FARMAKOKINETIK

Drugs cross lipid membranes mainly (a) by passive diffusional transfer and (b) carriermediated transfer
The main factor t/ determines the rate of passive diffusional transfer across membranes is a
drugs lipid solubility. Molecular weight is a less important factor.
With weak acids or bases only the unionised forms can diffuse across lipid membrane; this
gives rise to pH partition.
pH partition means t/ weak acids tend to accumulate in compartments of relatively high pH,
whereas weak bases do the reverse.(ion trapping phenomenon)
Carrier-mediated transport is important for some drugs t/ are chemically related to
endogenous substances.
difusi pasif : lipit solubility, ph & ionisasi, Most drugs across cell membrane by this transfer.
Not selective, no energy required, not saturable, cannot be inhibited
Carrier molecule: a protein which binds molecules or ions, and releases them on the other
side of the membrane.
CMT (carrier mediated transport) may operate without energy by facilitating the process of
transfer in the direction of its electrochemical gradient and the mechanism is called
facilitated diffusion. Eg.the transfer of glucose across a muscle cell membrane mediated by
GLUT4.
CMT can also occur against an electrochemical gradient and is called active transport. Eg.:
sodium pumps, Na-Ca exchange.
CMT shows the characteristic of saturation, and can be inhibited competitively by a second
ligand that binds the carrier.
subcutaneous administration
o Absorption is prompt, from aqueous solution, slow and sustained from repository
preparations.
o Suitable for poorly soluble suspensions and for instillation of slow-release implants
o Not suitable for large volumes
o Possible pain or necrosis from irritating substances
intramuscular
o Absorption is prompt from aqueous solution, slow and sustained from repository
preparations.
o Suitable for moderate volumes, oily vehicles, and some irritating substances.
o Precluded during anticoagulant therapy, and may interfere w/ interpretation of
certain diagnostic tests (e.g.creatine kinase)
oral / enteral
o Absorption is variable, depends on many factors
o Most common method of drug adminis-tration.It is also the safest,most conve-nient,
and most economical. Disadvantages include limitation of absorption of some drugs
because of their physical characteristics (eg.water solubility), it also requires patient
compliance
o Bioavailability is potentially erratic and incomplete.
Drugs w/ low lipid solubility are poorly absorbed from the gut.
A few drugs (eg.levodopa) are absorbed by CMT.
Absorption from the gut depends on: -GI motility, -GI pH, particle size, -physicochemical
interaction with gut contents (eg. Ca and tetracycline antibiotics)
Bioavailability is the fraction of an ingested dose of a drug that gains acces to the systemic
circulation. It may be low because absorption is incomplete, or because the drug is
metabolised in the gut wall or liver before reaching the systemic circulation.
Bioequivalence implies that if one formulation of a drug is substituted for another no clinical
untoward consequences will ensue.

methode for delaying absorbtion

o Addition of adrenaline (epinephrine) to a local anesthetic
o slow-release form : procaine-penicillin,medroxyprogesterone acetate, testosterone
propionat, flufenazine decanoate
o Insulin zinc suspensions
o Subcutaneous implantation of solid pellets
drugs distribution (vb)
o Vd : the volume of plasma that would contain the total body content of the drug at a
concentration equal to that in the plasma.
o Lipid insoluble drugs :confined to plasma and the interstitial fluids; most do not
enter the brain .
o Lipid-soluble drugs reach all compartments, and may accumulate in fat.
o For drugs that accumulate outside the plasma compartment (eg. in fat, or being
bound to tissues) Vd may exceed total body volume.
hanya obat yang bebas (tidak terikat protein plasma) yang bisa menyeberang di antara
compartment
hati : fenestrasi besar mengizinkan obat untuk masuk secara bebas dalam cairan interstisium
kapiler otak : adanya tight junction jadi tidak sembarang substansi bisa masuk otak (lipid
soluable bs masuk bebas
metabolisme obat
o Phase I reactions:oxidation,reduction & hydrolysis. These usually form more reactive
products,sometimes pharmacologically active, toxic or carcinogenic. Phase I oftenly
involve cytochrome P450 enzymes.
o Phase II reactions : conjugation (eg.glucuronidation) of a reactive group (often
inserted during phase I) and form inactive and readily excretable products.
o Some conjugated products are excreted via bile, are reactivated in the intestine and
then reabsorbed.
o Induction of enzymes by other drugs and chemicals can greatly accelerate hepatic
drug metabolism.
o Some drugs show rapid first-pass hepatic metabolism, and thus poor oral
bioavailability
penghambat p450 : Ketoconazole (an antifungal) which forms a complex with CYP3A4,
causes a non-competitive inhibition with a risk of a fatal cardiac arrhythmia if the drug is
given concomitantly with terfenadine (an antihistamine).
induksi p450 : Enzyme inducers: ethanol,rifampicin, carbamazepine,increase the activity of
microsomal oxidase and conjugating systems when administered repeatedly
toxic metabolis dari parasetamol : N-asetil - benzoquinon - imine
filtrasi glomelurus :
o obat dengan berat molekul < 20.000 bisa melewati ini tapi albumin (68000) tidak.
o If a drugs is highly bound to plasma albumin (eg. Warfarin 98% bound), its
concentration in glomerular filtrate is very low (only 2% warfarin).
sekresi tubular :
o 20% of renal plasma flow is filtered through the glomerulus, leaving 80% of the
delivered drug to pass on to the peritubular capillaries of the proximal tubule. Here
drug molecules are transferred to the tubular lumen by 2 independent carrier
systems.One of these transport acidic drugs, while the other handles organic bases.
o These active transport can transport drug molecules against an electrochemical
gradient and can, therefore , reduce the plasma concentration nearly to zero. Since
80% of the drug delivered to the kidney is presented to the carrier, tubular secretion
is potentially the most effective mechanism of renal drug elimination, even when
most of the drug is bound to plasma protein (e.g. penicillin)

difusi pada tubulus renalis :

o As the glomerular filtrate traverses the tubule, water is reabsorbed, so that the
volume of urine only about 1% of the filtrate.
o High-lipid soluble drugs are excreted slowly,while polar &low lipid soluble drugs
remain in the tubule & its concentration in the urine is 100 times >than in plasma.
o The ion-trapping effect :a basic drug is more rapidly excreted in an acid urine,
because the low pH within the tubule favours ionization and thus inhibits
reabsorption.
eksresi empedu dan sirkulasi enterohepatic
o Liver cells transfer various substances, including drugs, from plasma to bile by means
of transport systems similar to those of the renal tubule and which involve Pglycoprotein.
o Drug conjugates (particularly glucoronides) are concentrated in the bile and
delivered to the intestine where the glucuronide is usually hydrolysed, releasing
active drug once more. Free drugs can then be reabsorbed and the cycle repeated
(enterohepatic circulation).
o Examples :morphine, ethinylestradiol, and rifampicin.
bioavibility dari intravena : 100 %
(AUC = area under curve)Oral Bioavailability = AUCoral / AUCiv
saturation kinetic :
o E.g. Ethanol, phenytoin, salicylate
o The rate of disappearance of ethanol from the plasma is constant at about 4
mmol/L per hour irrespective of its plasma concentration.
o Also oftenly termed as zero-order kinetics
o The rate of drug metabolism by hepatic enzymes reaches a maximum at low plasma
concentration.