Revised drug therapy

DRUG DRUG THERAPTHERAP

YY

The Life of a DrugThe Life of a Drug

ABSORPTIONABSORPTION

DISTRIBUTIONDISTRIBUTION

EXCRETIONEXCRETION

METABOLISMMETABOLISM

Site of drug administrationSite of drug administration

From blood to the site of actionFrom blood to the site of action

Biotransformation of the drugBiotransformation of the drug

Removal of drug Removal of drug from the bodyfrom the body

PharmacokineticsPharmacokinetics

Is the drug Is the drug gettinggetting into the into the patient? patient?

AIM:AIM: Adequate drug doses must be Adequate drug doses must be

delivered to the target tissues delivered to the target tissues so that therapeutic yet non-so that therapeutic yet non-

toxic levels are obtainedtoxic levels are obtained

DISINTEGRATIODISINTEGRATIONN

BREAKDOWN OF BREAKDOWN OF SOLID FORM OF SOLID FORM OF

DRUG INTO SMALLER DRUG INTO SMALLER PARTSPARTS

DISSOLUTIONDISSOLUTIONDisintegration of Disintegration of smaller particles in smaller particles in

the GIT fluid for the GIT fluid for absorptionabsorption

RATE LIMITINGRATE LIMITING

Time it takes for the Time it takes for the drug to disintegrate & drug to disintegrate & become available for become available for

absorptionabsorption

BIOAVAILABILITYBIOAVAILABILITY FRACTION OF ADMINISTERED FRACTION OF ADMINISTERED

DRUG THAT REACHES THE DRUG THAT REACHES THE CIRCULATION IN A CIRCULATION IN A

CHEMICALLY UNCHANGED CHEMICALLY UNCHANGED FORMFORM

BIOAVAILABILITYBIOAVAILABILITY

If 100 mg of a drug is If 100 mg of a drug is administered orally and 70 administered orally and 70 mg of the drug is absorbed mg of the drug is absorbed

unchanged, the bioavailability unchanged, the bioavailability is 70%is 70%

ABSORPTIONABSORPTION Process by which drug Process by which drug molecules are transferred molecules are transferred

from the site of administration from the site of administration in the body to the circulating in the body to the circulating

fluidsfluids

PRINCIPAL PRINCIPAL MECHANISMS MECHANISMS

INVOLVED IN THE INVOLVED IN THE PASSAGE OF DRUGS PASSAGE OF DRUGS

ACROSS CELL ACROSS CELL MEMBRANESMEMBRANES

MECHANISMSMECHANISMS:: SIMPLE DIFFUSIONSIMPLE DIFFUSION AQUEOUS DIFFUSIONAQUEOUS DIFFUSION SPECIFIC CARRIER SPECIFIC CARRIER

MEDIATED TRANSPORT MEDIATED TRANSPORT SYSTEMSYSTEM

-Active Transport-Active Transport

-Passive Transport-Passive Transport

Cell Membranes: Cell Membranes:

This barrier is permeable to many drug molecules but This barrier is permeable to many drug molecules but not to others, depending on their lipid solubilitynot to others, depending on their lipid solubility

Small pores, 8 angstroms, permit small molecules such Small pores, 8 angstroms, permit small molecules such as alcohol and water to pass through. as alcohol and water to pass through.

A STEADY STATE is A STEADY STATE is achieved when the achieved when the

concentration of the concentration of the non-ionized species is non-ionized species is

the same on both the same on both sides of the sides of the membranesmembranes

SIMPLE DIFFUSIONSIMPLE DIFFUSIONLipid DiffusionLipid Diffusion

- LIKE dissolves LIKE- LIKE dissolves LIKE

- Drug molecules dissolves in - Drug molecules dissolves in the membrane to penetrate to the membrane to penetrate to the other sidethe other side

AQUEOUS DIFFUSIONAQUEOUS DIFFUSION

FILTRATION THROUGH FILTRATION THROUGH PORESPORES

The size of the drug molecule is The size of the drug molecule is relative to the size of the poresrelative to the size of the pores

H2O soluble drugs penetrate cell H2O soluble drugs penetrate cell membrane through this processmembrane through this process

