farmakologi umum2
TRANSCRIPT
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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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