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Pharmacokinetics

Nur Permatasari


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Site of Action

Dosage EffectsPlasmaConcen.

Pharmacokinetics Pharmacodynamics

PHARMACOKINETICS PHARMACODYNAMICS

The drug acts on the body,the body work on the drug


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Bound Free Free Bound

Therapeutics site of actionRECEPTORS

TISSUE

RESERVOIRS

SYSTEMICCIRCULATION

Free Drug

Bound Drug

ABSORPTION/LIBERATION

EXCRETION

BIOTRANSFORMATION

Unwanted ofsite of actionFREE BOUND

METABOLITE


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In order to reach their site of action, drugshave to pass through several membranes transmembrane transport AND

the plasma membrane represents thecommon barrier to drug distribution.


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Structure of the plasma membrane

The plasma membrane consists of a bilayer and membrane proteins

embedded in the bilayer


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Mechanisms of transmembran transport

Passive diffusion: passage of drugs through thelipid surface (major mechanism of drugabsorption) directly proportional to the magnitude of the concentration gradient across the membrane

Lipid-soluble drugsSmall water-soluble drugsNoncharged form of weak electrolytes

Drug absorption is depend on physicochemical properties of drug


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The rate of absorption is related to

the oil:water partition coefficient

The greater the partition coefficient, thehigher the lipid-solubility of the drug, andthe greater its diffusion across membranesor the faster its absorption


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Water-soluble drugs

Cell membranes are relatively permeable towater either by diffusion or by flow

resulting from hydrostatic or osmoticdifferences across the membrane, butbulk-flow transport is limited when themolecular mass of the solute exceeds 100to 200 daltons


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Weak electrolytes and membrane permeability

Most drugs are small (MW < 1000) weak electrolytes (acids/bases). In solution

exist in a non-ionized and an ionizedforms of drugs .

The fraction of drug that is non-ionized

depends on its chemical nature, its

pKa, and the local biophase pH...


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% Ionized vs. pH

For HA acids:% ionization = 100/(1 + 10 (pKa pH))

For BH + acids:% ionization = 100/(1 + 10 (pH

pKa))

Example: Percentage ionized pseudoephedrine HCl(pKa 9.9) in the small intestine at pH 8.0?


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Filtration: bulk flow of water-soluble drugsthrough pores (glomerular, capillary)

Facilitated diffusion: carrier-mediated,ATP not required (e.g., glucose)

Active transport: carrier-mediated, ATPrequired (e.g., Na +, K+, Ca++)

Endocytosis and exocytosis: (e.g., for verylarge compounds)

Other transmembrane transport


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Per oral is a major route of drugadministration .. Why ??

Relatively Fast Painless (usually)

Easy Safe No need for equipment or help Most drugs can be given orally

But. Some physiologic factors determinedthe drug absorption


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ORAL INGESTION , governed by:

surface area for absorption, blood flow,physical state of drug, concentration.

occurs via passive process.

In theory: weak acids optimally absorbed in

stomach, weak bases in intestine.

In reality: the overall rate of absorption ofdrugs is always greater in the intestine(surface area, organ function).


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Unique characteristics of the oral route

Influences of gastric emptying (acceleratesgastric emptying increase the rate ofabsorption)

Small intestine usually most important becauseof large surface area (folds of Kerckring, villi,microvilli)

The motility of the small intestineDrug inactivation important for oral routestomach (acid), small intestine (ester/other enzyme), distal small intestine/colon (gut bact)


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Ingestion of a solid dosage form with aglass of cold water, fasting, lying on theright side, hyperthyroidism accelerategastric emptying

Ingestion with a fatty meal, acidic drink, orwith another drug with anticholinergicproperties, lying on the left side,hypothyroidism, sympathetic output (as instress) retard gastric emptying.


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First-Pass Metabolism

Extent of metabolism occurring beforedrug enters systemic circulationMain site: Liver

Decrease in drug efficacy (orally) can beovercome by using a greater doseExample: Propranolol (5 mg vs. 100 mg)

Extensive metabolism may render oral

admin. impossibleExample: Lidocaine


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The fraction of drug eliminated fromportal blood during absorption hepaticextraction ratio (ER H)

ERH = ClH/ Q H

Bioavaibilty (F) F = 1- ERH


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Absorption describes the rate and extentat which a drug leaves its site ofadministration.

Bioavailability (F) is the extent to which adrug reaches its site of action, or to abiological fluid (such as plasma) from whichthe drug has access to its site of action.

Drug Absorption & Route of

administration


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AUCinjected I.v.