ACTIVE TRANSPORTACTIVE TRANSPORT Process by which a substance is Process by which a substance is

transported against a concentration transported against a concentration gradientgradient

Drug moves from LOWER- HIGHER Drug moves from LOWER- HIGHER concentrationconcentration

Energy dependentEnergy dependent Involves SPECIFIC CARRIERSInvolves SPECIFIC CARRIERS Driven by Hydrolysis of ATPDriven by Hydrolysis of ATP

PASSIVE PASSIVE TRANSPORTTRANSPORT

FACILITATED DIFFUSIONFACILITATED DIFFUSION

a passive process whereby drugs a passive process whereby drugs can move across cell membranes can move across cell membranes more rapidly than simple diffusionmore rapidly than simple diffusion

Vast majority of drugs gain access Vast majority of drugs gain access to the body by this processto the body by this process

PASSIVE TRANSPORTPASSIVE TRANSPORT

Involves the action of a Involves the action of a specific but saturable carrier specific but saturable carrier systemsystem

Can only work in the Can only work in the presence of an appropriate presence of an appropriate concentration gradientconcentration gradient

FACTORS AFFECTING FACTORS AFFECTING ABSORPTIONABSORPTION

Physico-chemical FactorsPhysico-chemical Factors Site of Absorption/ Blood Flow at Site of Absorption/ Blood Flow at

the Sitethe Site Drug SolubilityDrug Solubility Effects of FoodEffects of Food - Blood Flow- Blood Flow - Gastric Emptying- Gastric Emptying

PHYSICO-CHEMICAL PHYSICO-CHEMICAL FACTORSFACTORS

Lipid solubilityLipid solubility Degree of IonizationDegree of Ionization Effect of pH Effect of pH Molecular Weight, Size & ShapeMolecular Weight, Size & Shape Chemical StabilityChemical Stability

LIPID SOLUBILITYLIPID SOLUBILITY

SIMPLE DIFFUSIONSIMPLE DIFFUSION

- degree of lipid solubility of - degree of lipid solubility of the drug determines the total the drug determines the total

amount of drug being amount of drug being transferredtransferred

DEGREE OF IONIZATIONDEGREE OF IONIZATION

Most drugs are WEAK Most drugs are WEAK ELECTROLYTES either weak ELECTROLYTES either weak acids or weak basesacids or weak bases

Drugs that are weak electrolytes Drugs that are weak electrolytes dissociate in solution as both dissociate in solution as both NON-IONIZED & IONIZED NON-IONIZED & IONIZED FORMFORM

Most drugs are partially Most drugs are partially ionized at physiologic ionized at physiologic pH , and only the non-pH , and only the non-

ionized species is ionized species is soluble in lipidsoluble in lipid

DEGREE OF IONIZATIONDEGREE OF IONIZATION

Non-IonizedNon-Ionized - - Non-PolarNon-Polar - -Lipid SolubleLipid Soluble FormForm MoleculesMolecules

IonizedIonized - - Polar Polar - -Lipid InsolubleLipid Insoluble FormForm MoleculesMolecules

EFFECT OF pHEFFECT OF pH

DISSOCIATION DISSOCIATION CONSTANTCONSTANT

Measure of the strength of the Measure of the strength of the interaction of a compound interaction of a compound with a protonwith a proton

Indication of drug molecules Indication of drug molecules to be ionizedto be ionized

IONIZATION V.S pHIONIZATION V.S pH

Amount of ionization of a Amount of ionization of a drug depends on the pH at drug depends on the pH at the drug site in the tissues the drug site in the tissues & its dissociation & its dissociation characteristicscharacteristics

DISSOCIATION DISSOCIATION CONSTANTCONSTANT

The pKa of a compound is The pKa of a compound is the same as the pH at the same as the pH at which it would be half which it would be half dissociated & half ionizeddissociated & half ionized

CLINICAL CLINICAL SIGNIFICANCE:SIGNIFICANCE:

Knowing the pKa of a drug, Knowing the pKa of a drug, gives the patient the idea gives the patient the idea as to the extent to which it as to the extent to which it ionizes at any pHionizes at any pH

