Tri Widyawati

Dep. Farmakologi & Terapeutik,

Fakultas Kedokteran

Februari 2022, Blok 5, FKG USU

Pharmacokinetics (PK) and pharmacodynamics (PD)

Plasma Site
Dose Concen- of
Effects
tration Action

PK PD
 Pharmacokinetics

◼ how the human body act on the drugs?

the quantitative study of drug movement in, through and out of the body.

Pharmacokinetic properties of particular drug is important to determine the route of

administration, dose, onset of action, peak action time, duration of action and frequency of
dosing
The Pharmacokinetic Process
Biological Membrane
Relative Permeability of Synthetic Bilayers to Some Solutes

6
 Drug Transportation

◼ Drug molecules can cross cell membrane by:

◼ Passive Diffusion
◼ Protein – mediated transport (carrier mediated)
◼ Facilitated Transport
◼ Active trnsport
▪ Primary
▪ Secondary
 Passive transport (down hill movement)
• Most important mechanism for most of the Drugs Mekanisme yang paling penting untuk sebagian besar obat
• Majority of drugs diffuses across the membrane in the direction of
concentration gradient Sebagian besar obat berdifusi melintasi membran ke arah gradien konsentrasi
• No active role of the membrane Tidak ada peran aktif membran
• Proportional to lipid : water partition coefficient Sebanding dengan lipid : koefisien partisi air
• Lipid soluble drugs diffuse by dissolving in the lipoidal matrix of the membrane
• Characteristics: Obat larut lipid berdifusi dengan larut dalam matriks lipoidal membran
◼ Not requiring energy
◼ Having no saturation
◼ Having no carriers
◼ Not resisting competitive inhibition Tidak menolak hambatan kompetitif
 Passive transport

Affecting factors :
the size of molecule
lipid solubility polarity
degree of ionization
the PH of the environment such as:
fluid of body, fluid in cell blood, urine
ukuran molekul lipid kelarutan polaritas derajat ionisasi PH lingkungan
seperti: cairan tubuh, cairan dalam sel darah, urin
Notes…
◼ Unionized drugs, low polarity and higher lipid solubility
➔ easy to permeate membrane. Obat bersatu, polaritas rendah dan kelarutan lipid yang lebih tinggi
mudah menembus membran.

◼ Ionized drugs, high polarity and lower lipid solubility

➔ difficult to permeate membrane.
 pH Effect

◼ Most of drugs are weak acids or weak bases.

◼ The ionization of drugs may markedly reduce
Ionisasi obat dapat secara nyata mengurangi
their ability to permeate membranes. kemampuan mereka untuk menembus
membran.
◼ The degree of ionization of drugs is determined by
the surrounding pH and their pKa.
Tingkat ionisasi obat ditentukan oleh pH sekitarnya dan pKa mereka
 Henderson–Hasselbalch Equation

pKa = negative logarithm of acid dissociation constant

[A-] = ionized Drug

[HA] = unionized drug

The stronger an acid, the greater the ionization, the lower the pKa, and the lower the pH the
compound will produce in solution.
Consequences
◼ Acidic drugs re absorbed are largely unionized in stomach and
absorbed faster while basic drugs are absorbed faster in
intestines Obat asam yang diserap kembali sebagian besar disatukan dalam lambung dan diserap lebih cepat sementara
obat dasar diserap lebih cepat di usus
◼ Ion trapping
◼ Acidic drugs are excreted faster in alkaline urine – urinary
alkalizers Obat asam diekskresikan lebih cepat dalam urin alkali – alkalizer urin
◼ Basic drugs are excreted faster in acidic urine – urinary
acidifiers Obat dasar diekskresikan lebih cepat dalam urin asam – acidifiers urin
 Filtration
◼ Passage of trugs through aqueous pores in membrane or
through para cellular space Bagian trug melalui pori-pori berair di membran atau melalui ruang para seluler
Obat tidak larut
◼ Lipid insoluble drugs can cross – if the molecular size is small lipid dapat
menyeberang –
jika ukuran
◼ Majority of intestinal mucosa and RBCs have small pores molekulnya kecil
and drugs cannot cross Mayoritas mukosa usus dan sel darah merah memiliki pori-pori kecil dan obat-obatan tidak
dapat menyeberang
◼ But, capillaries have large paracellular space and most drugs
can filter through this Tapi, kapiler memiliki ruang paraseluler yang besar dan sebagian besar obat dapat menyaring
melalui ini
Filtration
 Carrier Mediated Transport
◼ Involve specific membrane transport proteins know as drug
transporters or carriers – specific for the substrate
Melibatkan protein transpor membran spesifik yang dikenal sebagai transporter obat atau pembawa – khusus untuk substrat