AUCoral

time

p l a s m a c o n c e n

t r a

t i o n o

f d r u g

Bioavailability = AUC oral

AUC injected i.v.X 100

AUC = area under the curve


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Important Properties Affecting

Drug AbsorptionChemical properties

acid or base

degree of ionization polaritymolecular weightlipid solubility or...

partition coefficient

Physiologic variablesgastric motility

pH at the absorption sitearea of absorbing surface

blood flow pre absorptive hydrolysisingestion w/wo food


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Advantage Relatively Fast Painless (usually) Easy Safe No need for equipment

or help Most drugs can begiven orally

E.g., medications in pill form, barbiturates, LSD,caffeine, alcohol

Disadvantage Not very fast Some drugs dont

withstand stomach/GIconditions (insulin,cocaine)

Drug absorption morevariable May cause GI distress Not suitable for

uncooperative, vomiting,unconscious

FIRST PASS through liver


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INJECTION

subcutaneous, intramuscular absorbed bydiffusion and affected by blood flow

intravenous, intraarterial injection avoidsabsorption

Other Injection types Intraperitoneal = (I.P.) into stomach cavity (between

organs). Faster than P.O.

Intrathecal = into subdural spaces of the spinal cord; bypasses blood- brain barrier but invasive

Intracerebroventricular = into the ventricles (wherecerebrospinal fluid is produced) in the brain;bypasses blood- brain barrier but extremelyinvasive Intracerebral = into the brain itself


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Injection, in general

Advantage Fast Bypasses first pass Bypasses digestion More accurate dose Can be done by

person with training

Disadvantage Painful Too fast to respond if

bad reaction or overdose Potential for infection Unless planning IV, must

be careful to avoid veins No recall of drug


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MUCOUS MEMBRANEsublingual, buccal, nasal, vaginal or rectalmucosa: passive diffusion

Advantage Quick absorption Easy and discreet Little chance of

infection or tissueharm (except with

vasoconstrictors)

Disadvantage Can taste bad or

irritate membranes Not all drugs absorbed readily

Ease and speed exacerbate abuseliabledrugs potential for abuse


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SKINTransdermal

Advantage Easy Not painful

Slow, sustainedrelease Bypasses GI tract

& first pass Only have to change

every few days /weeks

Disadvantage Can fall off Potential toxicity to

children and pets Very few drugsabsorbed sufficiently,low permeability ofskin

Local irritation possible Toxicity if additional

drug consumed


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DistributionOnly that fraction of drug which is non-protein-bound can bind to cellular receptors and pass across tissuemembranes, thus being distributed to other body

tissues, metabolized, and excreted.

The actual pattern of drug distribution reflects variousphysiological factors (blood perfusing organ, capillary

permeability ) and physicochemical properties (proteinplasma binding, lipid solubility) of the drug.


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Phases of Distribution

first phasereflects cardiac output and regionalblood flow. Thus, heart, liver,kidney & brain receive most of thedrug during the first few minutesafter absorption.

next phase

delivery to muscle, most viscera,skin and adipose is slower, andinvolves a far larger fraction of thebody mass.


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Central nervous system: permeable to lipid-solubledrugs only; limited permeability to water-solubledrugs when inflamed, that are highly bound toplasma proteins , that are weak acids (are highlyionized at the pH of blood, 7.4)

The view that the placenta is an absolute barrier todrugs is, however, completely inaccurate (in partbecause a number of influx transporters are alsopresent.The fetus is to some extent exposed to alldrugs taken by the mother.


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Plasma proteinalbumin- binds many acidic drugs

a1-acid glycoprotein for basic drugs

The fraction of total drug in plasma that isbound is determined by :

* its concentration,* its binding affinity,

* and the number of binding sites

Binding of drugs to plasma proteins such asalbumin is nonselective


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Drug Reservoirs

Body compartments where a drug canaccumulate are reservoirs. They havedynamic effects on drug availability.

GIT plasma proteins as reservoirs (binddrug)cellular reservoirs

Adipose (lipophilic drugs)Bone (crystal lattice)Transcellular (ion trapping)


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Bone Reservoir

Tetracycline antibiotics (and otherdivalent metal ion-chelating agents) andheavy metals may accumulate in bone.They are adsorbed onto the bone-crystalsurface and eventually becomeincorporated into the crystal lattice.

Bone then can become a reservoir forslow release of toxic agents (e.g., lead,radium) into the blood.


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Adipose Reservoir

Many lipid-soluble drugs are stored infat. In obesity, fat content may be as

high as 50%, and in starvation it maystill be only as low as 10% of bodyweight.

70% of a thiopental dose may befound in fat 3 hr after administration.


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GI Tract as Reservoir

Weak bases are passively concentrated inthe stomach from the blood because ofthe large pH differential.Some drugs are excreted in the bile inactive form or as a conjugate that can behydrolyzed in the intestine and

reabsorbed.In these cases, and when orallyadministered drugs are slowly absorbed,the GI tract serves as a reservoir.


