lec 2 drug absorption and distribution

1. ‫ﺑﺳم‬ ‫اﻟﻠﮫ‬ ‫اﻟرﺣﻣن‬ ‫اﻟرﺣﯾم‬
Faculty of Medicine
Pharmacology
Lecture 2
General Pharmacological Principles
PHARMACOKINETICS( Drug absorption and Distribution)

2. •Objectives :
• By the end of this lecture student will be able to:
• Identify the drug cross through biological membrane
• Discuss plasma concentration time curve
• Describe and discuss the drug absorption and distribution
• Disscuss factors Factors Influencing Drug Absorption
• Explain the drugs bioavailability

3. PHARMACOKINETICS
• Pharmacokinetics is derived from two words: Pharmacon
meaning drug and kinesis meaning movement.
• In short, it is ‘what the body does to the drug’. It includes
absorption (A), distribution (D), metabolism(M) and
excretion (E) of a drug.
• All these processes involve movement of the drug
molecule through various biological membranes.

5. • Pharmacokinetics is a time course of drug action.
• Dose –plasma concentration (PKs).
• Plasma Concentration - Action (PDs)
• Plasma concentration-time curve:
• MEC is least concentration produce effects.
 Onset of activity = time from administration to blood level
reaching minimal effective concentration (MEC).
 Duration of action = time plasma concentration remains greater
than MEC.
 Peak level (Cmax) = maximal drug level obtained with the dose.

7. Biological barriers (membranes)
• All biological membranes are made up of lipid bilayer.
• Intestinal space and blood vessels linings contain
pores
• Brain ,testis and placenta capillaries are very tights (no
pores)

8. • Drugs cross various biological membranes by the
following mechanisms:
• 1. Passive diffusion: It is a bidirectional process. The
drug molecules move from a region of higher
concentration to lower concentration until equilibrium is
attained. The rate of diffusion is directly proportional to
the concentration gradient across the membrane. Lipid-
soluble drugs are transported across the membrane by
passive diffusion. It does not require energy.

9. • 2. Filtration: Filtration depends on the molecular size and
weight of the drug. If the drug molecules are smaller than
the pores, they are filtered easily through the membrane.
• Carrier-mediated transport
• includes facilitated diffusion and primary and secondary
active transport.
• The characteristics of carrier-mediated transport are1.
1.Stereospecificity. For example, D-glucose (the natural
isomer) is
transported by facilitated diffusion, but the L-isomer is not.
Simple

10. • 2. Saturation. The transport rate increases as the concentration
of the solute increases, until the carriers are saturated.
• 3. Competition. Structurally related solutes compete for
transport sites on carrier molecules. For example, galactose is a
competitive inhibitor of glucose transport in the small intestine

11. • 3.Specialized transport:
• a. Active transport: The drug molecules move from a region of
lower to higher concentration against the concentration gradient.
• It requires energy, e.g. transport of sympathomimetic amines
into neural tissue, transport of choline into cholinergic neurons
and absorption of levodopa from the intestine.

12. • b.Facilitated diffusion: This is a type of
carrier-mediated transport and does not
require energy.
• The drug attaches to a carrier in the
membrane, which facilitates its diffusion
across the membrane. The transport of
molecules is from the region of higher to
lower concentration.
• An excellent example transport of D-glucose
into skeletal muscle and adipose tissue by the
GLUT4 transporter.

13. • Endocytosis or pinocytosis
• This is applicable to proteins
and other big molecules,
and contributes little to
transport of most drugs.
• Membrane mediated or
receptor mediated.

14. Drug absorption
• The movement of a drug from the site of administration into
the blood stream is known as absorption.
• For IV there is no absorption.
• Factors Influencing Drug Absorption:
1. Physicochemical properties of the drug:
a. Physical state: Liquid form of the drug is better absorbed
than solid formulations.
b. Lipid-soluble and unionized form of the drug is better
absorbed than the water-soluble and ionized form.

15. c. Particle size: Drugs with smaller particle size are
absorbed better than larger ones, e.g. microfine aspirin,
digoxin, griseofulvin, etc. are well absorbed from the gut and
produce better effects. Some of the anthelmintics have larger
particle size. They are poorly absorbed through
gastrointestinal (GI) tract and hence produce better effect on
gut helminths.
d. Disintegration time: It is the time taken for the formulation
(tablet or capsule) to break up into small particles and its variation
may affect the bioavailability.

16. e. Dissolution time: It is the time taken for the particles to go into
solution. Shorter the time, better is the absorption.
f. Formulations: Pharmacologically inert substances like lactose,
starch, calcium sulphate, gum, etc. are added to formulations as
binding agents. These are not totally inert and may affect the
absorption of drugs, e.g. calcium reduces the absorption of
tetracyclines.

18. • 2. Route of drug administration: A drug administered by
intravenous route bypasses the process of absorption, as it
directly enters the circulation. Some drugs are highly polar
compounds, ionize in solution and are not absorbed through GI
tract; hence are given parenterally, e.g. gentamicin.
• Drugs like insulin are administered parenterally because they are
degraded in the GI tract on oral administration.

19. 3. pH and ionization: Strongly
acidic (heparin) and strongly basic
(aminoglycosides) drugs usually
remain ionized at all pH; hence they
are poorly absorbed.
• Drug acidity or basicity
determined by pKa.
• pKa is related to molecule and
it’s a PH when the
concentration of ionized and
non ionized form is equal.

20. • Most drugs are either weak acids or weak
bases. Acidic drugs (HA) release a proton
(H+), causing a charged anion (A−) to form:
HA H+ + A−
• Weak bases (BH+) can also release an H+.
However, the protonated form of basic drugs is
usually charged, and loss of a proton produces
the uncharged base (B):
• BH+ B + H+

21. • The ratio between the two forms is, in turn, determined by the
pH at the site of absorption and by the strength of the weak acid
or base, which is represented by the ionization constant,
pKa.[Note: The pKa is a measure of the strength of the
interaction of a compound with a proton.
• The lower the pKa of a drug, the more acidic it is. Conversely,
thehigher the pKa, the more basic is the drug.]