◼ Drug molecules bind to the transporter, translocated across

the membrane, and then released on the on other side of the
membrane.

◼ Specific, saturable and inhibitable

◼ Depending on Energy requirement - Can be either Facilitated

(passive) or Active Transport
 Facilitative transporters
◼ Move substrate of a
single class (uniporters)
down a concentration
gradient

◼ No energy dependent
◼ Similar to entry of
glucose into muscle
(GLUT 4)
Mechanisms by Which Solutes & H2O Move Across Cell Membranes

20
Active Transport – energy dependent

◼ Active (concentrative) transporters

◼ can move solutes against a concentration gradient
◼ energy dependent
◼ Primary active transporters - generate energy themselves
(e.g. ATP hydrolysis)

◼ Secondary transporters - utilize energy stored in voltage and

ion gradients generated by a primary active transporter
(e.g. Na+/K+-ATPase)
◼
◼ Symporters (Co-transporters)
Antiporters (Exchangers)
 Major Drug Transporters
• ATP-Binding Cassette Transporters (ABC) Super
family – Primary active transport
• P-glycoprotein (P-gp encoded by MDR1)
• Intestinal mucosa, renal tubules and blood brain barrier etc.
• Mediate only efflux of solute from cytoplasm - detoxification
◼ Solute Carrier (SLC) transporters – Secondary
active transport
◼ Organic anion transporting polypeptides (OATPs)
◼ Organic cation transporters (OCTs)
◼ Expressed in liver and renal tubules – metabolism and
excretion of drugs
 Pinocytosis

◼ the invagination of a part of the cell membrane and

trapping within the cell of a small vesicle containing extra
cellular constituents.
◼ The vesicle contents can than be released within the cell,
or extruded from the other side of the cell.
◼ important for the transport of some macromolecules (e.g.
insulin through BBB).
 Absorption of Drugs
❖Absorption is the transfer of a drug
from its site of administration to the
blood stream
❖Most of drugs are absorbed by the way
of passive transport
❖Intravenous administration has no
absorption
❖Fraction of administered dose and rate
of absorption are important
 Factors affecting absorption
➢ Drug properties:
lipid solubility, molecular weight, and polarity etc
◼ Blood flow to the absorption site
◼ Total surface area available for absorption
◼ Contact time at the absorption surface
◼ Affinity with special tissue

Routes of Administration (important):

 Oral Administration – 1st pass metabolism

◼ Before the drug reaches the systemic

circulation
➔ the drug can be metabolized in the liver
or intestine ➔ the concentration of drug in the
systemic circulation will be reduced.
1st pass Elimination – Metabolism in liver

