Erythromycin. Theunmetabolized form is toxic and causeslethal arrhythmias. This is why Seldane wastaken off the market;

Cimetidine, Ketoconazole bind to theheme in Cyt P450, decreasing metabolism of


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Metabolism

Phase IIv Drug Conjugation reactions: detoxificationrxns: non-microsomal, primarily in the liver;also in plasma & GIT usually toglucuronides, making the drug more soluble.

vconjugates are highly polar, generallybiologically inactive (exception: morphine

glucuronide more potent analgesic than theparent compound) & tend to be rapidlyexcreted in urine or bile

v Enterohepatic recirculation: high molecularweight conjugates are more likely to beexcreted in bile nt st n s w r N lor l v t on u t on s r l s n /

t p r nt ompoun nto t s st m r ul t on

l p r nt ru l m n t on /


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R e a ctio n R e a cta n t tra n sfe ra se

su b stra te E x a m p le

-G lu cu ro n

id a tio n

G lu cu ro n i

c a cid

G lu cu ro n y

ltra n sfe ra s

e

,P h e n o ls

,a lco h o lsca rb o lic

,a cid sh yd ro xy la m i

,n e ssu lfo n a m id e s

M o rp h in e

a ce ta m in o ph e n

d ia zep a md ig ito x in

m e p ro b a m ate

A ce ty la tio

n

A ce tyl

C o A

- -N A ce ty l

tra n sfe ra se

A m in e s S u lfo n a m id

e s iso n ia zid clo n a ze p a md a p s o n e

m e sca lin eG lu ta th io n

eco n ju g a tio

n

G lu ta th io

n e

- -G S H Stra n sfe ra s

e

,E p o xid e s,n itro g ro u p s

h yd ro xy la m i

n e s

E th a cryn ica cid

b ro m o b e n z

e n e


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R e a ctio n R e a cta n t tra n sfe ra

se

su b stra te E x a m p le

S u lfa teco n ju g a ti

o n

-P h o s p h oa d e n o s y l-p h o s p h o

su lfa te

-S u lfotra n sfe ra

se

,Ph e n o ls,a lco h o lsa ro m a tic

a m in e s

Estronew a rfa rin

a ce ta m in o p

h e nm e th yld o p a

m e th y la ti

o n

-Sa d e n o s y l

m e th io n i

n e

-Transm e th y la s

e s

C a te ch o la m i

,n e sp h e n o lsa m in e s

D o p a m in ee p in e p h rin e

h ista m in e

,th io u ra cilp yrid in e


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Toxicity

vdrugs are metabolized to toxicproducts

vhepatotoxicity exhibited by

acyl glucuronidation of NSAIDSN-acetylation of IsoniazidAcetaminophen in high doses

glucuronidation & sulfation areusual conjugation reactions intherapeutic doses, but in highdoses, these get saturated so CytP450 metabolizes the drug, forming

hepatotoxic reactive electrophilic


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Reduction in Bioavailability

vFirst pass effectvIntestinal flora metabolize the drugvDrug is unstable in gastric acid e.g.

Penicillin

vDrug is metabolized by digestiveenzymes e.g. Insulin

vDrug is metabolized by intestinal wallenzymes e.g. sympathomimeticdrugs / catecholamines


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Excretion

vClearance CL removal of drug from theblood, or the amount of blood/plasmathat is completely freed of drug per unittime over the plasma concentration of

the drug CL = rate of elimination of drug plasma drug concentration

especially important for ensuringappropriate long-term dosing, or

maintaining correct steady state drugconcentrations

Renal clearance - unchanged drug, water-soluble metabolites glomerular filtration,active tubular secretion, passive tubular

reabsorption of lipid-soluble agentsHe atic clearance extraction of dru s after


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Excretion

vHalf life (t ) time required to decreasethe amount of drug in the body by 50%during elimination or during a constantinfusion; useful in

estimating time to steady-state:approximately 4 half-lives to reach 94%

Estimation of time required for drugremoval from the body

Estimation of appropriate dosing interval:drug accumulation occurs when dosinginterval is less than 4 half-lives

Affected by

Chronic renal failure decreases clearance,prolongs half-life


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Drug Elimination

vZero order kinetics rate of eliminationof the drug is constant regardless ofconcentration i.e. constant amount of

drug eliminated per unit time so thatconcentration decreases linearly withtime

examples: ethanol, phenytoin, aspirin

vFirst order kinetics rate of eliminationof the drug proportional to concentrationi.e. constant fraction of the drugeliminated per unit time so that

concentration decreases exponentially


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Excretion

vKIDNEYGLOMERULAR FILTRATION: Clearance of

the apparent volume of distribution bypassive filtration.