ASA – pKa 3.5 ASA – pKa 3.5 Stomach – pH 1.0-1.5Stomach – pH 1.0-1.5 At the pH of 3.5, ASA is 50% ionizedAt the pH of 3.5, ASA is 50% ionized

DECREASE pH below 3.5DECREASE pH below 3.5 DECREASE ionization to less DECREASE ionization to less than 50%than 50% thus thus INCREASE theINCREASE the amount of un-ionized form-amount of un-ionized form- GREATER drug absorptionGREATER drug absorption

MOLECULAR WEIGHT, MOLECULAR WEIGHT, SIZE AND SHAPESIZE AND SHAPE

Substances with high Substances with high molecular weight are not molecular weight are not usually absorbed intact usually absorbed intact except in minute quantitiesexcept in minute quantities

They are absorbed by They are absorbed by enzymatic actionsenzymatic actions


H2O soluble molecules small H2O soluble molecules small enough can pass through the enough can pass through the membrane channelsmembrane channels

30 Angstrom30 Angstrom - -capillary membranecapillary membrane 4 Angstrom4 Angstrom - -other cell membranesother cell membranes


Process of FILTRATION thru single Process of FILTRATION thru single cell membranes may occur with cell membranes may occur with drugs of molecular weight of 200 drugs of molecular weight of 200 daltons or lessdaltons or less

Drugs up to 60,000 daltons Drugs up to 60,000 daltons molecular weights can filter thru molecular weights can filter thru capillary membranescapillary membranes

CHEMICAL CHEMICAL STABILITYSTABILITY

Unstable drugs may be Unstable drugs may be inactivated in the GITinactivated in the GIT

SITE OF SITE OF ABSORPTIONABSORPTION

Total Surface Area available for Total Surface Area available for absorptionabsorption

Intestine has a surface area about Intestine has a surface area about 1,000 times larger than the stomach1,000 times larger than the stomach

Intestine surface is very rich in Intestine surface is very rich in microvillimicrovilli

Absorption in the intestine is much Absorption in the intestine is much efficient than the stomachefficient than the stomach

BLOOD FLOW TO THE BLOOD FLOW TO THE SITE OF SITE OF

ABSORPTIONABSORPTIONBlood flow from the Blood flow from the intestine is much greater intestine is much greater than the stomachthan the stomach

EFFECTS OF FOODEFFECTS OF FOOD

Food influences the amount of Food influences the amount of drug absorbed & the rate at drug absorbed & the rate at which drug is absorbed from the which drug is absorbed from the GIT by affecting theGIT by affecting the::

BLOOD FLOWBLOOD FLOW

GASTRIC EMPTYINGGASTRIC EMPTYING


LIQUID GLUCOSE MEALLIQUID GLUCOSE MEAL

DECREASES BLOOD FLOWDECREASES BLOOD FLOW


MEAL RICH IN PROTEINMEAL RICH IN PROTEIN

INCREASES BLOOD INCREASES BLOOD FLOWFLOW

Increase absorption in Increase absorption in the presence of food:the presence of food:

GriseofulvinGriseofulvinLithium CitrateLithium CitratePropoxyphenePropoxyphenePropanololPropanolol

Decrease absorption in Decrease absorption in the presence of food:the presence of food:

Aspirin Aspirin PenicillinPenicillinAcetaminophenAcetaminophen

GASTRIC EMPTYINGGASTRIC EMPTYING

Food that delays Gastric Food that delays Gastric Emptying also delays the Emptying also delays the

absorption of orally absorption of orally administered drugsadministered drugs

DELAY GASTRIC DELAY GASTRIC EMPTYINGEMPTYING

Low pH or High Fat Low pH or High Fat SolutesSolutes

Hot MealsHot Meals Solution Rich in Fats & Solution Rich in Fats &

CarbohydratesCarbohydrates

Slow gastric emptying Slow gastric emptying may also reduce the may also reduce the

amount of drug amount of drug absorbed because of absorbed because of

the degradation in the the degradation in the acidic contents of the acidic contents of the

stomachstomach!!

