Farmacologia I

Aula Terica 8
23.Fev. 2017
8h30
Farmacocintica: 7 Pontos Chave

1 Absoro
Farmacocintica: 7 Pontos Chave

1 Absoro
Farmacocintica: 7 Pontos Chave

2 Biodisponibilidade

75-85 % is metabolized by the

liver before it can reach the
circulation when taken orally.
Farmacocintica: 7 Pontos Chave

3 Transporte
(via proteica)

The surfaces of protein molecules are mostly hydrophilic, but they often have hydrophopic patches and crevices
that may bind hydrophobic drug molecules.

Protein binding is particularly common in blood plasma, which has a very high protein content (~60-80 grams
per liter).

Two thirds of the total plasma protein is made up by a single protein, namely albumin. Each albumin molecule
has eight hydrophobic binding pockets, which in regular physiology serve to transport free fatty acids. These
binding pockets also accommodate hydrophobic drug molecules.

Protein binding delays the distribution from the plasma into the tissues and slows down filtration in the kidneys,
and it thus also tends to delay the elimination of drug molecules.
Farmacocintica: 7 Pontos Chave

3 Transporte
(via proteica)

- A difuso passiva no especfica o modo mais comum de

transporte de frmacos atravs das membranas celulares;

- Uma importante classe de protenas de membrana

envolvidas no transporte de frmacos so os chamados
transportadores ABC;

- Transportadores ABC so encontrados em muitos lugares,

mas de forma proeminente no intestino delgado, no fgado, Bacterial and mammalian ABC transporters share a high degree of
nos rins e na barreira hemato-enceflica; structural homology.

- Tipicamente, estes transportadores resistem acumulao
intracelular de frmacos, levando-os de volta para o exterior
da clula (por vezes para dentro do lmen intestinal e para a
corrente sangunea);
Os transportadores ABC tendem a ter especificidades de
substrato bastante amplas, e podem portanto transportar um
nmero de frmacos elevado e diverso.
The left panel of this slide shows the structure of P-glycoprotein in its
inward-facing conformation. P-glycoprotein, also called MDR-1, for
multi-drug resistance, is a human ABC transporter notorious for its role in
the resistance of tumor cells to anticancer drugs.
The right panel shows the outward-facing conformation of the bacterial
ABC transporter Sav1866. In each panel, one of the two homologous
functional domains (MDR-1) or separate monomers (Sav1866) is
rendered in cartoon mode and in blue, while the other is shown in white
and in surface representation. The Sav1866 structure also contains two
molecules of a non-hydrolyzable ATP analogue - shown in red - within
the ATP binding sites, which are located at the interface of the two
subunits.
Farmacocintica: 7 Pontos Chave

3 Transporte
(via proteica)

The ABC transporters alternate between the inward- and the outward-facing conformation;
the cyclical transition between them is powered by ATP hydrolysis.

ABC transporters are involved in the transport of both drugs or other solutes and of
membrane lipids.

Substrates may be accepted from the cytosol or from the inner leaflet of the cell membrane.
The ATP-powered conformational change first sequesters the cargo molecule inside the
transporter and then expels it into the outer membrane leaflet or the extracellular space.
Farmacocintica: 7 Pontos Chave

3 Transporte
(via especfica)
Occasionally, active transport can work in favor of
drug distribution.

An important example is L-DOPA, which is the

biosynthetic precursor of the neurotransmitter
dopamine.
In Parkinsons disease, a specific group of
dopamine-producing cells in the brain stem -
named the substantia nigra - degenerates, and the
ensuing lack of dopamine causes the symptoms of
the disease. Parkinsons disease can be treated (not
cured) by the replacement of dopamine.

However, dopamine itself is not able to cross the

blood brain barrier; we therefore need a prodrug.
Fortunately, the immediate precursor of
dopamine, L-DOPA, structurally resembles the
aromatic amino acid Tyr, and it is transported
across the blood brain barrier by the same
transporter as Tyr.

