farmakologi umum2

7/24/2019 Farmakologi Umum2

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Physicochemical factors intransfer of drugs acrossmembranes1. Drug factors: sie and shape, degree of

ioniation, lipid solubility, protein binding.

!. "embrane factors: a bilayer amphipatic

lipids# proteins ser$e as receptors, channels,or transporters.

%. &ypes of transport: a) cellulars (passi$ediffusion, acti$e transport, facilitateddiffusion)# b) paracellular (filtration).


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Passive membrane transport isdirectly proportional to: Drug concentration gradient across the

membrane.

'ipid: water partition coefficient.

ell surface area

Differences in p


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'ipid "ucosal *arrier

p + 1.

p + -.

astric /uice

Plasma

0

12 13332 13312

&otal

02402

054 4

0

12 13332

054 413312

0 05

4 4

pK

a=

.6eak acidnonionied ionied


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Active membrane transport:

7e8uirement for energy.

0gainst electro5concentration gradient.

9aturability.

9electi$ity.

nhibited by cotransported compounds.


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Transporter proteins:

"ediate drug uptake or efflux.

P5glycoprotein is an important efflux

transporter in hepatocyte, brain capillaries,

and enterocyte.


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Transporter proteins (TP):

&here are two ma;or &P superfamilies: 1) 0* (0&Pbinding cassete)# !) 9' (9olute carriers).

&he 9' type of transporter mediate either uptake orefflux, whereas 0* transporters mediate only

unidirectional efflux. "ost 0* proteins are primary acti$e transporters, which

rely on 0&P hydrolysis to acti$ely pump their substratesacross. 0mong the best known transporter in the 0*superfamily is P glycoprotein (P5gp, also termed by"D71, encoded by 0*-).t is an important effluxtransporter in hepatocyte, brain capillaries, andenterocyte.


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Transporter Proteins (TP):

9' superfamily includes genes that encodefacilitated transporters and ion5coupled secondaryacti$e transporters that reside in $arious cellmembrane.

"any ser$e as drug targets or in drug absorptionand disposition. 6idely recognied transportersinclude the serotonin and dopamine transporters.

Drug transporters operate in pharmacokinetic and

pharmacodynamic pathways, including pathwaysin$ol$ed in both therapeutic and ad$erse effects.


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Absorption

The rate and the amount of a drugleaves its side of administration

Dierent sites of administration havedierent rate & extend of absorption

GI motility, malabsorptive states, andfood may alter the oral absorption

Physicochemical properties of thedrug aect its absorption


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Administration

0 knowledge of the ad$antages and

disad$antages of the different routes is of

primary importance in deciding the choice of

administration: oral, sublingual, suppository,inhalation, local, topical, intra$enous,

intramuscular, subcutan, etc.


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Bio-availability (1)

The rate & the amount ofadministered drug reaches thesystemic circulation intact

The rate depends on pharmaceuticalfactors and GI absorption, the extent

depends on the extent of absorptionand the extent of pre-systemicmetabolism


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Bio-availability (2)

Dosage form of a drug from dierentmanufacturers sometimes diered intheir bioavailability

ectal solution, but not suppositoryformulation, is absorbed better thanoral formulation, and the potential for

!rst pass-metabolism is less potential


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Distribution (1)

"nbound drug is distributed into interstitialand cellular #uids

The rate and the extent of a drugdistributed into extra vascular #uidsdepend on physiological factors,physiochemical properties, and the extendof its binding to plasma proteins

T$o phases of distribution% faster and

slo$er ipid solubility is an important determinant

of tissue upta'e


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Distribution (2)

(ighly bound drug $ill yield anincrease in unbound fraction in casesor renal impairment, the last

trimester of pregnancy, displacementby other drugs and saturability ofprotein binding

))) restricts the entry of drugs into*+ and * extra cellular space

Termination drug eect may alsoresult from redistribution


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Distribution of drugs into andout of CNS t is uni8ue because functional barriers are present *rain capillary endothelial cells ha$e continuous tight

;unction &he uni8ue precapillary cells also contribute to *** 0t the choroid plexus a similar barrier is also present. &he lipid solubility and the unbound of the drug is

determinant of its uptake by the brain 9 through $illi


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Placental Transfer

Drug may cause congenital anomalies

'ipid solubility, extend of plasma binding, and

degree of ioniation are determinant of the transfer

>etal plasma is slightly more acidic (p -.35-.!), sothat ion trapping of basic drugs occur

P5glycoprotein is present in placenta

&he $iew that placenta is an absolute barrier is

inaccurate


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Plasma Proteins ()

0cidic drugs are bound to albumin *asic drugs are bound to acid glycoprotein &he binding is usually re$ersible

Drugs bound to plasma is determined by conc.,affinity, and number of binding sites

Plasma binding is saturable process 6ithin the therapeutic ranges the unbound fraction

is relati$ely constant. ypoalbuminemia results in reduced binding


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Plasma Protein (!)