Rule of Thumb:Rule of Thumb:

If food reduces absorption of If food reduces absorption of drugs, giving the drug at least 1 drugs, giving the drug at least 1 hour before meals will minimize hour before meals will minimize this effectthis effect

If food enhances drug absorption If food enhances drug absorption the drug is given with mealsthe drug is given with meals


DISTRIBUTIONDISTRIBUTIONProcess by which the drug Process by which the drug becomes available to body becomes available to body

fluids such as plasma, fluids such as plasma, interstitial fluids & interstitial fluids &

intracellular fluids and body intracellular fluids and body tissuestissues

PRIMARY PURPOSE PRIMARY PURPOSE OFOF

DRUG TRANSPORT DRUG TRANSPORTAllow drug to reach its Allow drug to reach its site of action at specific site of action at specific tissue sitestissue sites

Transport In PlasmaTransport In Plasma


SITE SITE OFOF

ADMINISTRATIONADMINISTRATION PLASMAPLASMASITE SITE OF OF

ACTIONACTION

Receptors involved in the Receptors involved in the Action of Commonly Used Action of Commonly Used DrugsDrugs RECEPTORRECEPTOR

ADRENOCEPTORADRENOCEPTOR Alpha 1Alpha 1 Alpha 2Alpha 2 Beta 1Beta 1 Beta 2Beta 2

Main Action of Natural Main Action of Natural AgonistAgonist

VasoconstrictionVasoconstriction Hypotension/sedationHypotension/sedation Heart RateHeart Rate BronchodilationBronchodilation VasodilationVasodilation Uterine relaxationUterine relaxation

Receptors involved in the Receptors involved in the Action of Commonly Used Action of Commonly Used DrugsDrugs

RECEPTORRECEPTOR

CHOLINERGICCHOLINERGIC MuscarinicMuscarinic

NicotinicNicotinic


Heart RateHeart Rate

SecretionSecretion

Gut MotilityGut Motility

BronchoconstrictionBronchoconstriction Contraction of Striated Contraction of Striated

MuscleMuscle


RECEPTORRECEPTOR

HISTAMINEHISTAMINE H1H1

H2H2


BronchoconstrictionBronchoconstriction

Capillary DilationCapillary Dilation Increase Gastric AcidIncrease Gastric Acid


RECEPTORRECEPTOR

DOPAMINEDOPAMINE

OPIOIDOPIOID


CNS NeurotransmitterCNS Neurotransmitter

CNS NeurotransmitterCNS Neurotransmitter

FORMS OF DRUG FORMS OF DRUG INSIDE THE BODYINSIDE THE BODY

FREE / UNBOUNDFREE / UNBOUND

STATESTATE

ACTIVE FORMACTIVE FORM

Plasma H2OPlasma H2O

BOUND STATEBOUND STATE

INACTIVE FORMINACTIVE FORM

Albumins & GlobulinsAlbumins & Globulins

Only free drugs are Only free drugs are biologically active biologically active

and can cause a and can cause a pharmacologic pharmacologic

responseresponse

The patterns of The patterns of distribution in the body distribution in the body determine how rapidly a determine how rapidly a drug will elicit a desired drug will elicit a desired response, the duration of response, the duration of the response, & in some the response, & in some

cases whether a cases whether a response will be elicited response will be elicited

at allat all

Drug activity is Drug activity is related to its related to its

concentration in concentration in plasma H2Oplasma H2O

BIOLOGIC HALF-LIFEBIOLOGIC HALF-LIFE(t ½)(t ½)

Time necessary for the Time necessary for the body to eliminate half the body to eliminate half the quantity of the drug present quantity of the drug present in the circulationin the circulation

Biologic Half-LifeBiologic Half-Life

It takes several half lives It takes several half lives before more than 90% of the before more than 90% of the drug is eliminated in the drug is eliminated in the systemsystem

SHORT HALF-LIFESHORT HALF-LIFE (4-8 Hours)(4-8 Hours)

LONG HALF-LIFELONG HALF-LIFE (24 Hours or longer(24 Hours or longer))

Biologic Half-lifeBiologic Half-lifeASAASA- - 650 mg650 mg t1/2t1/2 -- 3 hrs.3 hrs.