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Redistribution

Termination of drug action is normallyby biotransformation/excretion, butmay also occur as a result ofredistribution between variouscompartments.

Particularly true for lipid-solubledrugs that affect brain and heart.


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Redistribution of thiopental after intravenous injection

T h i o p e n

t a l c o n c e n

t r a

t i o n

( a s p e

r c e n

t o

f i n i t i a l d o s e

)

100

50

0

minutes

1 10 100 1000

blood

brainmuscle adipose


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Drug Biotransformation

Usually inactivates the drug.Can generate active metaboliteCan generate toxic metabolite (isoniazid).Often generates polar, highly ionizedmetabolites.Conversion rate influences pharmacologicalactivity.Some drugs are eliminated unchanged (digoxin).


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Phase I functionalization reactions(oxidation, reduction, hydrolysis) introduce orexpose a functional group on the parentcompound result in loss of pharmacologicalactivity

Phase II conjugation reactions lead tocovalent linkage of a functional group on theparent drug or phase I metabolite withendogenously derived glucuronic acid, sulfate,methyl, glutathione, amino acids, acetate,acetylate etc result in highly polarconjugates


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Biotransformation of Major Functional

Groups

(-OH) oxidation, methylation, glucuronideconjugation, sulfate conjugation.

(-COOH) oxidation, glucuronideconjugation, glycine conjugation.

(-NH 2) deamination (and aldehydeformation), glucuronide conjugation,methylation.


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Phase I and Phase II Metabolic

Reactions

Drug

Phase I Absorption

Metabolite withmodified activity

Inactive metabolite

Metabolism

Lipophilic Hydrophilic

Phase II

Conjugate

Conjugate

Excretion


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Some Drugs Stimulate and SomeInhibit the drug metabolizing enzymes

Stimulation is via induction, which means anincrease in enzyme synthesis (oxidation,reduction, glucoronide formation).Phenobarbital and polycyslic aromatichydrocarbon (cigarette smoke) inducersInhibition is via competition, prodruginhibition or a decrease in the activity ofexisting enzyme.Cimetidine inhibitor


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Enzyme Induction

No induction

Phenobarbitalinduction

Benzopyreneinduction

Time (hrs)1

10

100

P l a s m a

L e v e

l

Z o x a z o

l a m

i n e

(m g

/ m l )

(Classic barbiturateeffect)

(Generated fromgrilling meat)


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ACETAMINOPHENMETABOLISM

1. Oxidation

2. Reactive Intermediate3. Glutathione Conjugation

4. Hepatic Cell Death


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Acetominophen Metabolism

Ac-glucuronide Ac Ac-sulfate

Cytochrome P-450

Reactive electrophiliccompound (Ac*)

Ac*-protein

Hepat ic c el l death

GSH

GS-Ac*

Ac-mercapturate

Good Bad


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Elimination Of Drugs

Metabolism: Liver

Excretion: KidneyLiver (bile)Lungs

Others : Feces, Saliva, Sweat, Milk


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Renal Excretion of Drugs

Filtration (Glomerulus)Secretion - Active Transport (Tubule)

Transporter for Organic AcidsTransporter for Organic Bases

Reabsorption - Passive Transport (Tubule)


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Glomerular Filtration

Only unbound drug is filtered.

Plasma Protein Binding of drug preventsfiltration: Thyroxine is 99% bound.Molecular Size:

Albumin (70,000) is not filtered.Inulin (5,500) is freely filtered; can beused to estimate GFR.


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Tubular Secretion

Active TransportOrganic Acids (inhibited by probenecid)

Organic BasesNo effect of protein binding on this processThe clearance of drug eliminated by tubularsecretion is a function of renal blood flow


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Tubular Reabsorption

Passive Transport:pH, concentration, size, lipid solubility,

ionization.acid urine favors reabsorption of weakacid, basic urine favors reabsorption ofweak base.pH urine is affected by diet,drugs, diurnal,condition of patients (respiratory andmetabolic acidosis)


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Enterohepatic Cycle

Liver

Common bile duct

Small intestine

Portal vein

3

4 1

2


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Factors affecting drug metabolism

reversible binding to plasma proteinslocalization of drugs (e.g., fat)hepatic blood flowAgegenetics-related deficiency or alteration in drugmetabolizing enzyme (e.g., acetylator,pseudocholinesterase deficiency and succinylcholine)pathologyinhibition / inductionof drug metabolizing enzyme (e.g.,by erythromycin, phenobarbital)Diet (carb-protein, vegetables, charcoal-broiled beef)Enviromental chemicals (alcohol, cigarette smoking,other chemicals)

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