Buccal cavity
Stomach

Vena
Intestine cava
Portal
vein

Rectum
 Buccal and Rectal – bypasses liver

Vena
cava

Buccal drug delivery avoids the first-pass effect

insufflation, suppository, intravenous, intramuscular, inhalational aerosol, transdermal, or
sublingual, avoid the first-pass effect because they allow drugs to be absorbed directly into the
systemic circulation
Absorption
• It is the passage of drug from the site of administration into the
circulation.
• Aqueous solubility
• If a drug given as water solution, it is absorbed faster
• Concentration.
• Drug given as concentrated solution is absorbed faster.
• Area of absorbing surface.
• If the area is larger, the absorption is faster.
• Vascularity of absorbing surface.
• Increased blood flow hastens drug absorption.
Oral absorption
• Unionized lipid soluble drugs (e.g. ethanol) are
readily absorbed from GIT.
• Highly ionized drugs, e.g. amikacin, gentamicin,
neostigmine, are poorly absorbed
• Acid drugs (aspirin, barbiturates etc.) are
predominantly unionized in the acid gastric juice
and are absorbed from stomach.
• Acid drugs absorption from stomach is slower,
because the mucosa is thick, covered with mucus and
the surface is small.
• Basic drugs (e.g. atropine, morphine etc.) are
largely ionized and are absorbed only from the
duodenum.
Oral absorption
• Presence of food dilutes the drug and retards
absorption.
• Food delays gastric emptying. The most drugs are
absorbed better if taken in empty stomach.
• Certain drugs form poorly absorbed complexes with
food constituents, e.g. tetracyclines with calcium
present in milk.
• Certain drugs are degraded in the GIT,
• e.g. penicillin G by acid, insulin by peptidases, and are
ineffective orally.
• Enteric coated tablets (having acid resistant coating)
and sustained released preparations can be used to
overcome acid ability, gastric irritancy and brief
duration of action.
Oral absorption
Drugs can also alter absorption by
• gut wall effect:
• altering motility (atropine, amitriptyline, pethidine,
methoclopramide) or
• causing mucosal damage (neomycin, methotrexate,
reserpine, vinblastine).
• Alteration of gut flora by antibiotics may disrupt
the enterohepatic recirculation of oral
contraceptives and digoxin.
• Intestinal absorption:
• duodenum (B1, Fe2+)
• ileum (B12, A, D, E, K)
• large intestine (water, Na+, Cl-, K+)
 A = Enterohepatic circulation

Systemic effect

Liver

A
Kidney

Small
Intestine

Pancreas

A
PIROXICAM : long t1/2 (> 45 hr) → enterohepatic cycle
Routes of administration

Concentration
of Cocaine in
plasma

• Drug half-life varies as a function of route of

administration
• Half-life = time for plasma drug conc. to fall to half of peak
level
Bioavailability
• refers to the rate and extent of absorption of a
drug from dosage form as determined by its
concentration-time curve in blood or by its
excretion in urine.
• It is a measure of the fraction (F) of administered dose
of a drug that reaches the systemic circulation in the
unchanged form.
• Bioavailability of drug injected iv. is 100%, but is
frequently lower after oral ingestion, because:
• The drug may incompletely absorb
• The absorbed drug may undergo first pass
metabolism in intestinal wall and/or liver or be
excreted in bile.
Plasma concentration (mcg/ml)
AUC – area under the curve
AUC p.o.
F – bioavailability F = ------------ x 100%
AUC i.v.

(i.v. application)

(p.o. application)

0 5 10 15
Time (h)
Plasma concentration time curves of the three preparations of a drug
which containing the same amount. Formulation B is more slowly absorb
than A and may not produced therapeutic effect. Formulation C is absorbed
to lesser extent (it has lower bioavailability).
Drug distribution
• It is the passage of drug from the circulation to the tissue and site of its
action.
• Drug must pass through many cell membranes (Cells in gut, blood vessels, glial cells,
neurons)
• Most important factor in achieving active dose at site of action (e.g., brain)
• The extent of distribution of drug depends on :
• its lipid solubility, ionization at physiological pH (dependent on pK), extent of binding to plasma
and tissue proteins and differences in regional blood flow, disease like CHF, uremia, cirrhosis.
• Movement of drug proceeds until an equilibration is established between
unbound drug in plasma and tissue fluids.
Drug Distribution
Route of Administration
Local activity only
Intramuscular or
Subcutaneous
Oral
Injection
Intravenous Topical
Injection Administration
Gastrointestinal
tract Tissue Depots