T 1/2T 1/2 Time ofTime of

EliminationElimination

Dosage Dosage

RemainingRemaining

% LEFT% LEFT

11 33 325325 5050

22 66 162162 2525

33 99 8181 12.512.5

44 1212 40.540.5 6.256.25

55 1515 2020 3.13.1

66 1818 1010 1.551.55

Without tissue Without tissue storage sites , many storage sites , many drugs would rapidly drugs would rapidly

be metabolized be metabolized &eliminated from the &eliminated from the

body ,having little body ,having little time to exert any time to exert any

effecteffect

STORAGE DEPOTSTORAGE DEPOT((Non-Specific SiteNon-Specific Site))

Areas for transient storageAreas for transient storage

It may prevent or prolong It may prevent or prolong the action of drugsthe action of drugs

Site of drug loss or storageSite of drug loss or storage

AFFINITY TISSUESAFFINITY TISSUES

May be sites of ACTION or May be sites of ACTION or AREAS OF TRANSIENT AREAS OF TRANSIENT STORAGESTORAGE

Particular Sites:Particular Sites: FAT EYEFAT EYE BONE MUSCLEBONE MUSCLE LIVERLIVER

AFFINITY TISSUES...AFFINITY TISSUES...

GuanethidineGuanethidine -binds to heart & -binds to heart & skeletal muscleskeletal muscle

QuinacrineQuinacrine -binds to liver & skeletal -binds to liver & skeletal musclemuscle

TetracyclineTetracycline -binds to bone & -binds to bone & enamelenamel

ThiopentaThiopentall -binds to adipose tissue-binds to adipose tissue

BIOTRANSFORMATIOBIOTRANSFORMATIONN

METABOLISMMETABOLISM

LIVERLIVER

Parent drug is Parent drug is converted by converted by enzymes into drug enzymes into drug metabolites ready metabolites ready to perform its to perform its action then action then preparing it for preparing it for excretionexcretion

Most Important Intracellular Most Important Intracellular Site of MetabolismSite of Metabolism

Endoplasmic ReticulumEndoplasmic Reticulum (Microsomes)(Microsomes) MitochondriaMitochondria

(Monoamine Oxidase)(Monoamine Oxidase) LysosomesLysosomes CytosolCytosol

(Alcohol Dehydrogenase & Xanthine (Alcohol Dehydrogenase & Xanthine Oxidase)Oxidase)

ROLE OF ROLE OF METABOLISMMETABOLISM It alters the pharmacologic It alters the pharmacologic

activity, usually decreasing it activity, usually decreasing it but sometimes converting the but sometimes converting the drug to a compound similar or drug to a compound similar or do have greater activity than do have greater activity than

the originalthe original

ROLE OF ROLE OF METABOLISMMETABOLISM Results in metabolites that are Results in metabolites that are

more water soluble & less lipid more water soluble & less lipid soluble than the parent soluble than the parent

compound & thus more readily compound & thus more readily excreted in the urine or excreted in the urine or

processed further by conjugationprocessed further by conjugation

3 DIFFERENT 3 DIFFERENT PATTERNS OF PATTERNS OF

ENZYMATIC ENZYMATIC MODIFICATION OF A MODIFICATION OF A PARENT COMPOUNDPARENT COMPOUND

Inactive CompoundInactive CompoundToTo

Active CompoundActive Compound(PRO-DRUG)(PRO-DRUG)

6- Mercaptupurine6- Mercaptupurine CONJUGATIONCONJUGATIONREACTIONREACTION

6-Mercaptupurine6-MercaptupurineRibonucleotideRibonucleotide

Active CompoundActive Compound22ndnd Active Compound Active CompoundInactive CompoundInactive Compound

PHENACETINPHENACETIN(Oxidation)(Oxidation)

ACETAMINOPHENACETAMINOPHEN(Conjugation Rxn)(Conjugation Rxn)

ACETAMINOPHENACETAMINOPHENGlucoronideGlucoronide

Active CompoundActive Compound To To

Inactive CompoundInactive Compound

PENTOBARBITALPENTOBARBITAL PENTOBARBITAL PENTOBARBITAL ALCOHOLALCOHOL

Subsequently Subsequently TransformedTransformedInto anotherInto anotherInactive formInactive form