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"at as #eservoir

'ipid soluble drugs are stored in the neutral fat

n obese the fat content may be as high as A3B of

body weight

>at ser$es as an important reser$oir for lipid solubledrugs. >or example, -3B thiopental may be present

in body fat % hours after administration.

"uscles, bones, and plasma proteins can ser$e as

drug reser$oirs


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#edistribution

>rom its site of action into other tissues

"ay terminate drug effect

&hiopental is a good example


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Biotransformation (1)

To generate more polar, inactive metabolitesthat are readily excreted from the body

*lassi!ed as phase I and Phase II reactions.Phase I results in the loss of pharmacologicalactivity/ phase II lead to con0ugate $ithendogenous compounds. *on0ugates are highlypolar, inactive, and rapidly excreted. Phase I isin 1% phase II is cytosolic.

There are three ma0or types of

biotransformation reactions% oxidative,hydrolysis, and con0ugation. *ytochrome P234 5,6, and 7 families 8G9P5,

*9P6, and *9P7: are responsible for theoxidative metabolism of numerous drugs


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Biotransformation (2)

*yp7;2 is involved in biotransformation ofa ma0ority of all drugs and it is expressed insigni!cant amount in GI tract.

The !rst-pass metabolism limits the oral

availability of highly metaboli


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$iotransformation (%)

lucoronidation is 8uantitati$ely the most importantcon;ugation reation.

@DP5glucoronyl transferases catalye the tranfer of anacti$ated glucoronic acid molecule to form glucoronide

con;ugates. &he increased water solubility of the glucoronide

con;ugates promotes their renal elimination. "ost phase reactions are cytosolic, but @DP5

glucoronyl tranferases are microsomal enymes. 0cetylated metabolites often are less water soluble, that

prolongs their elimination from the body.


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"actors a&ecting drugbiotransformation () 0 hallmark of drug metabolism is large $ariability. 0 combination of genetic, en$ironmental, and

physiological factors are in$ol$ed in regulation ofdrug biotransformation.

&he most important factors are geneticallydetermined polymorphism in drug oxidations andcon;ugations, concomitant use of other drugs,pollutants and chemicals, disease, and age. &hese

factors can decrease efficacy, prolong effects, orincrease toxicity.


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"actors a&ecting drugbiotransformation (!) 0 number of genetic polymorphisms are exist: poor,

intermediate, extensi$e, or ultrarapid metabolier. 0 polymorphism also occurs in =5acetyl transferase reater likelihood of type C side effects in poor

metabolier. Drugs and pollutants can induce the synthesis or inhibit

the action of PA3 protein. "any PA3 inducerscan also induce phase biotransformation. nhibition

drug biotransformation enymes results in ele$ated drugblood le$els, prolonged pharmacological effects, and anincreased incidence of drug toxicity.


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"actors a&ecting drugbiotransformation (%) mpairment of li$er function can alter hepatic drug

biotransformation. Decreases in hepatic blood flow can decrease the

biotransformation of drugs with high extraction ratio.

n the elderly, metabolic capacity is reduced. Drug metaboliing enymes de$elop early in fetal life, but thele$el e$en lower following !5 weeks postpartum.

nduction of certain metaboliing enymes occurs in the secondand third semester.

?ral contracepti$es are potent inhibitor of PA3


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Renal excretion

ipid soluble drugs are not readily eliminated until they aremetaboli


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Biliary, Fecal, and t!er"xcretion

=rganic anions including glucoronides, andorganic cations are actively transported byP-glycoprotein into bile. These metabolites

may be excreted in the feces/ but morecommonly they are reabsorbed into theblood and ultimately excreted in the urine.

Drugs in breast mil' are sources of

un$anted eects in nursing infant. >il' ismore acidic, basic compounds may beslightly concentrated.