DRUG DRUG
DRUG
DRUG
Systemic circulation
Drug
Lipid
DRUG Serum Albumin
+
Membranes
First Drug Metabolites
Drug Metabolites
Pass
Effect
Enterohepatic
Recirculation

Primarily the Liver Receptors Receptors

Bile Intestinal Kidney for desired for undesired
produces Drug Tract
Duct effects effects
Metabolites
Pharmacology
Route of Feces Urine: Drug &
Metabolism Drug Metabolite
Route of Elimination
Drug Distribution

• The total body water as a percentage of body mass varies from 50% to 70%, being
rather less in women than in man.
• Body water is distributed into the follow main compartments:
1. plasma (5% of body mass)
2. interstitial fluid (16%)
3. intracellular fluid (35%)
4. transcellular fluid (2%)
5. fat (20%)
Apparent volume of distribution (Vd)
It is accept that the body behaves as a single
homogeneous compartment with volume (Vd)
which drug gets immediately distributed:

Dose administered i.v.

Vd = -----------------------------
Plasma concentration
Apparent volume of distribution (Vd)
• Drugs extensively bound to plasma proteins are largely
restricted to the vascular compartment and have low Vd
• e.g. warfarin – 99% bound and its Vd is 0,1 L/kg.
• Drugs sequestrated in other tissues may have Vd much more
than total body water or even body mass,
• e.g. digoxin (6 L/kg) and propranolol (3 to 4 L/kg).
• Therefore, in case of poisoning, drugs with large Vd are not
easily removed by haemodialysis.
Classification of antibiotics in terms of their propensity to
partition into fat or water
Hydrophilic Smaller volume of Aminoglycosides
antibiotics distribution Beta-lactams
Likely to be renally Glycopeptides
eliminated unchanged
Increased clearance in
severe sepsis
Lipophilic Larger volume of Fluoroquinolones
antibiotics distribution Macrolides
Likely to be hepatically Rifampicin
metabolized Linezolid
More likely to penetrate
deep tissue
McKenzie C J. Antimicrob. Chemother. 2011;66:ii25-ii31
Redistribution. Highly lipid soluble drugs given i.v.
or by inhalationally get distributed to organs with high
blood flow (brain, heart, kidney, liver). Later they get
distributed to less vascular tissues (muscles and fat)
and the drug-plasma concentrations falls.

Greater the lipid solubility of the drug hastens its

redistribution. Anaesthetic action of thiopentone
(thiopental) is terminated in few minutes due to
redistribution. However, when the same drug is given
repeatedly or continuously over long periods the low
perfusion high capacity sites get progressively filled
up and the drug becomes longer acting.
Thiopental
redistribution
in muscle
and fat
(long post-
Narcotic sleep)
Blood-Brain Barrier
• Limits the ability of drugs to reach the brain, even
when they can reach other tissues
BBB is lipoidal and limits the entry of non-lipid soluble
drugs (amikacin, gentamicin, neostigmine etc.).
Only lipid soluble unionized drugs penetrate and
have action on the CNS.

Efflux carriers like P-gp (glycoprotein) present in brain

capillary endothelial cells (also in intestinal mucosal,
renal tubular, hepatic canicular, placental and testicular
cells) extrude drugs that enter brain by other processes

Inflammation of meanings of brain increases

permeability of BBB.

Dopamine (DA) does not enter brain, but its precursor

levodopa does. This is used latter in parkinsonism.
 Blood and
peripheral Brain
GIT
tissues
L-DOPA
(levodopa)
1-5%
DDC DDC