CONSIDERATIONS:CONSIDERATIONS:

Most drugs are somewhat Most drugs are somewhat LIPOPHYLIC and could LIPOPHYLIC and could remain in the body for remain in the body for prolonged times if not prolonged times if not transformed into a more transformed into a more H2O soluble derivativesH2O soluble derivatives

CONSIDERATIONS:CONSIDERATIONS:

Drug metabolism usually Drug metabolism usually decreases the activity of the decreases the activity of the therapeutic agents, but there therapeutic agents, but there are important exceptions are important exceptions where active or toxic where active or toxic metabolites are formedmetabolites are formed

2 GENERAL TYPES 2 GENERAL TYPES OF CHEMICAL OF CHEMICAL

REACTIONREACTIONNON-SYNTHETICNON-SYNTHETICSYNTHETICSYNTHETIC

PHASE 1 PHASE 1 METABOLISMMETABOLISMOXIDATIONOXIDATIONREDUCTIONREDUCTIONHYDROLYSISHYDROLYSIS

PHASE 1 PHASE 1 METABOLISMMETABOLISM

Conversion of lipophilic Conversion of lipophilic molecules into more polar molecules into more polar molecules by introducing or molecules by introducing or unmasking a polar functional unmasking a polar functional groupgroup

-OH, -COOH, -NH2-OH, -COOH, -NH2

PHASE 1 PHASE 1 METABOLISMMETABOLISM

May increase, decrease or May increase, decrease or leave unaltered the drug’s leave unaltered the drug’s pharmacologic activitypharmacologic activity

PHASE 2 METABOLISMPHASE 2 METABOLISM

CONJUGATION REACTIONCONJUGATION REACTION

ENDOGENOUS SUBSTRATEENDOGENOUS SUBSTRATE

Glucoronic AcidGlucoronic Acid

Sulfuric AcidSulfuric Acid

Acetic AcidAcetic Acid

Amino AcidAmino Acid

CYTOCHROME P-450CYTOCHROME P-450( Microsomal Mixed Function ( Microsomal Mixed Function Oxidase)Oxidase)

It absorbs light at 450 nm when It absorbs light at 450 nm when exposed to Carbon Monoxide exposed to Carbon Monoxide (Spectro-photometric Peak(Spectro-photometric Peak ) )

Most important enzymes in the Most important enzymes in the liverliver

INHIBITS MIXED FUNCTION INHIBITS MIXED FUNCTION OXIDASE ACTIVITYOXIDASE ACTIVITY

Liver P450 systemsLiver P450 systems Liver enzymes inactivate some drug Liver enzymes inactivate some drug

moleculesmolecules First pass effect First pass effect (induces enzyme activity)(induces enzyme activity)

PHASE 2 METABOLISMPHASE 2 METABOLISM

results to a more polar & results to a more polar & H2O soluble compound H2O soluble compound that are more often that are more often therapeutically inactivetherapeutically inactive

EXCRETIONEXCRETION

ORGAN FOR ORGAN FOR EXCRETIONEXCRETION

KIDNEYKIDNEY

Other Route:Other Route: LUNGSLUNGS SKINSKIN BILEBILE SALIVASALIVA FECESFECES BREAST MILKBREAST MILK

II .. KIDNEY KIDNEY

Most important routeMost important route

3 PROCESSES 3 PROCESSES IMPLICATED IMPLICATED

IN RENAL IN RENAL SECRETIONSECRETION

Glomerular Glomerular filtrationfiltration

Active Active secretionsecretion

Passive Passive reabsorptionreabsorption GF = glomerulus filtering. TR = GF = glomerulus filtering. TR =

tubular reabsorption. TS = tubular tubular reabsorption. TS = tubular secretion. secretion.

1.1.