Once inside the brain, L-DOPA can undergo

enzymatic decarboxylation to dopamine.
Application of L-DOPA is an important element in
the treatment of Parkinsons disease
Farmacocintica: 7 Pontos Chave

4 Distribuio

This picture summarizes the different compartments between which drugs may distribute.

Very large drug molecules - such as proteins and polysaccharides used as plasma expanders - cannot cross the basal membranes of the
capillaries to reach the interstitial space and will remain confined to the circulation; they will therefore occur in the blood plasma at
high concentrations.

On the other hand, drugs that are small enough to leave the capillaries and apolar enough to easily cross cell membranes will have low
plasma concentrations, particularly when they are very lipophilic and accumulate inside fat cells.

One useful, easily measured parameter that characterizes the distribution of a drug is the volume of distribution (Vd).
Farmacocintica: 7 Pontos Chave

4 Distribuio

The ability of drug molecules to cross a lipid bilayer by passive diffusion correlates with their
ability to partition into and out of the hydrophobic membrane interior.

A fairly but not excessively hydrophobic character is most conducive to transport; very polar
molecules will fail to enter the membrane, whereas extremely hydrophobic molecules will enter
readily but may have a hard time leaving it on the other side.
Farmacocintica: 7 Pontos Chave
Example drugs and their uptake and distribution parameters

4 Distribuio

Ibuprofen and olanzapine are very hydrophobic, whereas amoxicillin is more hydrophilic. Nevertheless, all three drugs are readily
taken up from the intestine; amoxicillin even has the best oral availability.

Note that the oral availability is not only affected by the traversal of the intestinal mucous membrane but also by the hepatic first-pass
effect.

Olanzapine has a very high Vd value, suggesting that it accumulates in some sort of compartment outside of the circulation, most
likely inside fat cells.

On the other hand, both ibuprofen and amoxicillin have low Vd values, suggesting that they are largely confined to the extracellular
compartment.

In the case of ibuprofen, retention in the extracellular space is likely promoted by strong binding to albumin.

The ineffective penetration of the intracellular compartment observed with amoxicillin is observed with many penicillins and
cephalosporins, and it limits the usefulness of these drugs with bacterial pathogens such as Listeria monocytogenes that persist
intracellularly.
Farmacocintica: 7 Pontos Chave

4 Distribuio
(Cintica)

In our above treatment of drug distribution, we implicitly assumed that drugs equilibrate readily between the different compartments,
and we neglected distinctions between different organs.

With the drug thiopental, the unequal rates of perfusion create a characteristic time course of distribution that is essential for this
drugs clinical use, namely the induction of a short-lived state of narcosis.

The plot above shows the time course of thiopental levels in various tissues after intravenous application. After a very short
initial phase of accumulation in the lung (not shown), thiopental redistributes to the next most strongly perfused organs such
as the brain and the liver.

From the brain, the drug then redistributes to skeletal muscle - which, in a resting patient, is not very strongly perfused - and finally
to fat tissue, which has the lowest rate of perfusion but accumulates the drug because of its lipophilicity. Ultimate elimination from
the body is very slow, but this does not affect the time course of the narcotic effect.
Farmacocintica: 7 Pontos Chave

5 Concentrao plasmtica do frmaco em funo do tempo

Farmacocintica: 7 Pontos Chave

6 Nveis teraputicos
Farmacocintica: 7 Pontos Chave

6 Nveis teraputicos
Repeated drug application can result in accumulation

In pharmacotherapy, we typically want to keep the concentration of a drug within its therapeutic range throughout, which means
that we have to repeat its application before the last dosage has been completely eliminated.

Such repeated application will cause accumulation, the extent of which will depend on the dosage interval and the drugs
half-life of elimination.

In the slide, this is illustrated for two hypothetical drugs, which have half-lives of 6 hours and of 24 hours, respectively. With both
drugs, application was assumed to occur in intervals of 12 hours, and absorption with a half life of 0.5 hours.