МАО COMT

85-90% 9%

DDC – DOPA-decarboxilase; COMT – catechol-О-methyltransferase

Plasma protein binding (PPB)
• Most drugs possess physicochemical affinity for
plasma proteins.
• acidic drugs bind to plasma albumin and
• basic drugs to α1-glycoprotein.
• Extent of binding depends on the individual
compound. Increasing concentration of drug
can progressively saturate the binding sites.
• The clinical significant implications of PPB are:
• Highly PPB drugs are largely restricted to the
vascular compartment and tend to have lower Vd.
• The PPB fraction is not available for action.
• There is an equilibration between PPB fraction of
drug and free molecules of drug.
Plasma protein binding (PPB)
• The drugs with high physicochemical affinity for plasma
proteins (e.g. aspirin, sulfonamides, chloramphenicol) can
replace the other drugs (e.g. acenocoumarol, warfarin) or
endogenous compounds (bilirubin) with lower affinity.
• High degree of protein binding makes the drug long
acting, because bound fraction is not available for
metabolism, unless it is actively excreted by liver or
kidney tubules.
• Generally expressed plasma concentrations of the drug
refer to bound as well as free drug.
• In hypoalbuminemia, binding may be reduced and high
concentration of free drug may be attained (e.g.
phenytoin).
Tissue Distribution
• Tissue storage. Drugs may also accumulate in specific organs or get
bound to specific tissue constituents, e.g.:
• Heart and skeletal muscles – digoxin (to muscle proteins)
• Liver – chloroquine, tetracyclines, digoxin
• Kidney – digoxin, chloroquine
• Thyroid gland – iodine
• Brain – chlorpromazine, isoniazid, acetazolamide
• Retina – chloroquine (to nucleoproteins)
• Iris – ephedrine, atropine (to melanin)
• Bones and teeth – tetracyclines, heavy metals (to mucopolysaccharide of
connective tissue)
• Adipose tissues – thiopental, ether, minocycline, DDT
METABOLISM
(BIOTRANSFORMATION)
• Metabolism includes chemical alteration of the drugs in
the body.
• Most hydrophilic drugs (amikacin, gentamycin,
neostigmine, mannitol) are not biotransformated and are
excreted unchanged.
• Mechanism which metabolize drugs is developed to
protect the body from toxins.
• The primary site for drug metabolism is liver, other sites
are kidney, intestine, lungs and plasma.
• Metabolism of drugs may lead to the following:
• Inactivation.
• Active metabolite from an active drug.
• Activation of inactive drug (PRODRUG)
Biotransformation

55
56
57
 Role of cyp enzymes in hepatic drug metabolism
In human beings, of the 1000 currently known cytochrome P-450s, about 50 are
functionally active.
These are categorised into 17 families, out of which the isoenzymes CYP3A4 and
CYP2D6 carry out biotransformation of largest number of drugs.

RELATIVE HEPATIC CONTENT % DRUGS METABOLIZED

OF CYP ENZYMES BY CYP ENZYMES
CYP2E1
CYP2D6 7%
2%

CYP 2C19
11%
CYP 2C9
CYP 2C 14%
CYP2D6
17%
23%
OTHER
36%
CYP 1A2
CYP 1A2 14%
12%

CYP 3A4-5 CYP2E1

CYP 3A4-5
26% 5%
33%

Tabele isoform CYP450

Substrates: Tolbutamide
Midazolam
Mephenytoin Nifedipine Caffeine Chlor- Dextrometo-
Warfarin Theophylline
Cumarins Omeprazole Erythromycin zoxazone rphan
Phenytoin Tacrine
Cyclosporine Sparteine
Debrisoquine

CYP3A4/5 CYP1A2
CYP2C19
CYP2C8/9/18 CYP2E1 CYP2D6 CYP1A1
CYP2B6 CYP2A6
(30–50%) ~15% <5%
<5% <5% ~20% ~10%

Inhibitors:
Methoxsalen Fluconazole Sulphaphenazole Ketoconazole Furafylline Tetrahydro- Quinidine
Gestodene Fluvoxamine furane

Inducers:
Phenobarbital Phenobarbital Phenobarbital Omeprazole Ethanol
Pheno- Nicotine Isoniazid
Rifampicin Rifampicin Rifampicin
barbital
Dexamethasone
Carbamazepine
 Excretion