GLOMERULAR GLOMERULAR FILTRATIONFILTRATION

Drug enters the Drug enters the kidney through the kidney through the

Renal ArteriesRenal Arteries

•Free drug flows thru Free drug flows thru the capillary slits into the capillary slits into the Bowman’s space the Bowman’s space

as part of the as part of the Glomerular FiltrateGlomerular Filtrate

•DRUG NOT TRANSFERED DRUG NOT TRANSFERED INTO THE GLOMERULAR INTO THE GLOMERULAR FILTRATE LEAVES THE FILTRATE LEAVES THE GLOMERULI THRU THE GLOMERULI THRU THE

EFFERENT ARTERIOLES W/C EFFERENT ARTERIOLES W/C DIVIDE TO FORM DIVIDE TO FORM

CAPILLARY PLEXUS CAPILLARY PLEXUS SURROUNDING THE SURROUNDING THE

NEPHRITIC LUMEN IN THE NEPHRITIC LUMEN IN THE PROXIMAL TUBULESPROXIMAL TUBULES

•Lipid solubility & pH Lipid solubility & pH do not influence the do not influence the passage of drug into passage of drug into

the glomerular the glomerular filtratefiltrate

2.2.Tubular Tubular

Reabsorption Reabsorption / / Active Secretion in Active Secretion in the Proximal Tubulethe Proximal Tubule

•Highly ionized acids & Highly ionized acids & bases are actively bases are actively

secreted by tubular secreted by tubular cells & clearance can cells & clearance can approach RPF of 600 approach RPF of 600

ml/minml/min

GFR = 125 ml / GFR = 125 ml / minmin

20% of the20% of the RENAL Plasma RENAL Plasma

FlowFlowRPF = 600 ml / RPF = 600 ml /

minmin

Neonates & elderly Neonates & elderly have low GFR & LOW have low GFR & LOW

Renal Blood FlowRenal Blood Flow

3.3.Tubular SecretionTubular Secretion / /

Passive Re-Passive Re-absorption in the absorption in the

Distal TubuleDistal Tubule

•As the drug moves toward the As the drug moves toward the distal convoluted tubule, its distal convoluted tubule, its concentration increases & concentration increases &

exceeds that of the exceeds that of the perivascular space. perivascular space.

The drug if uncharged, may The drug if uncharged, may diffuse out of the nephritic diffuse out of the nephritic

lumen back into the systemic lumen back into the systemic circulation.circulation.

•Manipulating the pH of Manipulating the pH of urine to increase the urine to increase the

ionized form of the drug in ionized form of the drug in the lumen may be used to the lumen may be used to

minimize the amount of minimize the amount of back diffusion & increase back diffusion & increase

the clearance of an the clearance of an undesirable drugundesirable drug..

Alkalinization of Alkalinization of UrineUrine NaNa

BICARBONATEBICARBONATE

Acidification of Acidification of UrineUrine

NH4ClNH4Cl

•When tubular urinary pH When tubular urinary pH is more alkaline than is more alkaline than

plasma , weak acids are plasma , weak acids are excreted more rapidlyexcreted more rapidly

•When tubular urinary pH When tubular urinary pH is more acidic than is more acidic than

plasma, weak acids are plasma, weak acids are excreted more slowlyexcreted more slowly

IIII .. ENTERO-HEPATIC ENTERO-HEPATIC CYCLECYCLE

Biliary Biliary ExcretionExcretion

1. 1. Active secretion of a Active secretion of a conjugated drug into conjugated drug into

the bilethe bile

2. 2. Unconjugated drug Unconjugated drug

liberated in the small liberated in the small intestine by hydrolysis & intestine by hydrolysis & free drug reabsorbed into free drug reabsorbed into

plasmaplasma

3.3. Some drug escapes Some drug escapes

reabsorption & reabsorption & appears in fecesappears in feces

IIIIII .. LUNGSLUNGS

Blood / Air Partition Blood / Air Partition CoefficientCoefficient LARGE VALUELARGE VALUE

- slow excretion .- slow excretion .

Rate of pulmonary circulation limitingRate of pulmonary circulation limiting

SMALL VALUESMALL VALUE

- more rapid excretion. - more rapid excretion.

Rate of pulmonary ventilation limitingRate of pulmonary ventilation limiting

IVIV.. SKINSKIN

Excretion via Excretion via sweat & may result sweat & may result in direct irritation in direct irritation

or allergic or allergic reactionsreactions

END OF TOPICEND OF TOPIC

Education

Revised drug therapy