Drug with MW < 5000 ------> it is completely filtered. Inulin is completely filtered, and its clearance can be

measured to estimate Glomerular Filtration Rate(GFR).

TUBULAR SECRETION: Active secretion.

Specific Compounds that are secreted: para-Amino Hippurate (PAH) is completelysecreted, so its clearance can be measured toestimate Renal Blood Flow (RBF).

Penicillin-G is excreted by active secretion.Probenecid can be given to block thissecretion.


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Anionic System: The anionic secretorysystem generally secretes weak ACIDS:

Penicillins, Cephalosporins Salicylates Thiazide Diuretics Glucuronide conjugates

Cationic System: The cationic secretory

system generally secretes BASES, orthings that are positively charged. Ion-Trapping: Drugs can be "trapped" in

the urine, and their rate of elimination canbe increased, by adjusting the pH of theurine to accommodate the drug. This is

useful to make the body get rid of poisonsmore quickly.

To increase excretion of acidic drugs, makethe urine more basic (give HCO3-)

To increase excretion of basic drugs, makethe urine more acidic.


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BILIARY EXCRETION: Some drugs areactively secreted in the biliary tract andexcreted in the feces. Some of the drug

may be reabsorbed via the enterohepaticcirculation. Transporters: The liver actively transporters

generally large compounds (MW > 300), orpositive, negative, or neutral charge.

Anionic Transporter: Transports some acids,

such as Bile Acids, Bilirubin Glucuronides,Glucuronide conjugates, Sulfobromophthalein,Penicillins

Neutral Transporter: Transports lipophilicagents, such as:

Steroids

OuabainCationic Transporter:Transports

positively charged agents, such as n-Methylnicotinamide, tubocurarine

Charcoal can be given to increase the fecalexcretion of these drugs and prevent


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vORDERS of EXCRETION:

ZERO-ORDER EXCRETION:The rateof excretion of a drug isindependent of its concentration.

General properties:

dC/dt = -K A plot of the drug-concentration -vs- time is

linear.

The half-life of the drug becomes continuallyshorter as the drug is excreted.

Examples: Ethanol is zero-order in moderate

quantities, because the metabolismsystem is saturated. The rate ofmetabolism remains the same no matterwhat the concentration.

Phenytoin and Salicylates follow zero-order kinetic at high concentration.


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FIRST-ORDER EXCRETION: The rate of excretion ofa drug is directly proportional to its concentration.

General properties:

dC/dt = -K[C] A plot of the log[conc] -vs- time is linear. slope of the

line = -Kel / 2.303

The half-life of the drug remains constant throughout itsexcretion

HALF-LIFE: The half-life is inversely proportional to the Kel,constant of elimination. The higher the eliminationconstant, the shorter the half-life.

v

v


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vCOMPARTMENTS:

One-Compartment Kinetics:Kinetics are calculated based on theassumption that the drug isdistributed to one uniform

compartment. One compartment kinetics implies that the

drug has a rapid equilibrium betweentissues and the blood, and that the releaseof the drug from any tissues is not rate-

limiting in its excretion. One-compartment kinetics also assumes

that the drug is distributed instantaneouslythroughout the body. This is only true forIV infusion.

v


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Multi-Compartment Kinetics: Mostdrugs follow multi-compartment

kinetics to an extent. Biphasic Elimination Curve: Many drugs

follow a biphasic elimination curve -- first asteep slope then a shallow slope.

STEEP (initial) part of curve ------> initialdistribution of the drug in the body.

SHALLOW part of curve ------> ultimate renalexcretion of drug, which is dependent onthe release of the drug from tissuecompartments into the blood.


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vCLEARANCE: The apparent volume of

bloodfrom which a drug is clearedper unit of time.

CLEARANCE OF DRUG =

(Vd)x(Kel) The higher the volume of distribution of thedrug, the more rapid is its clearance.

The higher the elimination constant, themore rapid is its clearance.


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This is based on the Dilution Principle: (Conc)(Volume) = (Conc)(Volume)

Total Amount = Total AmountMEANING: In first-order kinetics, drug

is cleared at a constant rate. Aconstant fraction of the Vd is

cleared per unit time. The higherthe Kel, the higher is that fraction ofvolume.