22. 4. Food: Presence of food in the stomach can affect the
absorption of some of the drugs. Food decreases the
absorption of rifampicin, levodopa, etc.; hence they should be
taken on an empty stomach for better effect. Milk and milk
products decrease the absorption of tetracyclines. Fatty meal
increases the absorption of griseofulvin.
5. Presence of other drugs: Concurrent administration of
two or more drugs may affect their absorption, e.g. ascorbic
acid increases the absorption of oral iron. Antacids reduce
the absorption of tetracyclines.

23. 6. Pharmacogenetic factors: Genetic factors may infl uence
drug absorption. In pernicious anaemia, vitamin B12 is not
absorbed from the gut due to lack of intrinsic factor.
7. Area of the absorbing surface: Normally, drugs are better
absorbed in the small intestine because of a larger surface area,
high blood supply, good permeability.
Resection of the gut decreases absorption of drugs due to a
reduced surface area.
.

24. • 8. Gastrointestinal and other diseases: In
gastroenteritis, there is increased peristaltic movement
that reduces the drug absorption. In achlorhydria,
absorption of iron from the gut is reduced. In congestive
cardiac failure (CCF), there is GI mucosal oedema that
reduces the absorption of drugs

25. • Bioavailability (F)
• Fraction or percentage of unchanged drug reach systemic
circulation following administration by any route.
• For example, if 100 mg of a drug are administered orally
and 70 mg of this drug are absorbed unchanged, the
bioavailability is 70 %
• -for IV route= 100%

26. • Calculation of bioavailability
from plasma conc.-time curve:
• Its calculated from AUC
assuming that the dose and
clearance is constant.
• The absolute bioavailability
calculated from total AUC
following extra vascular
administration divided by AUC
following intravenous
administration.
• The relative bioavailibity between
two route is determine when
there is no IV data .

28. • Not only the fraction of the
administered dose that gets
absorbed, but also the rate of
absorption is important.
• Note that formulation B is more
slowly absorbed than A,and
though ultimately both are
absorbed to the same extent (area
under the curve same), B may not
produce therapeutic effect; C is
absorbed to a lesser extent—lower
bioavailability
• Bioequivalence:
• Bioequivalence occurs when two
formulations of the same
compound have the same
bioavailability and the same rate
of absorption

29. • Causes of low oral bioavailability for some drugs:
1. Insufficient time of absorption:
A. Large MWT (greater than 400g/mol) streptokinase
B. Highly polar molecule (gentamicin)
2. Competing reaction:
 With intestinal enzyme (insulin)
 Acid hydrolysis (penicillin G and erythromycin)
 Complexation reaction (tetracyclin with divalent ion)
 Microflora oxidation (digoxin).
• Note that some drugs administered in different forms to
overcome these reaction (pivampicillin prodrug)

30. 3. First pass metabolism in :
A. Liver e.g. propranolol and verpamil
B. Intestine (microflora,estrase enzymes)e.g. oestrogen and
progesteron
C. Lung e.g. isoprenaline
3. Reverse transport reaction with P-glycoprotein (pump out
drug from gut wall to the lumen like digoxin ), this
transporter inhibited by grapefruit juice and may enhance
drug absorption which may lead to toxicity.
4. Presence of food dilutes the drug and retards absorption.
moreover food delays gastric emptying. Thus, most drugs
are absorbed better if taken in empty stomach.

31. DRUG DISTRIBUTION
• After reaching systemic circulation
the drug rapidly distributed between
erythrocyte ,plasma protein and
body water (blood→ interstitial and
intra cellular fluids {tissues}.

32. • Factors affect distribution:
1. Physicochemical prosperities of drug (e.g. lipid
solubility & MWT)
– The lipid soluble small drug passes through many
barriers and reach extra vascular fluid and distributed
in intracellular fluid of many cells.
2. Size of tissues and local blood flow (conc gradient
effect).
– Large tissues (skeletal muscle) take up more drug while
smaller tissues (brain) take up less drug →rate of
distribution. rate
– Well perfuse tissues(brain,heart,kidney &liver) uptake
the drug sonner than poorly perfused tissues (fat
&bone)→amount distributed. amount
3. Capillary permeability. (brain &non brain)
4. Binding to cell and tissues constituents e.g.
calcium in bones, iodide in thyroid gland and
tetracycline in bone and teeth.

33. 5. Plasma protein binding
• The main plasma proteins are albumin
( the most available one and have high
affinity to bind acidic drug more than
basic drug) and alpha-acid glycoprotein
(have affinity to bind basic drug)
• The bound drug part are:
 Inactive.
 Non diffusible.
 Neither metabolized nor excreted increase
duration.
 Bound and free drug existing in
equilibrium (provide reservoir).

34. • Clinical significance of plasma protein –drug binding:
1. Highly bound drugs have low Vd.
2. Prolong duration of action.
3. Provide a site of D-D interaction (drugs with higher affinity to
plasma protein can displace drug of lower one).
4. In hypoalbuminaemia, binding may be reduced and high
concentrations of free drug may be attained (lead to toxic
concentration)

35. • Drug distribution is rapid and reversible
process at equlibiriaton point the plasma
conc.= amount of drug/Vd.
• Vd = Amount of drug in the body
C0
• Vd is apparent volume of distribution.
• Apparent means that the volume is not
areal anatomical volume but it may reflect a
degree and site of drug distribution.
• Obesity alter fat and water ratio to total
body weight.