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#!armacodynamics

Is the study of the mechanism of action,the biochemical and physiologicaleects of drugs, and the relationship

bet$een concentration and eect


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'echanism of Action

&he effect of most drugs results frominteraction with macromolecules whichinitiates the biochemical and physiological

changes. 0 drug is potentially capable of altering the

rate of which any bodily function proceeds. Drugs do not create effects, but instead

modulate physiological function.


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Drug #eceptors

Proteins form the most important class of receptors. &hey ser$eas receptor for endogenous regulatory ligands.

"any drugs act selecti$ely on such physiological factors Drugs that bind to physiological receptor and mimic the effect of

the endogenous regulatory compounds are termed agonist.

Drugs that bind to receptors but do not mimic the effect ofendogenous agonist are termed antagonist.

Drugs that are partly as effecti$e as agonist are termed partialagonist.

Drugs that stabilie the receptor from conformational changesare termed negativeantagonist or inverseagonist.


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SA# and Drug Design

0ffinity of a drug for its receptor and its intrinsic acti$ity aredetermined by its chemical structure.

"inor modification in the drug molecule may result in ma;orchanges in pharmacological properties.


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Physiological "unction of#eceptors &he function of physiological receptors consist of binding

appropriate ligand and, in response, propagating its regulatorysignals in the target cell.

&he regulatory actions of a receptor may be exerted directly onits cellular target, effector protein, or may be con$eyed by

intermediary cellular molecules, tranducers. &he receptor, its cellular target, and any intermediary cellular

molecules are referred as receptor-effector system or signaltransduction pathway.

&he receptor act catalytically and hence are biochemical signal

amplifiers.


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Structural and "unctional"amilies of Physiological

#eceptors "embers of $arious classes of receptors and manyof the associated transducer and effector protein

ha$e been purified, and their mechanism of action

are understood in considerable biochemical detail.

7eceptors, transducers, and effectors can be

expressed $ia molecular genetic strategies and

studied in cultured cells. 0lternati$ely, they can be

expressed in large amounts in cell of bacteria oryeast to facilitate their purification.


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Structural and "unctional"amilies of Physiological

#eceptors (!)1. 7eceptor protein kinases (tyrosine phosphatase,adenyl cyclase).

!. on channels (nicotinic cholinergic, 0*0)

%.

5protein coupled receptors (for biologic amines,eicosanoids, peptide hormones)

. &ranscription factors (for steroid, thyroid, $it D,retinoids) that regulate the the transcription ofspecific genes.

A. ytoplasmic messengers (cyclic 0"P, a44).


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uantitativePharmacodynamics &he dose5response cur$e (D7) depicts the

obser$ed effect as a function of drug concentrationin the receptor. 0 dose5response cur$e is typified bya maximal asymptote $alue when all receptor sites

were occupied. 0 D7 is plotted with the log concentration. 0 D7 has three basic properties: threshold, slope,

and maximal asymptote. 0 drug does two things to receptor: bind and change

their beha$ior. *inding is go$erned by affinity#changing is go$erned by efficacy.


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#eceptor ccupancy Theory() Ea

0 4 7 07 9timulus 7esponse

7esponse + receptor x efficacy x receptor

occupancy number

(binding)


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#eceptor ccupancy Theory(!) 9timulus is the initial effect of drug upon the

receptor itself. 9timulus is then transduced by the system to

yield obser$ed response. 0ffinity is increased by the increase of Ea.

&he fraction of receptors occupied by thedrug is determined by the concentration thedrug and Ea.


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Bm

aximalre

sponsese

02 'og 02

A3

3

133

A3

3

133

0 *


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uantifying Agonism

Drugs ha$e two obser$ed properties in biological

systems, i.e. potency and magnitude of effects,

when a biological response is produced.

Potency is controlled by four factors: two relate tothe receptors (density and efficacy of the stimulus

response), and the other two relate to the drug5

receptor interaction (affinity and efficacy).


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uantifying Antagonism

0ntagonism is associated with blockade ofreceptors.

ompetiti$e antagonist: a drug lacks intrinsicefficacy but retains affinity and competes with the

agonistshift to the right of agonist dose5responsecur$e, and no change in maximal asymptoticresponse.

Partial agonist: increasing concentration of a partialagonist will inhibit response.

=on competiti$e antagonist: an antagonist thatdissociate too slowly from the receptor.


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B"

axima

lull agonist

Partial agonist

nacti$e

compound

n$erse agonist

Ri

DRi

DRi

DRi

DRa

DRa

DRa

Ra

D

D

D

D

!33

1A3

133

A3

3

'og Drug2

'e$elof7esponse(

arbitrary

units)


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