Drug Clearance of 120 ml/min ------> drug is

cleared at the same rate as GFR and isnot reabsorbed. Example = inulin

Drug clearance of 660 ml/min ------> drug iscleared at the same rate as RPF and is

actively secreted, and not reabsorbed.Example = PAH


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BIOAVAILABILITY: The proportion oforally-administered drug thatreaches the target tissue and has

activity.v


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AUCORAL = Area under the curve. The total amountof drug, through time, that has any activity whenadministered orally.

AUCIV = Area under curve. The total amount ofdrug, through time, that has any activity whenadministered IV. This is the maximum amount ofdrug that will have activity.

100% Bioavailability = A drug administeredby IV infusion.

BIOEQUIVALENCE: In order for two drugs tobe bioequivalent, they must have both thesame bioavailability andthe same plasmaprofile, i.e. the curve must have the sameshape. That means they must have the

same Cmax and Tmax.Cmax: The maximum plasma concentrationattained by a drug-administration.

vTmax: The time at which maximumconcentration is reached


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vREPETITIVE DOSES:FLUCTUATIONS: Drug levels fluctuate as you

give each dose. Several factors determinethe degree to which drug levels fluctuate.

There are no fluctuations with continuous IV infusion. Slow (more gradual) absorption also reduces

fluctuations, making it seem more like it werecontinuous infusion.

The more frequent the dosing interval, the less thefluctuations. Theoretically, if you give the drug,say, once every 30 seconds, then it is almost likecontinuous IV infusion and there are no

fluctuations.


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Steady-State Concentration (CSS): Theplasma concentration of the drug once it

has reached steady state. It takes 4 to 5 half-lives for a drug to reach thesteady state, regardless of dosage.

After one half-life, you have attained 50% of CSS.After two half-lives, you have attained 75%, etc.Thus, after 4 or 5 half-lives, you have attained

~98% of CSS, which is close enough forpractical purposes.

If a drug is dosed at the same interval as its half-life,then the CSS will be twice the C0 of the drug.

If you have a drug of dose 50 mg and a half-life of12 hrs, and you dose it every 12 hrs, then thesteady-state concentration you will achieve withthat drug will be 100 mg/L.


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D: Dose-amount. The higher the doseamount, the higher the Css.

v : Dosage interval. The shorter the dosage

interval, the higher the Css F: Availability Fraction. The higher the

availability fraction, the higher the Css.

Kel: Elimination Constant. The higher theelimination constant, the lower is the Css.

v Vd: Volume of Distribution. A high volume ofdistribution means we're putting the drug into alarge vessel, which means we should expect alow Css.

Cl: Clearance. The higher the drug-clearance, the lower the Css.


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If you know the desired steady-stateconcentration and the availability fraction,then you can calculate the dosing rate.

v LOADING DOSE: When a drug has a long half-life,this is a way to get to CSS much faster. Loading Dose = twice the regular dose, as long

as we are giving the drug at the same interval asthe half-life.

v INTRAVENOUS INFUSION: The CSS is equal to the

input(infusion rate x volume of distribution)divided by the output(Kel)


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R0 = the rate of infusion. Vd = the volume of distribution, which

should be equal to plasma volume, or3.15L, or 4.5% of TBW.

Kel = Elimination Constant

vLoading Dose in this case is just

equal to Volume of distribution time


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v RENAL DISEASE: Renal disease means the drug isnot cleared as quickly ------> the drug will havea higher Css ------> we should adjust the dose

downward to accommodate for the slowerclearance. If the fraction of renal clearance is 100% (i.e. the

drug is cleared only by the kidneys), then youdecrease the dosage by the same amount theclearance is decreased.

For example: If you have only 60% of renal functionremaining, then you give only 60% of the original dose. If the fraction of renal clearance is less then 100%,

then multiply that fraction by the percent of renalfunction remaining.

v For example: If you have only 60% of renal

function remaining, and 30% of the drug iscleared by the kidney, then the doseadjustment = (60%)(30%) = 20%. The doseshould be adjusted 20%, or you should give80% of the original dose


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G = The percentage of the original dose that weshould give the patient.

vIf G = 60%, then we should give thepatient 60% of the original dose. f= The fraction of the drug that is cleared by the

kidney.

vIf f is 100%, then the drug is cleared only

by the kidney. ClCr = Creatinine clearance of patient, and normalclearance. The ratio is the percent of normalkidney function remaining.

Renal disease increases the time to reachsteady-state concentration. Renal Disease

------> longer half-life ------> longer time toreach steady-state.

v

Jenny B . Jimenez , BSMT 3A

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Transcript of Jenny B . Jimenez , BSMT 3A