◼ a transport procedure which the prototype drug (or parent drug) or

other metabolic products are excreted through excretion organ or
secretion organ
◼ Hydrophilic compounds can be easily excreted.
◼ Routes of drug excretion
◼ Kidney
◼ Biliary excretion
◼ Sweat and saliva
◼ Milk
◼ Pulmonary
 Bile duct
Hepatic Excretion
◼Drugs can be excreted in Intesti Portal
bile, especially when the are nes vein
conjugated with – glucuronic
Acid

• Drug is absorbed → glucuronidated or sulfatated in the liver

and secreted through the bile → glucuronic acid/sulfate is
cleaved off by bacteria in GI tract → drug is reabsorbed
(steroid •hormones, rifampicin, amoxycillin, contraceptives)
Anthraquinone, heavy metals – directly excreted
in colon
Renal Excretion
◼ Glomerular Filtration
◼ Tubular Reabsorption
◼ Tubular Secretion
 Glomerular Filtration

• Normal GFR – 120 ml/min

• Glomerular capillaries have pores larger than usual
• The kidney is responsible for excreting of all water soluble substances
• All nonprotein bound drugs (lipid soluble or insoluble) presented to the
glomerulus are filtered
• Glomerular filtration of drugs depends on their plasma protein binding and
renal blood flow - Protein bound drugs are not filtered !
• Renal failure and aged persons
Tubular Re-absorption
◼ Back diffusion of Drugs (99%) – lipid soluble drugs
◼ Depends on pH of urine, ionization etc.
◼ Lipid insoluble ionized drugs excreted as it is – aminoglycoside
(amikacin, gentamicin, tobramycin)
◼ Changes in urinary pH can change the excretion pattern of drugs
◼ Weak bases ionize more and are less reabsorbed in acidic
urine.
◼ Weak acids ionized more and are less reabsorbed in alkaline
urine
◼ Utilized clinically in salicylate and barbiturate poisoning – alkanized
urine (Drugs with pKa: 5 – 8)
◼ Acidified urine – atropine and morphine etc.
Tubular Secretion
◼ Energy dependent active transport – reduces the free
concentration of drugs – further, more drug dissociation
from plasma binding – again more secretion (protein
binding is facilitatory for excretion for some drugs)
◼ OATP – organic acid transport
◼ OCT – organic base transport
◼ P-gp
◼ Bidirectional transport – Blood Vs tubular fluid
◼ Utilized clinically – penicillin Vs probenecid, probenecid
Vs uric acid (salicylate)
• Quinidine decreases renal and biliary clearance of
digoxin by inhibiting efflux carrier P-gp
Renal Excretion
◼ Acidic urine
◼ alkaline drugs eliminated
◼ acid drugs reabsorbed
◼ Alkaline urine
- acid drugs eliminated
- alkaline drugs absorbed
Kinetics of Elimination
◼ Pharmacokinetics - F, V and CL
◼ Clearance: The clearance (CL) of a drug is the
theoretical volume of plasma from which drug is
completely removed in unit time
CL = Rate of elimination (RoE)/C
Example = If a drug has 20 mcg/ml and RoE is 100
mcg/min
CL = 100/20 = 5 ml /min
Kinetics of Elimination
◼ First Order Kinetics (exponential): Rate of
elimination is directly proportional to drug
concentration, CL remaining constant
◼ Constant fraction of drug is eliminated per unit time
◼ Zero Order kinetics (linear): The rate of
elimination remains constant irrespective of drug
concentration
◼ CL decreases with increase in concentration
◼ Alcohol, theophyline, tolbutmide etc.
 CL = RoE/C

Plasma half-life V = dose IV/C

◼ Defined as time taken for its plasma concentration to be

reduced to half of its original value – 2 phases rapid
declining and slow declining

t1/2 = In2/k
In2 = natural logarithm of 2 (0.693)
k = elimination rate constant = CL / V
t1/2 = 0.693 x V / CL
Terimakasih

tw_rozan@yahoo.com

eRHaeS TriWidyawati

@triwidyawati9