It is clear that, all else being equal, a longer half-life of elimination gives rise to a greater extent of accumulation.
Accumulation through repeated application needs to be taken into account with drugs that have a small therapeutic range. One
way to deal with this is to use a larger initial loading dose that brings the concentration to the therapeutic level straight away,
followed by smaller repeat doses that are calculated to maintain the level established by the initial one.
Farmacocintica: 7 Pontos Chave

7 Excreo

The kidneys and the liver share in the work of getting rid of drugs and their
metabolites.

Very broadly speaking, hydrophilic drug molecules tend to be eliminated via the
kidneys directly, whereas hydrophobic drugs require metabolic transformation in the
liver before undergoing renal or biliary elimination. There are, however, numerous
exceptions to this rule.
Farmacocintica: 7 Pontos Chave

7 Excreo

The glomerular filtrate is extensively post-processed as it passes down the

tubule. Many solutes are recovered from the filtrate, whereas some other
solutes are secreted into the nascent urine by specific active transport.

Drugs can be substrates at all three stages; that is, they can be subject to
filtration, reuptake, and secretion.
Farmacocintica: Exerccio

Um frmaco D foi injectado de forma intravenosa em ratos (200 g) com uma dose de 185
mg/Kg. Em diversos perodos foram recolhidas amostras de sangue e a concentrao
plasmtica de D est descrita na seguinte Tabela.

Tempo (h) [D] no plasma (mg/mL)

0,2 4,20
0,4 3,83
1,0 2,90
2,0 1,83
4,0 0,726
6,0 0,288
Farmacocintica: Exerccio
1. Qual o tipo de cintica observada?

R. A representao do logaritmo da concentrao em funo do tempo linear, sendo tambm

por isso que a eliminao ser orientada igualmente por um processo de 1 ordem.

Observao: Numa cintica de 1 ordem a mudana de concentrao em cada tempo proporcional concentrao
presente em cada momento (dC/dt=-kC). As unidades da contante de velocidade so tempo-1 (ou h-1). Esta relao
representa um curva que descreve uma equao exponencial. Simplificando, esta representao na forma logaritmica
vem lnC=lnC0-K.t, sendo C0 a concentrao inicial de frmaco (t=0h). Deste modo, o tempo de semi-vida pode ser
calculado por t1/2=0,693/k.

(ln 2 ~ 0,693)
Plasma Concentration (mg/mL)

Time (h)
Farmacocintica: Exerccio

2. Existe algum tempo de semi-vida associado ao frmaco? Se sim, qual esse valor?

R. Tratando-se de uma cintica de ordem 1, o declive da representao grfica -0,462 e,

deste modo, o tempo de semi-vida pode ser calculado por t1/2=0,693/k (neste tipo de processo,
o tempo de semi-vida independente da concentrao de frmaco

K=-m=0,462 h-1
t1/2=0,693/0,462
t1/2=1,5 h
Farmacocintica: Exerccio

3. Qual a constante de velocidade para a perda do frmaco no plasma?

R. Corresponde ao declive da representao grfica lnC=f(t), isto :

k = - m; K = 0,462 h-1.
Farmacocintica: Exerccio

4. Calcule o volume de distribuio do frmaco (considere a dose de frmaco administrado

de forma IV de 37 mg).

R. A interseo no eixo do Y da representao lnC d 1,528 e, deste modo, pata t=0h, a

concentrao de frmaco (C0) 4,61 mg/mL.

Vd = 37 mg/4,61 mg/mL = 8,0 mL

Nota: esta quantidade do Vd muito menor do que a quantidade de gua total do rato (60% x
0,200 Kg = 120 mL) e, por isso, o frmaco D deve de estar confinado ao compartimento
extracelular (corrente sangunea).
 Dose eficaz mdia (ED50)

Dose capaz de causar a resposta desejada

em 50% dos indivduos
 Dose txica mdia (DT50)

Dose capaz de causar uma determinada resposta

indesejvel em 50% dos indivduos
ndice teraputico

Razo
DT50/DE50